WEBVTT

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JOANNE STUBBE: My lab works
on the only cool enzyme

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in the world--

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ribonucleotide reductase.

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It's the only way
in all organisms

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that you make the
building blocks de novo

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that are required for DNA
biosynthesis and repair.

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So if you inhibit this enzyme,
you have no building blocks.

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You can't survive.

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So from a practical
point of view,

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it's the target of drugs
they use therapeutically

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in the treatment of cancer.

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And I think in probably
not so distant future

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in the antibacterials
because I think

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there are sufficient differences
between humans and bacteria

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reductases that you could
make specific inhibitors.

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Why am I interested in it?

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Because the chemistry
is sort of unbelievable.

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So I mean it was the first
example where you learn,

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or you hear about--
you heard from John--

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radicals.

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They're reactive oxygen
species and nitrogen species

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that you can't control.

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They want to pick
up an extra electron

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and form a stable octet.

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And if you leave them
to their own demise,

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they react with
anything and destroy it.

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Well nature has figured
out how to harness

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the reactivity of radicals
to do really tough chemistry

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with exquisite specificity.

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And ribonucleotide reductases
have been the paradigm

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for thinking about that.

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And from bioinformatics
now there

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are 50,000 reactions
in metabolic systems

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that are going to be radical
mediated transformations,

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yet we never talk about radicals
in introductory courses.

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So I think that's
all going to change.

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So why is it unusual?

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Well, for the human
ribonucleotide reductase,

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the key to making this
work catalytically

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is the amino acid
side chain tyrosine

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needs to be oxidized
to a tyrosyl radical.

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So automatically
nobody believes that.

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A tyrosyl radical
in solution has

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a half-life of a microsecond.

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In the active site
of these enzymes,

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the half-life of the enzyme
can be on the order four days.

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And this radical, which
is again one electron

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oxidized amino acid--
if you reduce it

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with an electron and a proton,
the enzyme is completely dead.

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So this was the
first example of-- it

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would be another example of a
post-translational modification

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that we talked about earlier--
modifying your amino acids.

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And so nature has
figured out a way.

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How do you do this oxidation?

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She has a little metal cluster
right adjacent to where

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this tyrosine is.

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And the function of this
little metal cluster

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is to put this into the
oxidized state, which

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is essential for the
way the enzyme works.

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So the other thing that's
amazing about the enzyme

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is the chemistry.

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There are two subunits.

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The chemistry all
happens in this subunit,

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but the tyrosyl
radical is there.

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And this oxidation-- normally
when you do an oxidation

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the two atoms are sitting within
a few angstroms of each other--

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the oxidation happens
over 35 angstroms.

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So that's unprecedented.

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It involves hopping
radicals which

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no one has ever seen before.

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And so that was
another thing that

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was completely fascinating
from a chemical perspective

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about how the system works.

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The other reason that
people in biology

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are interested in this, besides
the fact that makes a building

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block for DNA, is that if
you believe in an RNA world

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where we have a ribosome where
a catalysis of peptide bond

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formation is all with the
RNA, not with the protein.

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How do you get from an
RNA world to a DNA world?

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The only enzyme that
does that transformation

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making these building blocks
are ribonucleotide reductases.

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And there are many classes of
ribonucleotide reductases--

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one uses this tyrosyl radical--

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but they all have
the same active site

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and do the same
chemistry, but they

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have different metal
cofactors depending

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on where they evolved.

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And the function of the
metal cofactors in all cases,

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even though one's cobalt,
one's iron sulfur cluster,

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one's manganese, one's iron--

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the function in all cases
is to generate a radical

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in the active site
and then the chemistry

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is the same in all these things.