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MATTHEW VANDER HEIDEN: OK.

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So welcome back,
everybody, to 705.

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I know this has been a really
challenging semester for all

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of us.

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I want to particularly
acknowledge for the seniors

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out there the tragedy of missing
the end of your senior year.

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Hopefully us, MIT can
somehow make it up to you.

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I can say for my part,
we will do our best

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to teach you
biochemistry remotely.

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And just as a couple
logistics, a reminder,

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I'm Matt Vander Heiden.

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I'm going to be covering
the remaining part of 705.

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For the rest of the
semester, we get

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to focus on biochemistry
of metabolism.

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We're going to learn
what metabolism

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is, why it's important.

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And basically, this can be
quite a polarizing topic.

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In my experience, people
tend to really love

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or really hate metabolism.

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It's interesting, because there
are some people out there who

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pretend to hate it, but actually
deep down really love it.

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Hopefully I will inspire you
over the rest of the semester

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to at least have some
appreciation for why metabolism

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is important.

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And regardless, for those of you
who want to go to med school,

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this is a favorite
topic of MCAT Exams.

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And also you will see
that it will come up

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in many different areas
of biology, regardless

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of whether you go to
med school or not.

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So if you do anything
further in biology,

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hopefully you'll find this
material somewhat useful.

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OK, so getting into
what metabolism is.

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So I think it's good to
start with a textbook

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definition of metabolism.

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And so metabolism is
the chemical reactions

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that all cells and organisms
use to do two things.

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One, extract energy
from the environment.

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And two, synthesize
the macromolecules

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that make up all life.

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So really, what
metabolism is then

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is the chemistry that
makes life possible.

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And so understanding
metabolism is really

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something that will help you
better understand your food.

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There's lots of
material out there

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in the popular press about
what's healthy and what's not.

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At least this will allow you to
form some of your own opinions

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about those claims, and
how they relate to what

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really goes on in
our cells and bodies.

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There's lots of
implications for medicine,

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very relevant to agriculture,
the energy sector,

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biofuels come from.

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And so metabolism
really matters to tackle

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many of the challenges
that face us in society.

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Now as a topic, this
can be very daunting.

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As shown here on this
image, we have hundreds,

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this is a typical
metabolic pathway chart

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that is hanging in the
walls of my office,

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many other laboratories
and academic places

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around the world.

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If you look at this chart,
it's filled with hundreds

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of enzymes, complex pathways.

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Our goal here is not
to memorize this chart.

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You can always look up details
of any pathway or reaction

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that you want.

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The goal here really is to
see beyond this complexity.

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I want you to appreciate
why metabolism

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works the way it does, why this
chart is organized as it is.

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Because what we will find
is that this chart is really

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variations on relatively
few reactions.

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It basically is life
repurposing similar chemistry

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to do many different things.

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I think there is a
beauty in how life

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can use these
reactions to get such

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a diversity of
macromolecules, and enable

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cells to solve all kinds
of different problems.

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You will see that
all of the pathways

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really follow common principles.

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These are shared across all
species and all forms of life.

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And so at the chemical level,
all life is really related.

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And this is why it's so
relevant to understanding

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many of the challenges in
medicine, understanding

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ecology, evolution.

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And for you MIT
students, you'll see

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it's also very critical for
using engineering approaches

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based on biology to solve
various problems in the world.

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OK.

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So now let's start getting
into this a bit more.

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Now, the first topic that
we're going to cover over

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the next several
lectures really relates

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to coming back to sugars
and carbohydrates, which

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I talked about and introduced
in my previous lecture.

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And we're going to do
this because sugars

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and carbohydrates are key
energy transduction molecules

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and cells.

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And it really facilitates a
discussion of the principles

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for how metabolism works.

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Now our goal here isn't
to memorize pathways.

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We could read about the
glycolytic pathway in an hour.

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I could draw it up here in
a very short period of time.

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Many of you have
probably already done

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this in high school.

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Our goal is instead to
understand this pathway

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at a deeper level, really see
why the breakdown of sugars

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works the way it does, how cells
use this to release energy,

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and how that can be used to
support other cell functions.

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And so before we
get to that, I want

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to start by introducing just
a couple high-level concepts

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about metabolism.

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And so really, based on
our definition before,

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metabolism is really
about two things.

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It's about making stuff, and
we have a fancy term for that.

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That is called anabolism.

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And it's about
breaking stuff down.

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And the term for that
is called catabolism.

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And anabolism, building
stuff-- that is,

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producing biomass, growing
all of the material

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that's out there, anabolic
steroids help you grow.

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This is anabolism
to build stuff.

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That is one side of metabolism.

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The other side is breaking
stuff down, catabolism.

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That is, breaking down
our food, eating food.

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Digesting our food is
a way to get energy.

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Now of course, to reproduce,
life has to build more cells.

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You need more stuff.

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You can't create
something from nothing,

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and so that requires
energy input.

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Anabolism typically
requires energy input.

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Whereas that energy has
to come from somewhere.

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And that's where
catabolism comes from.

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We have to break down food.

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And ultimately,
catabolism is the source

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for biological energy for
many different systems.

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Now, some of this is
actually somewhat intuitive.

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We all learned as
little kids that we

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need to eat food if we're
going to grow up and be

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big and strong.

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You also know that if
you're going to run a race,

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you've got to eat
a bunch of food,

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you need that energy
to fuel your activity.

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But maybe what's less
intuitive to many of you

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is we also need energy
to sustain life,

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even if we're doing
absolutely nothing.

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OK, adults, sit on
the couch all day,

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hopefully they're not growing.

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But they'll still starve if they
don't constantly eat some food,

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even if they're inactive.

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And so why is that the case?

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Well, hopefully some of
you recall the second law

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of thermodynamics.

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So what is the second
law of thermodynamics?

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It's, in effect, the entropy
of the universe is increasing.

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That the universe continually
tends towards disorder.

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Life is exactly the
opposite of this.

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Life is actually
maintaining extreme order

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in the face of the second law.

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And so all life must
constantly battle entropy.

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And many have described life
at the very highest level

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as being really the
ability to maintain order,

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to fight entropy, which of
course requires constant energy

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input.

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And metabolism is the process
that all cells use to do this.

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Now for humans, I
think we all know

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we need to eat and breathe
in order to stay alive.

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For you future MDs
out there, what

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happens if your heart stops,
or you stop breathing?

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Well, of course, you die in
a matter of several minutes.

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Why is that?

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Well, that's because
every cell in your body

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has to do constant catabolism
in order to derive energy,

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in order to remain viable.

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This means they need constant
food, and particularly

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oxygen delivery.

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And if you don't
get those things,

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metabolism can no longer
work, and the cells die.

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And so energy is sort
of this mystical concept

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that we like to talk about.

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And so before we delve
a little bit deeper

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into what I mean by
biological energy, what it is,

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why we have to constantly do
catabolism to maintain it,

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I want to go back and say
just a little bit more

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about carbohydrates and finish
our discussion there, and talk

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about carbohydrates and sugar
polymers, polysaccharides,

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because this has some
additional properties

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I didn't have time to cover
in my prior lecture that

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is important to
understand how it

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allows these molecules to store
energy in a very efficient way.

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And it will also enable us to
talk a little bit about how

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carbohydrates can also be
used as structural molecules

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for lots of different organisms.

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All right, so a little diversion
to discuss carbohydrates

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and polysaccharides.

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And so if you recall
from my prior lecture,

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sugars that are greater
than four to five carbons

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can exist either in open
chain or ring forms, furanose

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or pyranose rings.

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I'll just remind you by
redrawing up here, glucose.

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So this is D glucose, drawn
in the open chain form.

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Remember this can form a ring.

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OK.

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So it's a reminder,
carbon 1, 2, 3, 4, 5, 6.

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If we have this hydroxyl
group from carbon 5,

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form a hemiacetal bond with
the aldehyde at carbon 1,

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you get this ring structure.

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This would be alpha
or beta, depending

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on whether the hydroxyl
group here at carbon 1

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is pointing up or pointing down.

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D-glucopyranose.

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So this is review of what we
already talked about last time.

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Now, what I want
to talk about is

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that if we form a disaccharide
or a polysaccharide-- that is,

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begin to make sugar
bonds, and if we

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do that in a way that ties up
this hemiacetal or hemiketal

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bond, this then
prevents the ring

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from opening and gaining
access to that carbonyl,

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that aldehyde carbonyl, as this
moves between the open chain

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and the ring form.

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And so a good example of this
is the disaccharide sucrose.

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00:13:01,310 --> 00:13:07,330
So sucrose is a disaccharide
of glucose plus galactose.

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And here is what this
disaccharide looks like.

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OK, so you have here, glucose
in the alpha-D-pyranose form.

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Here's fructose in the
beta, because the OH group

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is pointing out.

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Fructofuranose form.

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And so the formal name for
this molecule, sucrose,

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would be
alpha-D-glucopyranosyl 1-2,

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because we're going from carbon
1 of glucose to carbon 2,

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there's 1, 2, 3, 4,
5, 6 of fructose.

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Beta-D-fructofuranose.

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Sucrose or
alpha-D-glucopyranosyl

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00:14:44,330 --> 00:14:48,340
1-2 beta-D-fructofuranose.

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00:14:48,340 --> 00:14:51,190
OK, so this disaccharide
forms a bond

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between carbon 1 and carbon 2.

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00:14:52,840 --> 00:14:56,320
That would be the
aldehyde in glucose,

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or the ketone tied
up in the hemiacetal

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00:14:59,530 --> 00:15:04,150
or the hemiketal bond
of these two molecules.

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00:15:04,150 --> 00:15:07,060
And so there's no way that
either of these sugars

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can access the open chain
form, without breaking

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this O-glycosidic bond.

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00:15:12,970 --> 00:15:15,760
And that's one reason why
sucrose is a very good storage

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molecule for carbohydrates,
because without breaking

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that bond, you prevent access
to gaining these reactive

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00:15:22,780 --> 00:15:25,420
aldehyde or ketone
bonds, that could

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react with some other
molecule in the cell.

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Now, I mention this
because whether or not

248
00:15:31,560 --> 00:15:35,250
a particular sugar is
enabled to get access

249
00:15:35,250 --> 00:15:39,540
to this reactive aldehyde
or ketone really forms

250
00:15:39,540 --> 00:15:44,430
the basis for a classic
sugar detection lab test.

251
00:15:44,430 --> 00:15:48,870
And this is relevant to discuss
this lab test because it

252
00:15:48,870 --> 00:15:51,820
explains some nomenclature
that is still used,

253
00:15:51,820 --> 00:15:54,150
and in fact, we
will continue to use

254
00:15:54,150 --> 00:15:58,020
a bit as we discuss some
aspects of sugar metabolism.

255
00:15:58,020 --> 00:16:00,720
So what this test
is, is basically,

256
00:16:00,720 --> 00:16:09,990
is that if you heat the sugar
with copper, which is blue,

257
00:16:09,990 --> 00:16:14,520
and that copper can gain access
to a free carbonyl--that is,

258
00:16:14,520 --> 00:16:18,450
if the sugar can access the
open chain form to expose

259
00:16:18,450 --> 00:16:24,780
the aldehyde or a ketone, that
copper can then become reduced

260
00:16:24,780 --> 00:16:25,950
to copper plus.

261
00:16:25,950 --> 00:16:29,470
That changes the color
from blue to red.

262
00:16:29,470 --> 00:16:34,950
And so if you reduce the copper,
you oxidize the bond there.

263
00:16:34,950 --> 00:16:40,710
And this test turns positive
if there is a reducing sugar,

264
00:16:40,710 --> 00:16:41,660
is what it's called.

265
00:16:44,640 --> 00:16:50,140
So a sugar that reduces the
copper from the blue 2 plus

266
00:16:50,140 --> 00:16:53,780
state to the red plus
state is a positive test.

267
00:16:53,780 --> 00:16:56,440
And so basically,
a reducing sugar

268
00:16:56,440 --> 00:17:16,424
is any sugar with an ability
to access an open chain form.

269
00:17:20,630 --> 00:17:23,900
Because that will
provide the free aldehyde

270
00:17:23,900 --> 00:17:29,570
or ketone to reduce the
copper in this test.

271
00:17:29,570 --> 00:17:33,070
So this term, reducing
sugar, obviously applies

272
00:17:33,070 --> 00:17:35,860
to all monosaccharides, because
every single one of them

273
00:17:35,860 --> 00:17:40,690
has an aldehyde or a ketone, and
can access the open chain form.

274
00:17:40,690 --> 00:17:44,650
But it will only apply
to some disaccharides

275
00:17:44,650 --> 00:17:46,570
or polysaccharides.

276
00:17:46,570 --> 00:17:48,940
So let's come back
to sucrose up there.

277
00:17:48,940 --> 00:17:51,130
So is sucrose a reducing sugar?

278
00:17:51,130 --> 00:17:53,710
No, it's not, because
there is no way

279
00:17:53,710 --> 00:17:56,890
that you can access a
free aldehyde or a ketone

280
00:17:56,890 --> 00:18:00,970
in sucrose, because it's
tied up in that O-glycosidic

281
00:18:00,970 --> 00:18:06,010
bond between carbon 1 of glucose
and carbon 2 of fructose.

282
00:18:06,010 --> 00:18:07,840
And so you need
to break that bond

283
00:18:07,840 --> 00:18:10,060
to give them monosaccharide
subunits in order

284
00:18:10,060 --> 00:18:13,030
to access the open chain form.

285
00:18:13,030 --> 00:18:17,200
However, let's give an
example of a disaccharide

286
00:18:17,200 --> 00:18:18,790
that is a reducing sugar.

287
00:18:18,790 --> 00:18:21,610
And that's the
disaccharide maltose.

288
00:18:21,610 --> 00:18:26,230
So maltose is basically
two glucose molecules.

289
00:18:26,230 --> 00:18:30,750
And those two glucose
molecules are like this.

290
00:18:59,650 --> 00:19:04,560
So this has a O-glycosidic
bond between carbon 1

291
00:19:04,560 --> 00:19:08,850
of this glucose, and
carbon 4 of that glucose.

292
00:19:08,850 --> 00:19:22,740
And so formally, this would
be alpha-D-glucopyranosyl 1-4

293
00:19:22,740 --> 00:19:27,130
alpha or beta.

294
00:19:27,130 --> 00:19:30,480
If it's pointing down, it's
alpha, pointing up, it's beta.

295
00:19:30,480 --> 00:19:31,650
D-glucopyranose.

296
00:19:38,470 --> 00:19:43,240
So maltose or
alpha-D-glucopyranosyl 1-4

297
00:19:43,240 --> 00:19:48,100
alpha or beta D-glucopyranose
is a reducing sugar,

298
00:19:48,100 --> 00:19:51,940
because this sugar could
access the open chain form.

299
00:19:51,940 --> 00:19:56,380
You could open up this carbonyl
and expose the free aldehyde

300
00:19:56,380 --> 00:19:58,360
at position 1.

301
00:19:58,360 --> 00:20:01,060
Now, we could also
refer to this sugar

302
00:20:01,060 --> 00:20:03,860
as having two different ends.

303
00:20:03,860 --> 00:20:13,070
We can refer to this end as
being the non-reducing end,

304
00:20:13,070 --> 00:20:19,850
and this end as being
the reducing end.

305
00:20:19,850 --> 00:20:24,890
Because of course, this
bond, this aldehyde

306
00:20:24,890 --> 00:20:29,660
on the first glucose is tied
up in this O-glycosidic bond,

307
00:20:29,660 --> 00:20:31,290
whereas the one on
this one is not.

308
00:20:31,290 --> 00:20:36,080
So this end is non-reducing,
and this end is reducing.

309
00:20:36,080 --> 00:20:38,480
Now this becomes
much more relevant

310
00:20:38,480 --> 00:20:41,700
if we start talking
about polymers.

311
00:20:41,700 --> 00:20:45,420
And so what starch is.

312
00:20:45,420 --> 00:20:48,950
So starch, what potatoes
are made out of,

313
00:20:48,950 --> 00:20:53,535
is basically a
polymer of maltose.

314
00:21:01,700 --> 00:21:03,720
Polymer of maltose molecules.

315
00:21:03,720 --> 00:21:08,105
So basically our glucose
with 1-4 linkages.

316
00:21:41,408 --> 00:21:46,350
OK, so I could draw that
end, the reducing end

317
00:21:46,350 --> 00:21:54,330
of the polymer, in
the alpha or beta.

318
00:21:54,330 --> 00:21:58,260
But this here, being
the non-reducing end.

319
00:22:01,930 --> 00:22:07,720
Every other subunit is tied up
in this 1-4 O-glycosidic bond.

320
00:22:07,720 --> 00:22:10,000
And so starch is
really a polymer

321
00:22:10,000 --> 00:22:15,220
of glucose molecules
with bonds between the 1

322
00:22:15,220 --> 00:22:19,830
and the 4 position
of each subunit.

323
00:22:19,830 --> 00:22:23,270
Now we will see
later that we build

324
00:22:23,270 --> 00:22:26,810
and break down starch
polymers from only one end,

325
00:22:26,810 --> 00:22:28,520
from the non-reducing end.

326
00:22:28,520 --> 00:22:31,850
And so having these terms,
reducing and non-reducing,

327
00:22:31,850 --> 00:22:37,700
provides the term to specify
different ends of a polymer.

328
00:22:37,700 --> 00:22:40,220
Reducing and non-reducing
ends turns out

329
00:22:40,220 --> 00:22:44,540
to also be important for naming
conventions for disaccharides

330
00:22:44,540 --> 00:22:46,250
or polysaccharides.

331
00:22:46,250 --> 00:22:49,100
And this becomes
relevant if we consider

332
00:22:49,100 --> 00:22:51,530
the disaccharide lactose.

333
00:22:51,530 --> 00:23:01,850
So lactose is also a polymer
of glucose plus galactose,

334
00:23:01,850 --> 00:23:07,710
except this polymer of glucose
plus galactose, unlike sucrose,

335
00:23:07,710 --> 00:23:12,420
is different because it
has a different linkage

336
00:23:12,420 --> 00:23:28,140
between the sucrose is a
disaccharide of glucose

337
00:23:28,140 --> 00:23:29,000
plus fructose.

338
00:23:35,444 --> 00:23:38,430
Fructose, I wrote
the name correctly.

339
00:23:38,430 --> 00:23:43,530
But lactose is a disaccharide
between glucose and galactose.

340
00:23:43,530 --> 00:23:45,420
And so I'll draw it here.

341
00:24:11,400 --> 00:24:14,900
OK, so this is lactose.

342
00:24:14,900 --> 00:24:19,670
This is galactose here
on the non-reducing end.

343
00:24:19,670 --> 00:24:22,820
So the formal name for
this would be beta,

344
00:24:22,820 --> 00:24:24,470
because there's a
beta linkage here

345
00:24:24,470 --> 00:24:32,330
between carbon 1
of this galactose

346
00:24:32,330 --> 00:24:35,000
and carbon 4 of this glucose.

347
00:24:35,000 --> 00:24:49,550
So be
beta-D-galactopyranosyl 1-4.

348
00:24:49,550 --> 00:24:55,050
And this is glucose
in the alpha or beta.

349
00:24:55,050 --> 00:24:56,118
D-glucopyranose.

350
00:25:04,050 --> 00:25:07,620
Lactose, or
beta-D-galactopyranosyl 1-4,

351
00:25:07,620 --> 00:25:11,070
alpha or beta, depending if
I drew down, alpha, up, beta.

352
00:25:11,070 --> 00:25:13,920
D-glucopyranose.

353
00:25:13,920 --> 00:25:25,720
Now, this also has
non-reducing and reducing ends.

354
00:25:25,720 --> 00:25:29,140
And by convention, you
would name the sugar

355
00:25:29,140 --> 00:25:31,930
from the non-reducing
end to the reducing end.

356
00:25:31,930 --> 00:25:38,650
Hence I put galactopyranosyl
1-4 alpha-D-glucopyranose,

357
00:25:38,650 --> 00:25:42,050
named them in that order.

358
00:25:42,050 --> 00:25:49,240
Now you'll note that lactose,
unlike starch, unlike maltose,

359
00:25:49,240 --> 00:25:53,890
unlike sucrose, links
these disaccharides

360
00:25:53,890 --> 00:25:58,510
with a beta linkage between
this sugar and that sugar,

361
00:25:58,510 --> 00:26:01,240
where the other ones
had alpha linkages.

362
00:26:01,240 --> 00:26:04,100
And structurally, this
is very different.

363
00:26:04,100 --> 00:26:06,130
And I just want
to point that out.

364
00:26:06,130 --> 00:26:12,940
So this here is basically
alpha-D-glucopyranose.

365
00:26:12,940 --> 00:26:16,600
And so alpha, this is carbon 1.

366
00:26:16,600 --> 00:26:18,520
This is the hydroxyl
pointing down.

367
00:26:18,520 --> 00:26:20,140
That's why it's alpha.

368
00:26:20,140 --> 00:26:23,270
If I make an O-glycosidic
bond to another sugar,

369
00:26:23,270 --> 00:26:27,680
you can see that it points and
creates this kinked structure.

370
00:26:27,680 --> 00:26:30,190
Now, if I were to
make this beta,

371
00:26:30,190 --> 00:26:32,440
this hydroxyl rather
than being here

372
00:26:32,440 --> 00:26:34,840
would be at this
position on carbon 1.

373
00:26:34,840 --> 00:26:36,340
You can see that
that now creates

374
00:26:36,340 --> 00:26:38,960
a very different geometry.

375
00:26:38,960 --> 00:26:44,390
Now you have a flat molecule,
as opposed to a kinked molecule.

376
00:26:44,390 --> 00:26:47,410
Now, this has
consequences, of course,

377
00:26:47,410 --> 00:26:50,380
for the enzymes that
break down the sugars.

378
00:26:50,380 --> 00:26:53,950
Obviously, it's going to be
a very different enzyme that

379
00:26:53,950 --> 00:26:56,680
breaks a bond in
this orientation,

380
00:26:56,680 --> 00:27:00,670
versus a bond in
that orientation.

381
00:27:00,670 --> 00:27:07,360
This has, basically implications
for what enzymes we have.

382
00:27:07,360 --> 00:27:11,470
And so lactose, of
course, is milk sugar.

383
00:27:11,470 --> 00:27:15,160
All mammals make
milk, so make lactose,

384
00:27:15,160 --> 00:27:17,980
and break it down
when we're babies.

385
00:27:17,980 --> 00:27:21,490
But most mammals tend
to lose expression

386
00:27:21,490 --> 00:27:27,070
of the enzyme lactase that's
able to break this 1-4 beta

387
00:27:27,070 --> 00:27:29,920
linkage as we age.

388
00:27:29,920 --> 00:27:31,870
And this is basically
what accounts

389
00:27:31,870 --> 00:27:34,420
for lactose intolerance.

390
00:27:34,420 --> 00:27:39,220
Now, if you think about it, in
the world, much of the world

391
00:27:39,220 --> 00:27:43,780
has issues with varying
degrees of lactose intolerance

392
00:27:43,780 --> 00:27:45,040
in adulthood.

393
00:27:45,040 --> 00:27:48,190
The exception to this is often
people of European ancestry.

394
00:27:48,190 --> 00:27:49,000
Why is this?

395
00:27:49,000 --> 00:27:53,780
Well, Europeans historically
drank milk well into adulthood.

396
00:27:53,780 --> 00:27:58,150
And so this selected
for continuous lactase,

397
00:27:58,150 --> 00:28:00,730
the enzyme that wouldn't
break that beta 1-4 linkage.

398
00:28:00,730 --> 00:28:04,280
The expression as people
move into adulthood.

399
00:28:04,280 --> 00:28:09,160
And so it's an example of how
cultural things, drinking milk

400
00:28:09,160 --> 00:28:14,320
into adulthood, really
affected evolution,

401
00:28:14,320 --> 00:28:16,960
such that that
subpopulation of people,

402
00:28:16,960 --> 00:28:21,430
people with that genetics to
increase lactase expression,

403
00:28:21,430 --> 00:28:26,260
don't become lactose
intolerant as they age.

404
00:28:26,260 --> 00:28:30,100
Now, this alpha
versus beta linkage--

405
00:28:30,100 --> 00:28:33,640
that is, whether or not you have
this more kinked versus more

406
00:28:33,640 --> 00:28:38,050
flat structure-- also
has a major effect

407
00:28:38,050 --> 00:28:42,890
on the structure of
a polymer as well.

408
00:28:42,890 --> 00:28:46,210
And so if we look here
at this starch polymer,

409
00:28:46,210 --> 00:28:50,260
it's basically this series
of glucose molecules

410
00:28:50,260 --> 00:28:53,660
stuck together with
alpha 1-4 linkages.

411
00:28:53,660 --> 00:28:56,980
So that's going to create
a kinked structure.

412
00:28:56,980 --> 00:28:59,398
This is best shown
here on this slide.

413
00:28:59,398 --> 00:29:00,940
So you can see this
kinked structure.

414
00:29:00,940 --> 00:29:02,740
And so when you
build this polymer,

415
00:29:02,740 --> 00:29:07,390
you're going to end up more with
this helical structure in 3D

416
00:29:07,390 --> 00:29:07,900
space.

417
00:29:07,900 --> 00:29:12,190
That's a very efficient way
to store glucose monomers

418
00:29:12,190 --> 00:29:14,890
in much less space than
you would otherwise

419
00:29:14,890 --> 00:29:18,460
get with beta linkages.

420
00:29:18,460 --> 00:29:23,140
Now, it turns out that nature
takes this a step further.

421
00:29:23,140 --> 00:29:26,350
And in addition to just
having this starch polymer,

422
00:29:26,350 --> 00:29:28,960
it turns out sometimes
you can add branches

423
00:29:28,960 --> 00:29:31,840
to the starch polymer
to further increase

424
00:29:31,840 --> 00:29:34,190
the efficiency of
energy storage.

425
00:29:34,190 --> 00:29:39,840
So if you have here
a starch polymer,

426
00:29:39,840 --> 00:29:42,495
so let me just draw
here a couple subunits.

427
00:30:01,430 --> 00:30:06,770
So this here is a starch
polymer, glucose polymer

428
00:30:06,770 --> 00:30:11,600
with alpha 1-4
linkages that I can

429
00:30:11,600 --> 00:30:18,680
put an additional branch on
this by adding on a linkage

430
00:30:18,680 --> 00:30:19,865
up here on the top.

431
00:30:36,350 --> 00:30:40,740
With an alpha 1-6 linkage.

432
00:30:40,740 --> 00:30:46,560
So the 1 position of here,
to the 6 position of here,

433
00:30:46,560 --> 00:30:54,020
which has the effect of creating
branches on this long polymer,

434
00:30:54,020 --> 00:31:02,250
such that you have a
single reducing end,

435
00:31:02,250 --> 00:31:10,910
and lots of non-reducing ends.

436
00:31:10,910 --> 00:31:14,450
Each of these non-reducing
ends has a polymer

437
00:31:14,450 --> 00:31:17,300
of alpha 1-4 linkages
that would be

438
00:31:17,300 --> 00:31:23,870
stuck to the main chain polymer
via this alpha 1-6 linkage.

439
00:31:23,870 --> 00:31:26,880
And this has a couple
implications for storage.

440
00:31:26,880 --> 00:31:30,610
The first is, by only
having one reducing end,

441
00:31:30,610 --> 00:31:34,760
it reduces maximally the
exposure to a free aldehyde.

442
00:31:34,760 --> 00:31:37,550
And so that makes it
a good storage sugar.

443
00:31:37,550 --> 00:31:39,500
And also as we will
see, we're going

444
00:31:39,500 --> 00:31:44,970
to break down these sugar
polymers biologically

445
00:31:44,970 --> 00:31:48,970
from the non-reducing ends,
and build from those ends.

446
00:31:48,970 --> 00:31:51,390
And so there's lots
of hooks or lots

447
00:31:51,390 --> 00:31:55,230
of places to either add
or remove sugars from,

448
00:31:55,230 --> 00:31:59,310
which allows you to
access carbohydrates

449
00:31:59,310 --> 00:32:01,000
quickly as needed.

450
00:32:01,000 --> 00:32:03,960
That's shown nicely
here on this slide,

451
00:32:03,960 --> 00:32:05,130
better than I can draw it.

452
00:32:05,130 --> 00:32:08,280
So up here, you have
your non-reducing end

453
00:32:08,280 --> 00:32:09,400
across the polymer.

454
00:32:09,400 --> 00:32:13,020
So this here would be starch
with the alpha 1-4 linkages

455
00:32:13,020 --> 00:32:14,970
on the polymer, or
reducing end on one side,

456
00:32:14,970 --> 00:32:17,010
non-reducing end on the other.

457
00:32:17,010 --> 00:32:18,990
You can then add
branch points to that

458
00:32:18,990 --> 00:32:22,440
by making an O-glycosidic
bond between carbon 1

459
00:32:22,440 --> 00:32:25,260
down to carbon 6,
creating a branch.

460
00:32:25,260 --> 00:32:27,750
And so you can see this
helical branch structure

461
00:32:27,750 --> 00:32:28,950
will then form.

462
00:32:28,950 --> 00:32:32,070
That is both very efficient
to pack lots of glucose

463
00:32:32,070 --> 00:32:36,420
into one place, and give
lots of non-reducing ends

464
00:32:36,420 --> 00:32:39,090
with which to build
and remove sugars

465
00:32:39,090 --> 00:32:44,100
from for biology to either
store or quickly access

466
00:32:44,100 --> 00:32:47,390
sugar molecules as needed.

467
00:32:47,390 --> 00:32:52,150
Now, in plants, of
course, potatoes

468
00:32:52,150 --> 00:32:54,700
use starch in a straight chain.

469
00:32:54,700 --> 00:32:55,720
We know that.

470
00:32:55,720 --> 00:33:00,190
However, plants also use
this branched structure.

471
00:33:00,190 --> 00:33:03,010
This is a molecule
called amylopectin.

472
00:33:05,660 --> 00:33:09,860
Amylopectin is better known in
the food industry as Sure-Jell.

473
00:33:09,860 --> 00:33:13,220
It's the material that
allows you to make jelly.

474
00:33:13,220 --> 00:33:15,530
It's the jelling agent in jelly.

475
00:33:15,530 --> 00:33:26,160
And effectively, this
has every 24 to 30 units.

476
00:33:26,160 --> 00:33:29,370
There would be a branch with
one of these alpha 1-6 linkages

477
00:33:29,370 --> 00:33:32,220
to give you this
multi-branched structure.

478
00:33:32,220 --> 00:33:35,430
Now, animals don't make starch.

479
00:33:35,430 --> 00:33:37,650
Animals don't make amylopectin.

480
00:33:37,650 --> 00:33:40,230
But animals make
another molecule

481
00:33:40,230 --> 00:33:45,930
called glycogen. Glycogen,
also a sugar polymer,

482
00:33:45,930 --> 00:33:49,980
exactly like amylopectin.

483
00:33:49,980 --> 00:33:53,250
Alpha 1-4 linkages
with the alpha 1-6

484
00:33:53,250 --> 00:33:55,260
to create branch points.

485
00:33:55,260 --> 00:33:57,810
Just like amylopectin,
except glycogen

486
00:33:57,810 --> 00:34:03,120
has even more branches
with a branch every 8

487
00:34:03,120 --> 00:34:07,590
to 12 glucose units.

488
00:34:07,590 --> 00:34:10,290
And so, this is a
very complex structure

489
00:34:10,290 --> 00:34:14,520
for both plants and animals
to quickly store and quickly

490
00:34:14,520 --> 00:34:19,290
release glucose molecules
when they're needed.

491
00:34:19,290 --> 00:34:24,630
Now, this is in contrast
to a glucose polymer

492
00:34:24,630 --> 00:34:28,850
that can be done that has a
very different 3D structure.

493
00:34:28,850 --> 00:34:31,230
So what if we take
starch, and rather

494
00:34:31,230 --> 00:34:34,770
than have these
alpha 1-4 linkages,

495
00:34:34,770 --> 00:34:40,484
but instead replace these
with beta 1-4 linkages?

496
00:34:43,080 --> 00:34:45,810
OK, so now beta linkages.

497
00:34:45,810 --> 00:34:48,120
Looks simple
enough, but changing

498
00:34:48,120 --> 00:34:51,750
the geometry from the alpha to
the beta bond removes the kink.

499
00:34:51,750 --> 00:34:54,420
Now it's much more
of a flat structure.

500
00:34:54,420 --> 00:34:59,490
Turns out this is,
shown on an image here.

501
00:34:59,490 --> 00:35:01,760
So here's a beta
linkage, and suddenly you

502
00:35:01,760 --> 00:35:03,680
have this flat structure.

503
00:35:03,680 --> 00:35:07,520
This is the same polymer
as starch chemically,

504
00:35:07,520 --> 00:35:11,060
but has a different linkage,
the beta 1-4 linkage.

505
00:35:11,060 --> 00:35:20,030
And that polymer with the
beta 1-4 linkage is cellulose.

506
00:35:20,030 --> 00:35:24,170
And cellulose is, of course,
what wood is made out of.

507
00:35:24,170 --> 00:35:27,920
And so wood and potatoes,
cellulose and starch,

508
00:35:27,920 --> 00:35:29,990
exactly the same polymer.

509
00:35:29,990 --> 00:35:33,860
Same number of calories, if you
could access the glucose units.

510
00:35:33,860 --> 00:35:37,400
But the alpha and beta bonds
make them very different.

511
00:35:37,400 --> 00:35:41,540
Obviously, wood and cellulose is
a very good structural polymer

512
00:35:41,540 --> 00:35:42,260
for plants.

513
00:35:42,260 --> 00:35:44,180
We build houses out of it.

514
00:35:44,180 --> 00:35:45,890
We don't build houses
out of potatoes,

515
00:35:45,890 --> 00:35:47,150
but we eat a lot of potatoes.

516
00:35:47,150 --> 00:35:51,440
So equally good molecule
for plants to store lots

517
00:35:51,440 --> 00:35:53,660
of food for energy.

518
00:35:53,660 --> 00:35:56,600
Turns out wood is a great
source of energy too.

519
00:35:56,600 --> 00:35:58,130
You just need to
have an enzyme that

520
00:35:58,130 --> 00:36:01,250
can break the beta 1-4 bond.

521
00:36:01,250 --> 00:36:04,190
Termites have symbiotic microbes
that allow them to do this,

522
00:36:04,190 --> 00:36:08,330
and this is why termites can eat
wood, a lot of energy tied up

523
00:36:08,330 --> 00:36:10,530
in wood.

524
00:36:10,530 --> 00:36:14,070
Now, we lack the time to go
into the details about how

525
00:36:14,070 --> 00:36:17,460
this relates to other
structural carbohydrates.

526
00:36:17,460 --> 00:36:19,950
But in general,
structural carbohydrate or

527
00:36:19,950 --> 00:36:23,730
carbohydrate-like molecules
form polymers of sugar

528
00:36:23,730 --> 00:36:27,210
or related molecules, also
with these beta linkages.

529
00:36:27,210 --> 00:36:29,820
And a good example is
chitin, so the material

530
00:36:29,820 --> 00:36:32,730
in the insect
shells, is basically

531
00:36:32,730 --> 00:36:34,800
a sugar-like molecule
that's a polymer

532
00:36:34,800 --> 00:36:37,630
with a beta linkage in it.

533
00:36:37,630 --> 00:36:40,530
Same thing with cartilage
in humans and animals.

534
00:36:40,530 --> 00:36:43,110
And you can look up
the details of what

535
00:36:43,110 --> 00:36:46,140
these things look like, of
course, if you're interested.

536
00:36:46,140 --> 00:36:51,150
Chitin and cartilage aren't
made of true polysaccharide

537
00:36:51,150 --> 00:36:54,090
polymers, but they're very
related to polysaccharides.

538
00:36:54,090 --> 00:36:56,580
And they really
illustrate how nature

539
00:36:56,580 --> 00:36:59,940
can take carbohydrate
chemistry and repurpose

540
00:36:59,940 --> 00:37:02,910
it to basically act
as an energy source,

541
00:37:02,910 --> 00:37:06,750
but also build all kinds
of structural molecules

542
00:37:06,750 --> 00:37:11,440
that are really
useful in biology.

543
00:37:11,440 --> 00:37:13,780
All right, now I
want to go back to,

544
00:37:13,780 --> 00:37:16,720
here's ways that one can
store and use carbohydrates

545
00:37:16,720 --> 00:37:18,230
in interesting ways.

546
00:37:18,230 --> 00:37:21,580
But now I want to come back
to them as energy sources,

547
00:37:21,580 --> 00:37:23,950
and assuming you can
access the glucose

548
00:37:23,950 --> 00:37:28,300
and whatever polymer
it's present in, how can

549
00:37:28,300 --> 00:37:31,000
you actually metabolize
it to provide energy

550
00:37:31,000 --> 00:37:33,910
in a way that sustains life?

551
00:37:33,910 --> 00:37:35,500
And this means
we're going to turn

552
00:37:35,500 --> 00:37:39,640
to another topic, a
topic that's typically

553
00:37:39,640 --> 00:37:43,540
referred to as bioenergetics.

554
00:37:50,580 --> 00:37:54,450
Bioenergetics, which is
really the discussion

555
00:37:54,450 --> 00:38:00,120
of how energy is transduced
in biological systems.

556
00:38:00,120 --> 00:38:01,960
I'm going to introduce
this topic today,

557
00:38:01,960 --> 00:38:05,282
we're going to revisit
it throughout the course.

558
00:38:05,282 --> 00:38:07,240
But it's really important
to ask this question.

559
00:38:07,240 --> 00:38:09,990
We really want to
consider, what do we mean

560
00:38:09,990 --> 00:38:12,540
when we say biological energy?

561
00:38:12,540 --> 00:38:15,560
What is biological energy?

562
00:38:15,560 --> 00:38:18,050
Well, someone probably made
you memorize in high school,

563
00:38:18,050 --> 00:38:21,440
and often you were
thinking, oh, it's just ATP.

564
00:38:21,440 --> 00:38:26,030
And certainly, ATP,
adenosine triphosphate,

565
00:38:26,030 --> 00:38:33,000
is a very important molecule for
biological energy transduction.

566
00:38:33,000 --> 00:38:39,380
But I want to actually explore
why ATP is actually useful.

567
00:38:39,380 --> 00:38:45,350
And if ATP is energy, why don't
we just eat all kinds of ATP?

568
00:38:45,350 --> 00:38:48,320
I can say for a fact that
absolutely none of you

569
00:38:48,320 --> 00:38:51,020
had ATP today for breakfast.

570
00:38:51,020 --> 00:38:54,830
No one sells ATP as
an energy booster.

571
00:38:54,830 --> 00:38:57,380
And so if ATP is such
a great energy source,

572
00:38:57,380 --> 00:38:59,420
why don't we just eat it?

573
00:38:59,420 --> 00:39:03,440
And to really understand
ATP, how it works,

574
00:39:03,440 --> 00:39:06,200
what biological
energy really is,

575
00:39:06,200 --> 00:39:09,080
we really need to revisit
some very basic topics

576
00:39:09,080 --> 00:39:11,250
in thermodynamics.

577
00:39:11,250 --> 00:39:15,350
Now, thermodynamics strikes
fear into the hearts of students

578
00:39:15,350 --> 00:39:16,730
everywhere.

579
00:39:16,730 --> 00:39:20,120
You can get details of
thermodynamics and the theory

580
00:39:20,120 --> 00:39:22,280
around these things
in other courses.

581
00:39:22,280 --> 00:39:25,070
That's not really what
we're going to try

582
00:39:25,070 --> 00:39:27,380
to accomplish here in 705.

583
00:39:27,380 --> 00:39:30,500
Our goal here is really
a practical understanding

584
00:39:30,500 --> 00:39:34,730
of how thermodynamics applies
to biology and metabolism.

585
00:39:34,730 --> 00:39:36,500
And we need to go into
this, because it's

586
00:39:36,500 --> 00:39:40,790
key to understanding
why we store energy,

587
00:39:40,790 --> 00:39:42,770
go through all this
trouble to store energy

588
00:39:42,770 --> 00:39:46,370
as these carbohydrate
polymers to begin with.

589
00:39:46,370 --> 00:39:52,040
Why we eat potatoes and
not ATP, as well as why ATP

590
00:39:52,040 --> 00:39:55,970
is actually useful to cells.

591
00:39:55,970 --> 00:39:58,610
And so let's take a step
back and just think about it.

592
00:39:58,610 --> 00:39:59,600
Let's think about wood.

593
00:39:59,600 --> 00:40:04,160
I just told you, wood is a
polymer of glucose molecules

594
00:40:04,160 --> 00:40:07,520
with beta 1-4 linkages.

595
00:40:07,520 --> 00:40:12,950
How can we, forget as
organisms, as cells.

596
00:40:12,950 --> 00:40:16,280
But how can you release
energy from wood,

597
00:40:16,280 --> 00:40:17,870
to do other kinds of work?

598
00:40:17,870 --> 00:40:19,560
Well, we can burn it.

599
00:40:19,560 --> 00:40:22,190
And so what's the
chemistry of burning wood?

600
00:40:22,190 --> 00:40:25,100
Well, it's a
carbohydrate polymer.

601
00:40:25,100 --> 00:40:32,120
So it has this CnH2n formula.

602
00:40:32,120 --> 00:40:36,260
If we combine that
carbohydrate with oxygen,

603
00:40:36,260 --> 00:40:45,340
it releases CO2 and water,
plus some light, plus heat.

604
00:40:45,340 --> 00:40:52,280
This light and heat
is energy, because we

605
00:40:52,280 --> 00:40:54,890
can use it to do work.

606
00:40:54,890 --> 00:40:58,050
Boil water, turn a
turbine, make electricity.

607
00:40:58,050 --> 00:40:58,550
Whatever.

608
00:41:01,480 --> 00:41:04,660
Warm ourselves by the fire.

609
00:41:04,660 --> 00:41:07,900
Use the light to do
some other things.

610
00:41:07,900 --> 00:41:13,150
And so this burning of wood is
certainly release of energy.

611
00:41:13,150 --> 00:41:16,930
Now, we lack the enzymes to
do this reaction in wood,

612
00:41:16,930 --> 00:41:20,410
because we can't break
that beta 1-4 linkage.

613
00:41:20,410 --> 00:41:25,390
But we certainly can break that
alpha 1-4 linkage in starch

614
00:41:25,390 --> 00:41:26,800
from potatoes.

615
00:41:26,800 --> 00:41:29,860
And we use the
exact same chemistry

616
00:41:29,860 --> 00:41:34,090
to burn that glucose
and release energy.

617
00:41:34,090 --> 00:41:37,030
Except the difference
is that if I burn wood,

618
00:41:37,030 --> 00:41:39,580
I do this all in one step.

619
00:41:39,580 --> 00:41:42,100
But life is a much better
engineer than that.

620
00:41:42,100 --> 00:41:44,560
It basically, rather
than releasing

621
00:41:44,560 --> 00:41:47,500
all of that energy in
one step, it really

622
00:41:47,500 --> 00:41:50,950
releases it stepwise
in a manner that's

623
00:41:50,950 --> 00:41:53,620
actually useful to cells.

624
00:41:53,620 --> 00:41:56,720
But it's exactly the
same release of energy.

625
00:41:56,720 --> 00:42:00,880
And so what life
is, or extracting

626
00:42:00,880 --> 00:42:04,030
biological energy
is, is it's really

627
00:42:04,030 --> 00:42:16,000
the ability to do stepwise
oxidation of glucose

628
00:42:16,000 --> 00:42:16,870
or other carbon.

629
00:42:16,870 --> 00:42:18,430
I'll write glucose for now.

630
00:42:21,520 --> 00:42:27,710
To get energy.

631
00:42:27,710 --> 00:42:32,610
So we burn wood, that's
favorable, it releases energy.

632
00:42:32,610 --> 00:42:36,120
If we do stepwise
oxidation, we also

633
00:42:36,120 --> 00:42:38,050
can release energy as well.

634
00:42:38,050 --> 00:42:41,470
Same reaction, also
releases energy.

635
00:42:41,470 --> 00:42:44,430
How much energy do
we get from releasing

636
00:42:44,430 --> 00:42:48,930
us burning glucose, as you
do and burning it in a fire?

637
00:42:48,930 --> 00:42:51,630
Well, it has to be exactly
the same amount, because it's

638
00:42:51,630 --> 00:42:54,100
exactly the same reaction.

639
00:42:54,100 --> 00:42:56,790
So we burn wood, we
get light and heat.

640
00:42:56,790 --> 00:43:00,150
Cells burn glucose, it
releases the exact same amount

641
00:43:00,150 --> 00:43:01,050
of energy.

642
00:43:01,050 --> 00:43:04,110
It just does so in a way
that allows the cells to do

643
00:43:04,110 --> 00:43:06,520
biologically useful things.

644
00:43:06,520 --> 00:43:07,210
What are those?

645
00:43:07,210 --> 00:43:08,250
Well, it could be heat.

646
00:43:08,250 --> 00:43:09,780
All of us maintain temperature.

647
00:43:09,780 --> 00:43:12,270
So heat is a
conversion of energy

648
00:43:12,270 --> 00:43:15,467
that of course, is
useful to biology.

649
00:43:15,467 --> 00:43:16,800
But it can do other things, too.

650
00:43:16,800 --> 00:43:18,150
It can allow cells to move.

651
00:43:18,150 --> 00:43:20,940
It can allow them
to do any reaction

652
00:43:20,940 --> 00:43:25,300
to fight that entropy
that allows life to exist.

653
00:43:25,300 --> 00:43:31,150
And so all things,
including ourselves,

654
00:43:31,150 --> 00:43:34,930
have to follow the same
laws of thermodynamics.

655
00:43:34,930 --> 00:43:37,820
Life is not special
in that regard.

656
00:43:37,820 --> 00:43:40,240
And so burning
wood is favorable,

657
00:43:40,240 --> 00:43:43,060
because it increases the
entropy of the universe.

658
00:43:43,060 --> 00:43:46,000
You're breaking up this polymer
into a bunch of monomers.

659
00:43:46,000 --> 00:43:47,920
That's going to be spontaneous.

660
00:43:47,920 --> 00:43:53,850
That is in accordance with the
second law of thermodynamics.

661
00:43:53,850 --> 00:43:57,120
True if cells burn it as well.

662
00:43:57,120 --> 00:43:59,180
But remember, the
second law says

663
00:43:59,180 --> 00:44:03,557
that net entropy of the
universe must always increase.

664
00:44:03,557 --> 00:44:05,390
And so if we're going
to do something that's

665
00:44:05,390 --> 00:44:09,350
not energetically favorable,
like build a glucose polymer,

666
00:44:09,350 --> 00:44:12,790
we obviously have to
put energy into it.

667
00:44:12,790 --> 00:44:15,520
And to do so, the
energy that's released

668
00:44:15,520 --> 00:44:20,980
must be greater than the
energy that we actually store.

669
00:44:20,980 --> 00:44:24,850
And so this is actually a really
key point, because anything

670
00:44:24,850 --> 00:44:29,620
that we do that requires
energy input for a cell

671
00:44:29,620 --> 00:44:33,520
to carry out that process
requires a source of energy

672
00:44:33,520 --> 00:44:37,690
release somewhere else that is
equivalent or greater than what

673
00:44:37,690 --> 00:44:40,040
is actually put in.

674
00:44:40,040 --> 00:44:43,730
And so cells need
energy, because they

675
00:44:43,730 --> 00:44:47,210
do lots of thermodynamically
unfavorable things,

676
00:44:47,210 --> 00:44:50,450
fighting that entropy
of the universe.

677
00:44:50,450 --> 00:44:54,110
And all of those processes must
come from the release of energy

678
00:44:54,110 --> 00:44:59,260
elsewhere, like the
burning of carbohydrate.

679
00:44:59,260 --> 00:45:02,280
And so that constant
energy input

680
00:45:02,280 --> 00:45:04,920
is at the very
highest level, why

681
00:45:04,920 --> 00:45:09,660
we need to do constant
metabolism in order to maintain

682
00:45:09,660 --> 00:45:12,580
order and survive as organisms.

683
00:45:12,580 --> 00:45:15,030
Now this, of course,
comes from things

684
00:45:15,030 --> 00:45:19,410
like burning of carbohydrate.

685
00:45:19,410 --> 00:45:22,660
But of course, that carbohydrate
has to come from somewhere.

686
00:45:22,660 --> 00:45:26,280
And so ultimately, you have
to have an external source.

687
00:45:26,280 --> 00:45:28,440
That external source
is of course, the sun.

688
00:45:28,440 --> 00:45:31,890
Photosynthetic organisms can
use light energy from the sun

689
00:45:31,890 --> 00:45:34,080
to do exactly the same things.

690
00:45:34,080 --> 00:45:35,820
Build those excess
polymers, and that's

691
00:45:35,820 --> 00:45:39,090
why we as animals
or anything that

692
00:45:39,090 --> 00:45:41,760
eats other animals
as a way to live

693
00:45:41,760 --> 00:45:43,590
is ultimately
depending on eating

694
00:45:43,590 --> 00:45:45,270
photosynthetic
organisms, because

695
00:45:45,270 --> 00:45:49,410
photosynthetic organisms
do this by harvesting

696
00:45:49,410 --> 00:45:52,880
energy of the sun.

697
00:45:52,880 --> 00:45:54,790
Now that's all very high level.

698
00:45:54,790 --> 00:45:58,300
But I want to come back to
the specifics of metabolism,

699
00:45:58,300 --> 00:46:02,780
ultimately, and understand those
as how they relate to enzymes'

700
00:46:02,780 --> 00:46:04,210
reactions and pathways.

701
00:46:04,210 --> 00:46:07,600
That is, how do you get that
complex series of reactions

702
00:46:07,600 --> 00:46:10,840
that make life
possible, and ultimately

703
00:46:10,840 --> 00:46:15,280
still be guided by these
exact same principles?

704
00:46:15,280 --> 00:46:20,740
In other words, how do we couple
the energy releasing reactions,

705
00:46:20,740 --> 00:46:23,740
like burning glucose,
in a way that

706
00:46:23,740 --> 00:46:27,340
obeys the laws of thermodynamics
and operates under biologically

707
00:46:27,340 --> 00:46:31,690
acceptable conditions in
order to do things that

708
00:46:31,690 --> 00:46:33,470
are biologically unfavorable.

709
00:46:33,470 --> 00:46:36,340
That's really what
bioenergetics is.

710
00:46:36,340 --> 00:46:39,430
And so the next thing we
want to consider then,

711
00:46:39,430 --> 00:46:41,890
if we want to understand
this, is really,

712
00:46:41,890 --> 00:46:44,060
let's ask the question.

713
00:46:44,060 --> 00:47:03,440
What determines if a
specific reaction occurs?

714
00:47:03,440 --> 00:47:07,190
That is, what determines if
something like burning wood

715
00:47:07,190 --> 00:47:09,760
actually spontaneously happens?

716
00:47:09,760 --> 00:47:11,930
If you light wood on
fire, it will burn.

717
00:47:11,930 --> 00:47:13,670
It does so every
single time, everyone

718
00:47:13,670 --> 00:47:15,140
has had that experience.

719
00:47:15,140 --> 00:47:18,440
But no one has ever seen
CO2 and water spontaneously

720
00:47:18,440 --> 00:47:20,300
come together and form a tree.

721
00:47:20,300 --> 00:47:21,930
That doesn't happen.

722
00:47:21,930 --> 00:47:24,740
So what determines
whether you burn wood

723
00:47:24,740 --> 00:47:27,950
and that is
favorable, versus why

724
00:47:27,950 --> 00:47:32,300
it is that CO2 and water don't
come together and spontaneously

725
00:47:32,300 --> 00:47:33,710
form a tree?

726
00:47:36,420 --> 00:47:40,960
Do not think that this is
determined entirely by enzymes.

727
00:47:40,960 --> 00:47:42,180
Enzymes are catalysts.

728
00:47:42,180 --> 00:47:47,050
Enzymes are the spark that makes
the burning of wood possible.

729
00:47:47,050 --> 00:47:50,820
But remember, enzymes cannot
change thermodynamics.

730
00:47:50,820 --> 00:47:54,900
Enzymes only change the rate
at which a reaction happens.

731
00:47:54,900 --> 00:47:57,180
It does not change
the equilibrium.

732
00:47:57,180 --> 00:48:03,480
That tree wants to, if given the
catalyst, form CO2 and water.

733
00:48:03,480 --> 00:48:05,850
That reaction is
spontaneous because it

734
00:48:05,850 --> 00:48:08,580
is thermodynamically favorable.

735
00:48:08,580 --> 00:48:11,280
That tree will not
take CO2 and water

736
00:48:11,280 --> 00:48:13,470
and spontaneously reform a tree.

737
00:48:13,470 --> 00:48:15,300
And there's no amount
of enzyme that will

738
00:48:15,300 --> 00:48:18,790
make that happen all by itself.

739
00:48:18,790 --> 00:48:20,070
And so remember that.

740
00:48:20,070 --> 00:48:25,650
If you have any reaction
between A and B,

741
00:48:25,650 --> 00:48:28,920
there is some
equilibrium, as defined

742
00:48:28,920 --> 00:48:31,500
by the chemical
properties of A and B,

743
00:48:31,500 --> 00:48:36,520
such that the equilibrium lies
far to one side or the other.

744
00:48:36,520 --> 00:48:39,450
And that equilibrium is
determined by thermodynamics.

745
00:48:39,450 --> 00:48:42,930
It is not determined by enzymes.

746
00:48:42,930 --> 00:48:46,110
I don't care how
much enzyme I add.

747
00:48:46,110 --> 00:48:50,010
If the equilibrium lies
towards A as I draw it,

748
00:48:50,010 --> 00:48:55,650
I can add all the enzyme I want,
and I can never create more B.

749
00:48:55,650 --> 00:48:59,610
And so, this is super
important, and is actually

750
00:48:59,610 --> 00:49:03,640
a point that is gotten
wrong by lots of biologists.

751
00:49:03,640 --> 00:49:05,580
They think, oh, this
enzyme is expressed.

752
00:49:05,580 --> 00:49:07,710
Therefore, this pathway
must be happening,

753
00:49:07,710 --> 00:49:11,000
or this reaction must
be happening faster.

754
00:49:11,000 --> 00:49:14,220
You need an enzyme to
catalyze a reaction.

755
00:49:14,220 --> 00:49:16,820
So a reaction may
not occur, your wood

756
00:49:16,820 --> 00:49:19,580
may not burn unless you
give it a spark, a catalyst

757
00:49:19,580 --> 00:49:21,470
to actually make it happen.

758
00:49:21,470 --> 00:49:26,030
But you cannot add a catalyst
to fight thermodynamics.

759
00:49:26,030 --> 00:49:28,550
You cannot take that CO2
and water and turn it back

760
00:49:28,550 --> 00:49:29,600
into a tree.

761
00:49:29,600 --> 00:49:30,740
And the same thing is true.

762
00:49:30,740 --> 00:49:33,380
You can add all the enzyme
in the world you want,

763
00:49:33,380 --> 00:49:38,390
and all it will do is help A
and B establish the equilibrium

764
00:49:38,390 --> 00:49:41,540
that is defined by
the thermodynamics

765
00:49:41,540 --> 00:49:44,780
of the relationship
between A and B.

766
00:49:44,780 --> 00:49:47,450
Now, what determines
the equilibrium

767
00:49:47,450 --> 00:49:49,640
between any two species?

768
00:49:49,640 --> 00:49:53,000
That's a topic for another
class, why a species is favored

769
00:49:53,000 --> 00:49:55,110
to be one side or another.

770
00:49:55,110 --> 00:49:59,090
However, a useful tool to think
about this in biochemistry

771
00:49:59,090 --> 00:50:02,030
and quantify this for
any pair of reactions

772
00:50:02,030 --> 00:50:04,427
is something you've probably
learned about before.

773
00:50:04,427 --> 00:50:06,260
It's something called
the Gibbs free energy.

774
00:50:13,120 --> 00:50:18,150
Gibbs free energy, or delta G.

775
00:50:18,150 --> 00:50:22,470
Delta G is related
to the way we'll talk

776
00:50:22,470 --> 00:50:29,590
about the equilibrium constant.

777
00:50:29,590 --> 00:50:31,480
And it's basically
a term that we

778
00:50:31,480 --> 00:50:37,520
can use to specify if a
reaction is favorable or not.

779
00:50:37,520 --> 00:50:41,650
And so hopefully you learned
in an introductory class

780
00:50:41,650 --> 00:50:53,760
that if delta G is less than
0, our reaction is spontaneous.

781
00:50:53,760 --> 00:51:00,940
If delta G equals 0, our
reaction is that equilibrium.

782
00:51:05,000 --> 00:51:17,510
If delta G is greater
than 0, our reaction

783
00:51:17,510 --> 00:51:24,060
is not spontaneous.

784
00:51:24,060 --> 00:51:28,250
All right, if we
take our log and ask,

785
00:51:28,250 --> 00:51:32,960
what is delta G to turn that
log into CO2 plus water,

786
00:51:32,960 --> 00:51:36,620
it is less than 0, because
it is very spontaneous.

787
00:51:36,620 --> 00:51:38,420
We take a pile of
ashes and ask what

788
00:51:38,420 --> 00:51:41,030
delta G is to recreate the log.

789
00:51:41,030 --> 00:51:44,760
It's greater than 0, because
it ain't going to happen.

790
00:51:44,760 --> 00:51:50,950
And if it's at some equilibrium,
delta G is equal to 0.

791
00:51:50,950 --> 00:51:57,580
Now, delta G depends
entirely on conditions,

792
00:51:57,580 --> 00:51:59,330
as we will see in a minute.

793
00:51:59,330 --> 00:52:06,490
And because of that,
this means that there

794
00:52:06,490 --> 00:52:16,510
can be conditions where
absolutely any reaction can

795
00:52:16,510 --> 00:52:19,570
be favorable if the
conditions are right.

796
00:52:19,570 --> 00:52:23,620
And we'll see that this becomes
very relevant to understand

797
00:52:23,620 --> 00:52:25,610
how metabolism works.

798
00:52:25,610 --> 00:52:28,990
And so let's go back
and just now consider

799
00:52:28,990 --> 00:52:32,910
some generic reaction, A and B.

800
00:52:32,910 --> 00:52:36,400
So at equilibrium, what happens?

801
00:52:36,400 --> 00:52:46,820
So at equilibrium,
the concentration of A

802
00:52:46,820 --> 00:52:51,800
and the concentration
of B are not changing.

803
00:52:51,800 --> 00:52:54,530
Delta G equals 0.

804
00:52:54,530 --> 00:52:56,250
These two things
are at equilibrium,

805
00:52:56,250 --> 00:52:58,600
whatever that equilibrium is.

806
00:52:58,600 --> 00:53:02,660
A and B are not changing
in concentration.

807
00:53:02,660 --> 00:53:08,100
Now if I come and I add more A
to this side of the equation,

808
00:53:08,100 --> 00:53:08,970
what does that mean?

809
00:53:08,970 --> 00:53:11,210
Well, you know from Le
Chatelier's principle

810
00:53:11,210 --> 00:53:13,460
that that's going
to favor production

811
00:53:13,460 --> 00:53:17,430
of B. We have shifted things
now out of equilibrium.

812
00:53:17,430 --> 00:53:29,410
So if I add A, that
leads the production of B

813
00:53:29,410 --> 00:53:32,410
to re-establish
this equilibrium.

814
00:53:32,410 --> 00:53:39,040
That means that delta G
from A to B is less than 0

815
00:53:39,040 --> 00:53:41,380
until I've reestablished
equilibrium,

816
00:53:41,380 --> 00:53:44,830
and now delta G is
back to 0 again.

817
00:53:44,830 --> 00:53:46,555
Now, what happens if I add B?

818
00:53:46,555 --> 00:53:51,010
Well, if I add B, now I'm
going to produce some A. So

819
00:53:51,010 --> 00:54:02,160
add B. That leads
the production of A,

820
00:54:02,160 --> 00:54:05,640
until I reestablish
that equilibrium.

821
00:54:05,640 --> 00:54:09,780
So delta G, in that
case, to go from B

822
00:54:09,780 --> 00:54:14,880
back to A. The reverse
reaction is less than 0.

823
00:54:14,880 --> 00:54:18,512
Or I could also say that
delta G, to go to A to B

824
00:54:18,512 --> 00:54:20,220
here, because that's
not going to happen.

825
00:54:20,220 --> 00:54:21,637
I just added more
B. I'm not going

826
00:54:21,637 --> 00:54:24,750
to suddenly create
more B from A.

827
00:54:24,750 --> 00:54:30,120
So here now, delta
G is greater than 0.

828
00:54:30,120 --> 00:54:33,180
Now note when I did
this, I don't actually

829
00:54:33,180 --> 00:54:37,860
have to specify how much A
or how much B I've added.

830
00:54:37,860 --> 00:54:46,290
The equilibrium depends
on the ratio of B to A.

831
00:54:46,290 --> 00:54:50,620
Not the absolute concentration
of either species.

832
00:54:50,620 --> 00:54:53,910
And so having a way to think
about this equilibrium,

833
00:54:53,910 --> 00:54:57,960
it turns out, is also useful
for biological systems

834
00:54:57,960 --> 00:55:04,110
to divine some delta G
that is helpful to relate

835
00:55:04,110 --> 00:55:07,110
to this equilibrium constant.

836
00:55:07,110 --> 00:55:12,015
And that is this concept
of delta G 0 prime.

837
00:55:16,030 --> 00:55:20,560
A standard free energy,
which for biological systems,

838
00:55:20,560 --> 00:55:23,200
relates to the equilibrium
constant at 25 degrees,

839
00:55:23,200 --> 00:55:25,750
or the pH of 7 and 1 atmosphere.

840
00:55:25,750 --> 00:55:28,720
Pretty typical
biological conditions.

841
00:55:28,720 --> 00:55:30,700
And this here is
basically related

842
00:55:30,700 --> 00:55:32,590
to the equilibrium constant.

843
00:55:32,590 --> 00:55:35,830
And we can calculate
the actual delta G

844
00:55:35,830 --> 00:55:37,600
by the following formula.

845
00:55:37,600 --> 00:55:42,970
Delta G equals delta
G 0 prime plus RT

846
00:55:42,970 --> 00:55:49,500
times the log of the
products over the reactant.

847
00:55:49,500 --> 00:55:54,720
So this would be drawn
for the reaction A to B.

848
00:55:54,720 --> 00:55:58,020
So the reaction
A to B is related

849
00:55:58,020 --> 00:56:01,450
to delta G 0 prime, which is
related to the equilibrium

850
00:56:01,450 --> 00:56:01,950
constant.

851
00:56:01,950 --> 00:56:04,260
I'll tell you how in the second.

852
00:56:04,260 --> 00:56:09,150
Plus R is the gas constant, T
is the temperature in Kelvin

853
00:56:09,150 --> 00:56:12,900
times the natural log of
the ratio of products,

854
00:56:12,900 --> 00:56:20,600
B over reactants, A. This
tells you whether or not

855
00:56:20,600 --> 00:56:24,260
at specific
concentrations of B and A,

856
00:56:24,260 --> 00:56:26,990
that is a specific
ratio of B and A,

857
00:56:26,990 --> 00:56:30,890
whether it is favorable
to go from A to B, delta G

858
00:56:30,890 --> 00:56:34,550
less than 0, or whether it is
favorable to go from B to A,

859
00:56:34,550 --> 00:56:37,310
delta G greater than 0.

860
00:56:37,310 --> 00:56:41,630
And so this should begin to make
it clear that whether or not

861
00:56:41,630 --> 00:56:45,350
a specific reaction
occurs is affected

862
00:56:45,350 --> 00:56:47,600
by the actual
conditions present.

863
00:56:47,600 --> 00:56:52,590
And you can calculate that
based on this relationship.

864
00:56:52,590 --> 00:56:55,850
And so if I specify
concentrations of A and B,

865
00:56:55,850 --> 00:56:58,820
as well as delta
G 0 prime, I can

866
00:56:58,820 --> 00:57:03,950
know, at those concentrations,
which direction of the reaction

867
00:57:03,950 --> 00:57:05,880
is favored.

868
00:57:05,880 --> 00:57:10,850
Now of course, my drawing A
to B is entirely arbitrary.

869
00:57:10,850 --> 00:57:14,090
I could equally draw
it B to A. And if I

870
00:57:14,090 --> 00:57:21,320
did that, so this is delta
G 0 prime, A to B, all I do

871
00:57:21,320 --> 00:57:22,460
is flip the signs.

872
00:57:22,460 --> 00:57:26,480
So delta G equals
delta G 0 prime.

873
00:57:26,480 --> 00:57:33,440
The negative of A to B is equal
to the positive of delta G 0

874
00:57:33,440 --> 00:57:38,570
prime from B to A, because
the direction is arbitrary.

875
00:57:38,570 --> 00:57:42,230
Plus RT log in this case.

876
00:57:42,230 --> 00:57:46,940
Now I have A is my product,
and B is my reactant.

877
00:57:46,940 --> 00:57:51,350
If I just flip the
sign, flip that ratio,

878
00:57:51,350 --> 00:57:55,220
it's just going to change
the sign of my product

879
00:57:55,220 --> 00:57:58,610
and give me exactly the same
result with the opposite sign,

880
00:57:58,610 --> 00:58:00,530
which makes sense.

881
00:58:00,530 --> 00:58:02,480
What's favorable
in one direction

882
00:58:02,480 --> 00:58:06,620
is not favorable in the other
direction, and vice versa.

883
00:58:06,620 --> 00:58:11,050
Now, I can also set
delta G equals 0.

884
00:58:11,050 --> 00:58:12,800
That's equilibrium.

885
00:58:12,800 --> 00:58:20,710
If I do that, then delta G
0 prime equals negative RT.

886
00:58:20,710 --> 00:58:26,120
So this would be for A to
B. I'll use the top example.

887
00:58:26,120 --> 00:58:28,630
So delta G equals 0.

888
00:58:28,630 --> 00:58:37,000
Then I have delta G 0 prime
equals RT times log B over A.

889
00:58:37,000 --> 00:58:39,460
So if I know two things
are at equilibrium,

890
00:58:39,460 --> 00:58:44,890
I can calculate delta G 0 prime,
and know what the equilibrium

891
00:58:44,890 --> 00:58:46,270
constant is.

892
00:58:46,270 --> 00:58:50,470
And so it follows from this
then that if delta G 0 prime

893
00:58:50,470 --> 00:58:59,670
is negative, that means B is
favored over A at equilibrium.

894
00:59:04,610 --> 00:59:07,670
And if delta G 0
prime is positive,

895
00:59:07,670 --> 00:59:12,040
that means A is favored
over B at equilibrium.

896
00:59:16,910 --> 00:59:21,770
And so delta G 0 prime
really is a convenient way

897
00:59:21,770 --> 00:59:26,720
to look at a reaction, and know
which direction the equilibrium

898
00:59:26,720 --> 00:59:27,860
lies.

899
00:59:27,860 --> 00:59:30,680
So A and B, delta G
0 prime is negative,

900
00:59:30,680 --> 00:59:35,270
equilibrium lies to B. Between
A and B, if delta G 0 prime

901
00:59:35,270 --> 00:59:39,830
is positive, the
equilibrium lies towards A.

902
00:59:39,830 --> 00:59:43,760
But the key concept is that
for any specific reaction,

903
00:59:43,760 --> 00:59:48,620
any specific conditions of
A and B, whether or not A

904
00:59:48,620 --> 00:59:53,180
is converted to B will be
defined by the equilibrium

905
00:59:53,180 --> 00:59:54,230
constant.

906
00:59:54,230 --> 00:59:58,280
But it will also be
defined about what delta

907
00:59:58,280 --> 01:00:01,150
is under those conditions.

908
01:00:17,630 --> 01:00:32,250
So to be clear, delta G
will depend on conditions,

909
01:00:32,250 --> 01:00:35,340
because I'll write
it again, delta G

910
01:00:35,340 --> 01:00:46,040
equals delta G 0 prime plus RT
times the log for the reaction,

911
01:00:46,040 --> 01:00:49,310
A goes to B. So
products over reactants.

912
01:00:49,310 --> 01:00:54,380
And so whether or not
A is converted to B

913
01:00:54,380 --> 01:00:57,920
will be a property of
the equilibrium constant,

914
01:00:57,920 --> 01:01:01,850
plus the concentration of B
and the concentration of A,

915
01:01:01,850 --> 01:01:06,200
that ratio of concentrations
at the conditions present.

916
01:01:06,200 --> 01:01:11,600
And if in that calculation,
delta G is less than 0,

917
01:01:11,600 --> 01:01:16,410
that reaction is spontaneous.

918
01:01:16,410 --> 01:01:20,730
If delta G is greater
than 0, that reaction

919
01:01:20,730 --> 01:01:25,380
is not spontaneous.

920
01:01:25,380 --> 01:01:29,970
Or to put it another way,
if delta G is less than 0

921
01:01:29,970 --> 01:01:36,930
under those conditions,
energy is released.

922
01:01:36,930 --> 01:01:41,490
Or if delta G is greater
than 0, that reaction

923
01:01:41,490 --> 01:01:54,440
will not occur
without energy input.

924
01:02:00,650 --> 01:02:02,690
If I burn wood,
energy is released.

925
01:02:02,690 --> 01:02:04,640
But there's no way
I can reassemble

926
01:02:04,640 --> 01:02:10,540
that log without some
kind of energy input.

927
01:02:10,540 --> 01:02:13,750
And really getting
this concept is

928
01:02:13,750 --> 01:02:17,320
central to understanding
metabolism, as well as

929
01:02:17,320 --> 01:02:20,560
what biological energy means.

930
01:02:20,560 --> 01:02:24,690
And hopefully, what
is now apparent,

931
01:02:24,690 --> 01:02:32,990
based on what I just said, is
that what really determines

932
01:02:32,990 --> 01:02:35,390
delta G is two things.

933
01:02:35,390 --> 01:02:38,370
Of course it's the
equilibrium constant.

934
01:02:38,370 --> 01:02:42,290
But in essence, delta
G for any reaction

935
01:02:42,290 --> 01:02:49,880
is proportional to the
ratio of the reactants

936
01:02:49,880 --> 01:02:51,720
over the products.

937
01:02:51,720 --> 01:02:54,800
And that I can come
up, at least in theory,

938
01:02:54,800 --> 01:03:01,250
with any relationship, any
ratio of reactants to products

939
01:03:01,250 --> 01:03:03,490
to make this favorable.

940
01:03:03,490 --> 01:03:06,910
At some tiny, tiny
concentration,

941
01:03:06,910 --> 01:03:09,640
if I have nothing
but CO2 and water,

942
01:03:09,640 --> 01:03:13,480
and infinite time and infinite
catalysis, a tiny bit of wood

943
01:03:13,480 --> 01:03:15,910
could spontaneously form.

944
01:03:15,910 --> 01:03:19,060
And so life really
creates the conditions

945
01:03:19,060 --> 01:03:23,230
that allow that, and select for
that to happen, and of course,

946
01:03:23,230 --> 01:03:26,230
add energy input so it
can actually happen more.

947
01:03:26,230 --> 01:03:28,450
And so this should
be very clear to you

948
01:03:28,450 --> 01:03:32,440
that absolutely no
reaction is irreversible.

949
01:03:32,440 --> 01:03:34,420
I don't care what
your textbook says.

950
01:03:34,420 --> 01:03:37,750
Lots of sources will discuss
irreversible reactions.

951
01:03:37,750 --> 01:03:41,750
I'll talk about irreversible
reactions later in the course.

952
01:03:41,750 --> 01:03:45,190
But what we mean when we say the
word irreversible reaction is

953
01:03:45,190 --> 01:03:46,750
these are under
conditions that are

954
01:03:46,750 --> 01:03:49,420
found in cells and in nature.

955
01:03:49,420 --> 01:03:51,160
And I stress this
because if we want

956
01:03:51,160 --> 01:03:54,610
to understand the energetics
for how pathways work,

957
01:03:54,610 --> 01:04:00,670
we have to appreciate that
life can create conditions

958
01:04:00,670 --> 01:04:04,630
to do unfavorable things,
because that's the only way

959
01:04:04,630 --> 01:04:07,680
that pathways can work.

960
01:04:07,680 --> 01:04:10,750
All right, what what
do I mean by that?

961
01:04:10,750 --> 01:04:16,160
Well, suppose again, we'll
come back to our reaction.

962
01:04:16,160 --> 01:04:21,980
A goes to B. Suppose I need
to build a pathway where

963
01:04:21,980 --> 01:04:25,640
I need to convert A to
B, because B is actually

964
01:04:25,640 --> 01:04:30,150
useful for some purpose
that I need to do in a cell.

965
01:04:30,150 --> 01:04:33,680
However, what if
this is at least

966
01:04:33,680 --> 01:04:35,480
by equilibrium, unfavorable?

967
01:04:35,480 --> 01:04:40,240
What if the equilibrium
lies towards A?

968
01:04:40,240 --> 01:04:46,990
That means delta G 0 prime is
positive, is greater than 0,

969
01:04:46,990 --> 01:04:48,580
for A to B.

970
01:04:48,580 --> 01:04:49,630
What does that mean?

971
01:04:49,630 --> 01:04:52,735
Delta G 0 prime greater than
0, for the reaction A to B?

972
01:04:52,735 --> 01:04:57,610
That means the equilibrium
lies towards A.

973
01:04:57,610 --> 01:04:59,620
And so there is no
amount of enzyme

974
01:04:59,620 --> 01:05:03,280
I can add that will
allow me to net convert A

975
01:05:03,280 --> 01:05:08,560
to B, because the equilibrium
lies far towards A.

976
01:05:08,560 --> 01:05:13,420
However, whether or not a cell
is able to build a pathway,

977
01:05:13,420 --> 01:05:18,430
where it converts A to
B depends on delta G,

978
01:05:18,430 --> 01:05:22,730
not the equilibrium constant
for that specific reaction.

979
01:05:22,730 --> 01:05:24,520
So how can I turn A into B?

980
01:05:24,520 --> 01:05:28,930
Well, I could turn A into B if I
keep the concentration of B low

981
01:05:28,930 --> 01:05:32,770
enough that delta G, not
delta G 0 prime, that's

982
01:05:32,770 --> 01:05:35,830
the equilibrium
constant, but delta G

983
01:05:35,830 --> 01:05:38,290
favors A to B conversion?

984
01:05:38,290 --> 01:05:42,840
That is, delta G for
A to B is less than 0.

985
01:05:42,840 --> 01:05:43,930
How can I do that?

986
01:05:43,930 --> 01:05:49,980
Well, remember delta G equals
delta G 0 prime plus RT

987
01:05:49,980 --> 01:06:00,970
log of B over A. So this term
is positive, because I told you,

988
01:06:00,970 --> 01:06:04,960
the equilibrium
lies towards A. So I

989
01:06:04,960 --> 01:06:08,920
need a concentration,
a ratio of B to A,

990
01:06:08,920 --> 01:06:15,790
such that B is low enough that
this term is more negative

991
01:06:15,790 --> 01:06:18,400
than that term is positive.

992
01:06:18,400 --> 01:06:21,730
And if that's the case,
delta G will be less than 0,

993
01:06:21,730 --> 01:06:24,590
and I can net move that forward.

994
01:06:24,590 --> 01:06:25,740
So how can I do that?

995
01:06:25,740 --> 01:06:29,080
How can I keep the
concentration of B low?

996
01:06:29,080 --> 01:06:32,350
Well, I can build a
pathway that consumes

997
01:06:32,350 --> 01:06:38,080
B in a way to keep it low,
which favors A to B conversion.

998
01:06:38,080 --> 01:06:43,390
In other words, I can build a
pathway, A goes to B goes to C.

999
01:06:43,390 --> 01:06:47,380
So even here, where
delta G 0 prime

1000
01:06:47,380 --> 01:06:58,280
is greater than 0, if delta G
0 prime for this reaction, B

1001
01:06:58,280 --> 01:07:05,600
to A, is much less than 0,
such that equilibriums strongly

1002
01:07:05,600 --> 01:07:11,720
favor C, that means my
unfavorable equilibrium here

1003
01:07:11,720 --> 01:07:16,610
can be overcome by the very
favorable equilibrium of B

1004
01:07:16,610 --> 01:07:23,120
to C. In essence, I can use
B to C to pull A to B, such

1005
01:07:23,120 --> 01:07:24,980
that it actually happens.

1006
01:07:24,980 --> 01:07:33,320
Produce this intermediate that's
useful on the path to making C.

1007
01:07:33,320 --> 01:07:38,600
This strategy is used in
lots of metabolic pathways.

1008
01:07:38,600 --> 01:07:43,490
And it's useful to
generate lots of chemically

1009
01:07:43,490 --> 01:07:46,100
useful intermediates.

1010
01:07:46,100 --> 01:07:55,280
Now note that this only will
work if conversion of A to C

1011
01:07:55,280 --> 01:07:56,330
is favorable.

1012
01:07:56,330 --> 01:08:01,460
That is, if delta G 0
prime is less than 0.

1013
01:08:01,460 --> 01:08:06,830
I can only pull this reaction if
delta G 0 prime is less than 0.

1014
01:08:06,830 --> 01:08:10,220
That is, if equilibrium
favors A to C,

1015
01:08:10,220 --> 01:08:15,350
I can build a pathway this way
to do something unfavorable

1016
01:08:15,350 --> 01:08:19,050
on the way to making C.

1017
01:08:19,050 --> 01:08:21,990
This brings up
another key point,

1018
01:08:21,990 --> 01:08:25,080
in that everything
that we discuss,

1019
01:08:25,080 --> 01:08:28,020
relationship between
any two metabolites

1020
01:08:28,020 --> 01:08:32,850
in any single
reaction, also must

1021
01:08:32,850 --> 01:08:35,310
be true for entire pathways.

1022
01:08:35,310 --> 01:08:37,859
So I have a three-step
pathway from A

1023
01:08:37,859 --> 01:08:42,569
to C. Whether I turn
A into C in one step,

1024
01:08:42,569 --> 01:08:46,120
or turn A into C
in multiple steps,

1025
01:08:46,120 --> 01:08:49,330
the free energy is
exactly the same.

1026
01:08:49,330 --> 01:08:53,890
If I burn wood by
lighting it on fire,

1027
01:08:53,890 --> 01:08:56,620
it releases the same
amount of energy

1028
01:08:56,620 --> 01:08:59,020
than if a termite
has an enzyme that

1029
01:08:59,020 --> 01:09:02,080
breaks that beta 1-4
linkage in the wood,

1030
01:09:02,080 --> 01:09:06,550
and can burn that glucose
stepwise through metabolism,

1031
01:09:06,550 --> 01:09:09,819
the exact same amount
of energy is released.

1032
01:09:09,819 --> 01:09:14,140
Glucose on one side, CO2
and water on the other side,

1033
01:09:14,140 --> 01:09:15,970
exactly the same
amount of energy

1034
01:09:15,970 --> 01:09:18,520
released, whether I
do it in one step,

1035
01:09:18,520 --> 01:09:20,529
or I do it in multiple steps.

1036
01:09:20,529 --> 01:09:24,250
The equilibrium constant between
those has to be the same,

1037
01:09:24,250 --> 01:09:28,420
and the delta G has to be
the same between all of it.

1038
01:09:28,420 --> 01:09:31,779
And so it should become
apparent, then, that A to C

1039
01:09:31,779 --> 01:09:36,520
has to be favorable if I'm going
to use this trick of keeping

1040
01:09:36,520 --> 01:09:41,260
product low in order to pull an
otherwise unfavorable reaction

1041
01:09:41,260 --> 01:09:42,380
forward.

1042
01:09:42,380 --> 01:09:45,069
In other words,
there's no way for me

1043
01:09:45,069 --> 01:09:49,850
to keep B low and net convert
A to B all on its own.

1044
01:09:49,850 --> 01:09:51,520
That will not work.

1045
01:09:51,520 --> 01:09:55,390
And it's these unfavorable
reactions that ultimately

1046
01:09:55,390 --> 01:09:58,420
then require energy input.

1047
01:09:58,420 --> 01:10:04,180
And this is where ATP now starts
becoming useful for cells.

1048
01:10:26,650 --> 01:10:30,550
OK, so now I want
to talk a little bit

1049
01:10:30,550 --> 01:10:35,380
about how ATP provides
energy that allows otherwise

1050
01:10:35,380 --> 01:10:39,250
unfavorable reactions to occur.

1051
01:10:39,250 --> 01:10:43,810
And ATP is useful
because delta G

1052
01:10:43,810 --> 01:10:48,200
applies to sets of
reactions in the same way it

1053
01:10:48,200 --> 01:10:49,460
applies to single reactions.

1054
01:10:49,460 --> 01:10:51,260
That is, it applies
to whole systems.

1055
01:10:51,260 --> 01:10:53,900
All reactions are a
series of reactions,

1056
01:10:53,900 --> 01:10:56,950
whether they happen alone
or coupled together.

1057
01:10:56,950 --> 01:11:00,760
All have to follow
the same rules.

1058
01:11:00,760 --> 01:11:03,700
So now let's make our
reaction more complicated.

1059
01:11:03,700 --> 01:11:09,720
Let's say A plus B goes to C
plus D, where this is really

1060
01:11:09,720 --> 01:11:11,760
two reactions coupled together.

1061
01:11:11,760 --> 01:11:16,920
A being turned into C,
and B being turned into D.

1062
01:11:16,920 --> 01:11:19,920
All right, so will
this reaction happen?

1063
01:11:19,920 --> 01:11:22,770
Can I turn A plus
B into C plus D?

1064
01:11:22,770 --> 01:11:23,830
Well, how do I know?

1065
01:11:23,830 --> 01:11:27,180
Well, it's going to be,
got to calculate delta G.

1066
01:11:27,180 --> 01:11:35,220
And so it's going to be delta
G 0 prime for A going to C,

1067
01:11:35,220 --> 01:11:42,720
plus delta G 0 prime
for B going to D.

1068
01:11:42,720 --> 01:11:45,360
So those will relate to
what's the equilibrium

1069
01:11:45,360 --> 01:11:48,630
constant, the equilibrium
relationship between A and C

1070
01:11:48,630 --> 01:11:52,290
and B and D. If
it's less than 0,

1071
01:11:52,290 --> 01:11:53,940
equilibrium will
favor to the right.

1072
01:11:53,940 --> 01:11:55,500
If it's greater
than 0, equilibrium

1073
01:11:55,500 --> 01:11:58,320
will favor to the left
of A and C and B and D.

1074
01:11:58,320 --> 01:12:02,430
Add them together, that gives
me my overall delta G 0 prime

1075
01:12:02,430 --> 01:12:04,230
for those two reactions.

1076
01:12:04,230 --> 01:12:09,750
Plus RT times the
log of the products.

1077
01:12:09,750 --> 01:12:22,200
So that's C and D over A and
B. Products over the reactants.

1078
01:12:22,200 --> 01:12:27,210
So if I take an unfavorable
reaction-- say, A to C,

1079
01:12:27,210 --> 01:12:33,180
if delta G 0 prime is greater
than 0, so it would favor A,

1080
01:12:33,180 --> 01:12:36,180
and I couple it to
another reaction, B

1081
01:12:36,180 --> 01:12:40,760
to D that's very favorable,
because I add these two

1082
01:12:40,760 --> 01:12:42,410
terms together.

1083
01:12:42,410 --> 01:12:45,350
I can now take something
where the equilibrium

1084
01:12:45,350 --> 01:12:49,460
would be unfavorable,
and make it favorable.

1085
01:12:49,460 --> 01:12:53,840
However, whether or not
this actually happens still

1086
01:12:53,840 --> 01:12:59,720
depends on this ratio of
products to reactants.

1087
01:12:59,720 --> 01:13:03,920
So it still depends on
the ratio of C to A,

1088
01:13:03,920 --> 01:13:10,350
and D to B in our
hypothetical thing here.

1089
01:13:10,350 --> 01:13:13,850
So to know if a specific
reaction will actually occur,

1090
01:13:13,850 --> 01:13:17,690
we have to take into account
both the sum of the delta G

1091
01:13:17,690 --> 01:13:20,450
primes related to the
equilibrium constant,

1092
01:13:20,450 --> 01:13:25,980
and the actual ratios
that are present in cells.

1093
01:13:25,980 --> 01:13:28,220
And so the net
effect is that I can

1094
01:13:28,220 --> 01:13:32,810
couple more favorable
reactions to make otherwise

1095
01:13:32,810 --> 01:13:36,110
unfavorable reactions
now become favorable.

1096
01:13:36,110 --> 01:13:39,200
That is, have energy input.

1097
01:13:39,200 --> 01:13:42,630
But it still depends
on conditions.

1098
01:13:42,630 --> 01:13:47,060
And so let's think a little
bit about the polymer synthesis

1099
01:13:47,060 --> 01:13:50,570
that we learned from
Professor Yaffe.

1100
01:13:50,570 --> 01:13:53,520
And so in that process,
what did we do?

1101
01:13:53,520 --> 01:13:56,210
We made several polymers, and
you learned about the chemistry

1102
01:13:56,210 --> 01:13:56,720
to do this.

1103
01:13:56,720 --> 01:14:02,750
We made DNA, we made
RNA, and we made protein.

1104
01:14:02,750 --> 01:14:05,240
These are polymers
of nucleic acids.

1105
01:14:05,240 --> 01:14:08,880
Protein is a polymer
of amino acids.

1106
01:14:08,880 --> 01:14:10,980
All of these fight
entropy, right?

1107
01:14:10,980 --> 01:14:14,190
We're building polymers,
not breaking them down.

1108
01:14:14,190 --> 01:14:17,790
And all of them were
synthesized using

1109
01:14:17,790 --> 01:14:21,750
reactions that hydrolyzed ATP.

1110
01:14:21,750 --> 01:14:25,560
In fact, those
reactions actually

1111
01:14:25,560 --> 01:14:28,450
hydrolyzed ATP in
the following way.

1112
01:14:28,450 --> 01:14:35,090
And every single one of those
cases, if you look back,

1113
01:14:35,090 --> 01:14:37,520
what you will see
is that they all

1114
01:14:37,520 --> 01:14:42,680
had steps where ATP
was taken to AMP

1115
01:14:42,680 --> 01:14:47,060
plus 2 inorganic phosphates.

1116
01:14:47,060 --> 01:14:50,750
This reaction is very favorable.

1117
01:14:50,750 --> 01:14:52,940
In fact, it's two reactions.

1118
01:14:52,940 --> 01:15:03,030
It's really ATP goes to
AMP plus pyrophosphate.

1119
01:15:03,030 --> 01:15:08,910
And then that pyrophosphate
goes to 2 inorganic phosphates.

1120
01:15:08,910 --> 01:15:20,200
It turns out that delta
G 0 prime is less than 0

1121
01:15:20,200 --> 01:15:22,720
for both of these reactions.

1122
01:15:22,720 --> 01:15:27,350
That means the equilibrium lies
towards AMP plus pyrophosphate.

1123
01:15:27,350 --> 01:15:32,740
And here, the equilibrium lies
towards 2 inorganic phosphates.

1124
01:15:32,740 --> 01:15:35,870
And so there's actually two
tricks here by metabolism.

1125
01:15:35,870 --> 01:15:40,030
One is, it's two very
favorable reactions

1126
01:15:40,030 --> 01:15:42,310
that we're coupled to do
something unfavorable,

1127
01:15:42,310 --> 01:15:43,750
build a polymer.

1128
01:15:43,750 --> 01:15:47,080
And use the trick of
keeping pyrophosphate low

1129
01:15:47,080 --> 01:15:50,740
by coupling it to a downstream,
very favorable reaction, which

1130
01:15:50,740 --> 01:15:58,510
even further pulls
this reaction, and is

1131
01:15:58,510 --> 01:16:02,830
why ATP hydrolysis here
becomes so useful as a way

1132
01:16:02,830 --> 01:16:05,460
to build these polymers.

1133
01:16:05,460 --> 01:16:08,460
Let's just go quickly
and add a few numbers

1134
01:16:08,460 --> 01:16:13,680
to show exactly what I mean
by how ATP hydrolysis can

1135
01:16:13,680 --> 01:16:16,120
be useful in this setting.

1136
01:16:16,120 --> 01:16:19,990
And so, let's do something
a little simpler.

1137
01:16:19,990 --> 01:16:26,250
Let's go to ATP plus ADP
plus to inorganic phosphate.

1138
01:16:26,250 --> 01:16:29,880
So let's give this some
numbers, delta G 0 prime

1139
01:16:29,880 --> 01:16:36,360
in this case is equal to
negative 7.5 kcals per mole.

1140
01:16:36,360 --> 01:16:39,600
All right, what does this mean?

1141
01:16:39,600 --> 01:16:43,470
Delta G 0 prime is related
to the equilibrium constant.

1142
01:16:43,470 --> 01:16:47,190
It's less than 0, which
means the equilibrium lies

1143
01:16:47,190 --> 01:16:52,140
towards ADP plus phosphate.

1144
01:16:52,140 --> 01:16:54,570
Now let's see how
this actually helps

1145
01:16:54,570 --> 01:16:58,320
by considering what the
first step in glucose

1146
01:16:58,320 --> 01:17:01,200
metabolism by cells is.

1147
01:17:01,200 --> 01:17:04,200
So the first step cells
do in glucose metabolism

1148
01:17:04,200 --> 01:17:07,970
is add an inorganic
phosphate group to glucose.

1149
01:17:07,970 --> 01:17:14,430
So it's this reaction,
glucose plus inorganic

1150
01:17:14,430 --> 01:17:20,700
phosphate goes to
glucose phosphate.

1151
01:17:20,700 --> 01:17:25,090
Just a quick note on shorthand
that I will use in this course.

1152
01:17:25,090 --> 01:17:28,080
So PI, of course, is
inorganic phosphate.

1153
01:17:28,080 --> 01:17:34,720
That is this PO43 minus group.

1154
01:17:34,720 --> 01:17:38,580
When it forms a
phosphodiester bond,

1155
01:17:38,580 --> 01:17:40,890
like to an alcohol and one
of the glucose molecules,

1156
01:17:40,890 --> 01:17:43,110
I'll draw this in
a future lecture.

1157
01:17:43,110 --> 01:17:45,120
I'll oftentimes
indicate it by putting

1158
01:17:45,120 --> 01:17:47,020
a circle around the phosphate.

1159
01:17:47,020 --> 01:17:49,350
And so adding this
phosphate to glucose

1160
01:17:49,350 --> 01:17:52,580
is a step that traps
that glucose in cells.

1161
01:17:52,580 --> 01:17:55,260
For now, let's just
consider this reaction.

1162
01:17:55,260 --> 01:17:59,270
And so delta G 0
prime of this reaction

1163
01:17:59,270 --> 01:18:05,750
is positive 3.3 kcals per mole.

1164
01:18:05,750 --> 01:18:06,710
What does that mean?

1165
01:18:06,710 --> 01:18:09,260
Delta G 0 prime relates to
the equilibrium constant.

1166
01:18:09,260 --> 01:18:12,080
It says the equilibrium
constant lies here to the left,

1167
01:18:12,080 --> 01:18:15,390
to the glucose plus
phosphate side.

1168
01:18:15,390 --> 01:18:21,150
So if we want to net trap
glucose phosphate in cells,

1169
01:18:21,150 --> 01:18:23,520
well, it's not going to
happen spontaneously.

1170
01:18:23,520 --> 01:18:25,800
You need some kind
of energy input.

1171
01:18:25,800 --> 01:18:28,920
That can come from ATP.

1172
01:18:28,920 --> 01:18:32,670
And so if we couple those
two reactions as follows.

1173
01:18:38,430 --> 01:18:52,010
So we now have glucose plus
ATP goes to glucose phosphate

1174
01:18:52,010 --> 01:18:56,240
plus ADP.

1175
01:18:56,240 --> 01:18:59,120
Now let's draw this out.

1176
01:18:59,120 --> 01:19:00,420
Will this happen?

1177
01:19:00,420 --> 01:19:07,650
So we can calculate delta G.
Delta G equals delta G 0 prime.

1178
01:19:07,650 --> 01:19:09,560
So there's two reactions
happening here,

1179
01:19:09,560 --> 01:19:12,710
glucose to glucose
phosphate, and ATP to ADP.

1180
01:19:12,710 --> 01:19:15,880
We know what delta G 0 prime
is by adding those together.

1181
01:19:15,880 --> 01:19:22,430
So it's 3.3 plus negative 7.5.

1182
01:19:22,430 --> 01:19:27,380
That equals negative 4.2.

1183
01:19:27,380 --> 01:19:28,560
What does that tell us?

1184
01:19:28,560 --> 01:19:30,950
That says, now we've
created conditions

1185
01:19:30,950 --> 01:19:33,770
where the equilibrium constant
lies towards the right,

1186
01:19:33,770 --> 01:19:37,280
towards the glucose
phosphate plus ADP side.

1187
01:19:37,280 --> 01:19:40,640
But how much of this
occurs or whether it occurs

1188
01:19:40,640 --> 01:19:42,830
isn't just the property
the equilibrium constant.

1189
01:19:42,830 --> 01:19:44,660
It's also how much is there.

1190
01:19:44,660 --> 01:19:50,330
And so that's RT times
the log of the products,

1191
01:19:50,330 --> 01:19:51,962
glucose phosphate.

1192
01:19:55,410 --> 01:20:01,035
And ADP over glucose.

1193
01:20:05,540 --> 01:20:07,760
And ATP.

1194
01:20:07,760 --> 01:20:15,310
And so, if this term
is less than 4.2--

1195
01:20:15,310 --> 01:20:18,265
that is, if the ratio of glucose
phosphate to glucose and ADP

1196
01:20:18,265 --> 01:20:25,340
to ATP in this term ends up
being less than positive 4.2,

1197
01:20:25,340 --> 01:20:27,050
this reaction is spontaneous.

1198
01:20:27,050 --> 01:20:28,850
It is favored.

1199
01:20:28,850 --> 01:20:30,410
Lots of conditions
where that would

1200
01:20:30,410 --> 01:20:35,820
be the case, although if
this term is 4.2 or greater,

1201
01:20:35,820 --> 01:20:38,010
now it will no longer occur.

1202
01:20:40,840 --> 01:20:42,770
How much ATP is needed?

1203
01:20:42,770 --> 01:20:46,030
Well, it's hard to answer this
question in absolute terms,

1204
01:20:46,030 --> 01:20:48,100
because if there's
a lot of ADP around,

1205
01:20:48,100 --> 01:20:52,690
you need a lot more ATP
for the ADP to be useful.

1206
01:20:52,690 --> 01:20:57,320
And this is the problem with
equating ATP with energy.

1207
01:20:57,320 --> 01:21:02,920
The energy here is in the ratio
of ATP to ADP, or ADP to ATP.

1208
01:21:02,920 --> 01:21:05,860
And this is something
that we we'll come back to

1209
01:21:05,860 --> 01:21:08,860
in the next lecture,
because in the end,

1210
01:21:08,860 --> 01:21:12,790
this is what will determine
if a reaction has happened.

1211
01:21:12,790 --> 01:21:16,000
It is not the absolute
concentration of ATP.

1212
01:21:16,000 --> 01:21:20,500
It's the fact that ATP
hydrolysis is favorable.

1213
01:21:20,500 --> 01:21:24,040
But how favorable
that is depends

1214
01:21:24,040 --> 01:21:29,320
on the relevant
concentrations of ATP or ADP.

1215
01:21:29,320 --> 01:21:33,520
And relative concentrations
are all that matters

1216
01:21:33,520 --> 01:21:34,720
in thermodynamics.

1217
01:21:34,720 --> 01:21:37,600
It is not absolute
concentrations.

1218
01:21:37,600 --> 01:21:41,890
It is the ATP-ADP ratio
that is the correct way

1219
01:21:41,890 --> 01:21:43,480
to think about energy.

1220
01:21:43,480 --> 01:21:47,680
And this is true for any
reaction with respect

1221
01:21:47,680 --> 01:21:49,240
to energetics.

1222
01:21:49,240 --> 01:21:52,330
If an ATP-ADP ratio
exists, such that when

1223
01:21:52,330 --> 01:21:55,510
coupled to a reaction,
delta G is less than 0,

1224
01:21:55,510 --> 01:21:57,250
then it becomes spontaneous.

1225
01:21:57,250 --> 01:22:00,730
And this is how ATP
provides energy.

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01:22:00,730 --> 01:22:04,580
And we will come back to this
more in the next lecture.

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01:22:04,580 --> 01:22:06,270
Thank you.