WEBVTT 00:00:00.500 --> 00:00:03.920 [SOUND EFFECTS] 00:00:16.680 --> 00:00:20.340 PROFESSOR: OK, I just want to just highlight your attention 00:00:20.340 --> 00:00:21.300 to things. 00:00:21.300 --> 00:00:23.460 Like every day, I get that MIT news feed. 00:00:23.460 --> 00:00:25.170 I get a couple of other news feeds. 00:00:25.170 --> 00:00:28.530 And I just thought this was really sort of a striking image 00:00:28.530 --> 00:00:33.060 and I think a great way to convey science and engineering 00:00:33.060 --> 00:00:37.300 is through sort of really eye catching imagery. 00:00:37.300 --> 00:00:41.190 This is a synapse, which is where nerves contact 00:00:41.190 --> 00:00:43.740 to other nerves or to the neuromuscular junction 00:00:43.740 --> 00:00:46.890 in order to trigger activity. 00:00:46.890 --> 00:00:52.050 And this is a piece of research out of the Cima-- whoops, 00:00:52.050 --> 00:00:55.440 go back one-- whoops, go back one more-- 00:00:55.440 --> 00:00:58.980 between the Cima and Langer labs, 00:00:58.980 --> 00:01:03.080 where they've designed little tiny microchip probes. 00:01:03.080 --> 00:01:05.670 They're about 10 microns big. 00:01:05.670 --> 00:01:09.420 They can be planted in the brain in different sites, 00:01:09.420 --> 00:01:12.160 hopefully non-invasively. 00:01:12.160 --> 00:01:14.850 And they can report on concentrations 00:01:14.850 --> 00:01:17.530 of this neurotransmitter, dopamine. 00:01:17.530 --> 00:01:19.860 And the reason you might want to be able to do that 00:01:19.860 --> 00:01:22.560 is that there is a dopamine deficit in a lot 00:01:22.560 --> 00:01:24.400 of neurologic disorders. 00:01:24.400 --> 00:01:27.540 So you would like to understand what the deficits are 00:01:27.540 --> 00:01:32.320 and pinpoint points of the brain where there may be issues. 00:01:32.320 --> 00:01:38.640 And in fact, they used it to track Parkinson's disease. 00:01:38.640 --> 00:01:40.890 Because Parkinson's disease, some 00:01:40.890 --> 00:01:45.690 of the therapeutic approaches involve deep brain stimulation. 00:01:45.690 --> 00:01:47.220 But you can't really tell if it's 00:01:47.220 --> 00:01:49.710 working unless you can measure something. 00:01:49.710 --> 00:01:51.240 And the thing that you could measure 00:01:51.240 --> 00:01:54.840 would be the absolute levels of this neurotransmitter, 00:01:54.840 --> 00:02:00.540 dopamine, which, by the way, is originated from the amino acid 00:02:00.540 --> 00:02:01.980 tyrosine. 00:02:01.980 --> 00:02:04.650 You could sort of spot some of the parts of that. 00:02:04.650 --> 00:02:07.410 That would be the carbon. 00:02:07.410 --> 00:02:11.790 Becomes a c-- there's a carboxylate and an amine. 00:02:11.790 --> 00:02:14.110 Oh, I've drawn the alcohol. 00:02:14.110 --> 00:02:15.560 This should be an NH2. 00:02:15.560 --> 00:02:17.640 Sorry, I just added this at last minute. 00:02:17.640 --> 00:02:21.690 So dopamine actually though originates from tyrosine. 00:02:21.690 --> 00:02:24.390 So I just thought you would be interested because when 00:02:24.390 --> 00:02:27.720 I talk about the highlighting things that are in the news, 00:02:27.720 --> 00:02:31.710 I mean things like this where we're all kind of interested. 00:02:31.710 --> 00:02:32.340 It's cool. 00:02:32.340 --> 00:02:34.620 It's relevant to what we do. 00:02:34.620 --> 00:02:37.980 And it really combines the efforts 00:02:37.980 --> 00:02:42.180 of scientists and engineers to make tools and methods 00:02:42.180 --> 00:02:45.000 and invent methods to make measurements 00:02:45.000 --> 00:02:47.310 that are quantitative enough to guide 00:02:47.310 --> 00:02:51.010 the analysis of a disorder. 00:02:51.010 --> 00:02:54.940 So I just want to wrap up a little bit on the aspects. 00:02:54.940 --> 00:02:58.440 I was showing you the energy diagrams in the last class 00:02:58.440 --> 00:03:03.720 and telling you how enzymes affect the course of a reaction 00:03:03.720 --> 00:03:06.480 by lowering the energy of activation, 00:03:06.480 --> 00:03:09.720 by stabilizing a transition state or a high energy 00:03:09.720 --> 00:03:11.370 intermediate state. 00:03:11.370 --> 00:03:13.280 So the energy of activation becomes 00:03:13.280 --> 00:03:15.670 smaller in the catalyzed reaction, 00:03:15.670 --> 00:03:18.930 therefore faster than any uncatalyzed reaction. 00:03:18.930 --> 00:03:21.450 And I did not give you this number last time. 00:03:21.450 --> 00:03:25.890 Enzymes catalyze reactions through about 10 00:03:25.890 --> 00:03:29.730 to the 6, a million 10 to the 10-fold. 00:03:29.730 --> 00:03:32.850 So these are dramatic increases in rates 00:03:32.850 --> 00:03:36.660 that are really physio-- we depend on physiologically. 00:03:36.660 --> 00:03:38.340 They ensure specificity. 00:03:38.340 --> 00:03:40.500 And they're essential in all systems. 00:03:40.500 --> 00:03:47.040 And the way we discuss energetic changes in reaction diagrams 00:03:47.040 --> 00:03:49.170 is by looking at what's known as the delta 00:03:49.170 --> 00:03:52.140 G. It's the change in free energy. 00:03:52.140 --> 00:03:56.370 What I show you here is an exergonic reaction, where 00:03:56.370 --> 00:04:00.120 it is a negative delta G. I didn't reinforce that point 00:04:00.120 --> 00:04:01.530 enough last time. 00:04:01.530 --> 00:04:04.980 The energy of the products is lower than the energy 00:04:04.980 --> 00:04:06.280 of the substrates. 00:04:06.280 --> 00:04:09.900 So energy is given out at the end of the transformation. 00:04:09.900 --> 00:04:13.350 That means the reaction is favorable with respect 00:04:13.350 --> 00:04:16.649 to an equilibrium, a thermodynamic parameter. 00:04:16.649 --> 00:04:18.750 And then it's the enzyme that takes 00:04:18.750 --> 00:04:23.800 care of the kinetic aspects of the reaction. 00:04:23.800 --> 00:04:26.630 So just to sort of show you the correlate, 00:04:26.630 --> 00:04:29.970 an endergonic reaction would look like this, 00:04:29.970 --> 00:04:32.250 where the delta G is positive. 00:04:32.250 --> 00:04:35.380 The products are less stable than the starting materials, 00:04:35.380 --> 00:04:38.190 which would mean the reaction is not favorable. 00:04:38.190 --> 00:04:41.130 But it will still proceed in the presence of a catalyst. 00:04:41.130 --> 00:04:42.690 And in this next small bit where we 00:04:42.690 --> 00:04:46.110 talk about pathways and different aspects 00:04:46.110 --> 00:04:48.630 of metabolism, I'm going to tell you 00:04:48.630 --> 00:04:51.640 how we get around the unfavorable equilibrium 00:04:51.640 --> 00:04:52.140 problem. 00:04:52.140 --> 00:04:55.860 Because that's obviously a big predicament in biochemistry. 00:04:55.860 --> 00:04:58.170 If reactions aren't favorable, why 00:04:58.170 --> 00:05:04.330 do they go far enough to be useful to us in metabolism? 00:05:04.330 --> 00:05:08.790 So that reaction would have a positive delta G. 00:05:08.790 --> 00:05:11.460 And then I also mentioned these two terms. 00:05:11.460 --> 00:05:15.590 Anabolic refers to the endergonic reactions. 00:05:15.590 --> 00:05:17.340 I don't know why you're doing this to me-- 00:05:17.340 --> 00:05:19.170 the endergonic reactions. 00:05:19.170 --> 00:05:23.730 And catabolic refers to the exergonic reactions. 00:05:23.730 --> 00:05:25.770 OK, then this last point-- 00:05:25.770 --> 00:05:28.020 I showed you this slide last time. 00:05:28.020 --> 00:05:30.360 But I think it was important to think about, 00:05:30.360 --> 00:05:32.460 why are enzymes so big? 00:05:32.460 --> 00:05:36.840 And I want to give one example of an additional genetic 00:05:36.840 --> 00:05:41.250 mutation that causes a human disorder, where I at least show 00:05:41.250 --> 00:05:44.160 you how the mutations are spread quite 00:05:44.160 --> 00:05:46.950 a distance from the reaction center 00:05:46.950 --> 00:05:50.610 to show you that all of that structure that you see 00:05:50.610 --> 00:05:55.020 in an enzyme as it interacts with a small substrate 00:05:55.020 --> 00:05:57.270 is critical for catalysis. 00:05:57.270 --> 00:06:00.640 So we see small substrates in each case. 00:06:00.640 --> 00:06:03.030 But we have this very large enzyme, 00:06:03.030 --> 00:06:07.890 which is many, many times its size, all engaged in catalysis. 00:06:07.890 --> 00:06:10.840 But what's the proof of that? 00:06:10.840 --> 00:06:12.330 So why are enzymes so big? 00:06:12.330 --> 00:06:15.780 So phenylketonuria is a human disorder. 00:06:15.780 --> 00:06:19.620 It's one of those disorders that neonates, 00:06:19.620 --> 00:06:22.070 brand newborns are tested for. 00:06:22.070 --> 00:06:25.410 They are checked for the genetic signal 00:06:25.410 --> 00:06:27.450 that shows that the protein will have 00:06:27.450 --> 00:06:29.640 mutations in its structure. 00:06:29.640 --> 00:06:34.080 And there are many mutations associated with a defect 00:06:34.080 --> 00:06:35.820 in this particular protein. 00:06:35.820 --> 00:06:37.950 And the protein that I'm talking about 00:06:37.950 --> 00:06:40.560 is phenylalanine hydroxylase. 00:06:40.560 --> 00:06:43.860 So the disorder is related to defects 00:06:43.860 --> 00:06:45.600 in phenylalanine hydroxylase. 00:06:45.600 --> 00:06:47.370 Now what does that enzyme do? 00:06:47.370 --> 00:06:51.510 It takes phenylalanine and installs a hydroxyl group 00:06:51.510 --> 00:06:54.300 opposite to where it's attached to the amino acid. 00:06:54.300 --> 00:06:57.540 So this is the hydrophobic amino acid phenylalanine. 00:06:57.540 --> 00:07:00.360 And this is another one of the hydrophobic amino acids 00:07:00.360 --> 00:07:02.940 in a similar family that's tyrosine. 00:07:02.940 --> 00:07:07.080 And in fact, it's the precursor to dopamine physiologically. 00:07:07.080 --> 00:07:09.420 Now it turns out there can always 00:07:09.420 --> 00:07:11.470 be too much of a good thing. 00:07:11.470 --> 00:07:13.920 So if you have too much phenylalanine, 00:07:13.920 --> 00:07:17.100 it has to be converted to a different amino acid. 00:07:17.100 --> 00:07:19.410 Because the build up of phenylalanine 00:07:19.410 --> 00:07:22.590 gets to a certain stage where it is converted itself 00:07:22.590 --> 00:07:25.260 to a toxic byproduct that actually 00:07:25.260 --> 00:07:29.260 causes severe mental disorders and seizures. 00:07:29.260 --> 00:07:33.870 So the body needs to monitor the levels of phenylalanine. 00:07:33.870 --> 00:07:36.900 And at a certain stage, phenylalanine hydroxylase 00:07:36.900 --> 00:07:38.760 will convert it to tyrosine. 00:07:38.760 --> 00:07:41.100 So even though phenylalanine is essential, 00:07:41.100 --> 00:07:43.900 too much phenylalanine is a bad thing. 00:07:43.900 --> 00:07:48.630 So that enzyme is the one that is associated with defects-- 00:07:48.630 --> 00:07:49.940 with mutations. 00:07:49.940 --> 00:07:53.690 The lower the activity of the phenylalanine hydroxylase 00:07:53.690 --> 00:07:58.170 and end you up accumulating phenylalanine too high. 00:07:58.170 --> 00:08:02.010 And so the PAH regulates the clearance 00:08:02.010 --> 00:08:04.470 from the body converting it to tyrosine. 00:08:04.470 --> 00:08:08.970 So why-- you know, I told you I would give you some insight 00:08:08.970 --> 00:08:14.850 into how entire enzymes are in fact critical for cat lysis. 00:08:14.850 --> 00:08:18.030 So what I'm showing you on this a little movie is 00:08:18.030 --> 00:08:22.200 that the sites shown in magenta all around this protein, 00:08:22.200 --> 00:08:24.570 the active site would be where this big ball is. 00:08:24.570 --> 00:08:27.480 It's actually cofactor iron. 00:08:27.480 --> 00:08:30.900 But the sites that are involved in the reduction of activity 00:08:30.900 --> 00:08:34.710 of phenylalanine hydroxylase are way out on the protein, 00:08:34.710 --> 00:08:36.120 out on its perimeters. 00:08:36.120 --> 00:08:40.590 So this protein is about 49 angstroms, 00:08:40.590 --> 00:08:43.450 4.9 nanometers across. 00:08:43.450 --> 00:08:46.380 But the sites that cause a reduction in activity 00:08:46.380 --> 00:08:49.910 are a long way away, 10 angstroms longer, 00:08:49.910 --> 00:08:52.050 15 angstroms, 16. 00:08:52.050 --> 00:08:54.570 So it turns out that enzymes as catalysts 00:08:54.570 --> 00:08:57.540 don't just use the local environment right near where 00:08:57.540 --> 00:08:58.830 chemistry happens. 00:08:58.830 --> 00:09:03.630 The entire protein collaborates to make the changes happen 00:09:03.630 --> 00:09:04.950 in catalysis. 00:09:04.950 --> 00:09:07.380 So enzymes are big, because you're not just 00:09:07.380 --> 00:09:10.080 using this inner shell of functional groups 00:09:10.080 --> 00:09:11.460 where the substrate binds. 00:09:11.460 --> 00:09:15.330 You're actually using a lot of the dynamics of the enzyme 00:09:15.330 --> 00:09:17.520 to promote catalysis. 00:09:17.520 --> 00:09:21.000 And just this sort of visual shows you 00:09:21.000 --> 00:09:23.520 how far away things can be where they 00:09:23.520 --> 00:09:25.950 suppress the activity of a protein 00:09:25.950 --> 00:09:27.690 and make it a poorer catalyst. 00:09:27.690 --> 00:09:29.460 OK. 00:09:29.460 --> 00:09:34.430 So as I said, this is one of the disorders, 00:09:34.430 --> 00:09:37.860 the genetic mutations that is tested for at birth. 00:09:37.860 --> 00:09:40.770 If you have one of these set of mutations, 00:09:40.770 --> 00:09:44.700 you immediately have to be put on a diet that's 00:09:44.700 --> 00:09:47.730 low in phenylalanine, so you don't bombard your body 00:09:47.730 --> 00:09:53.550 with too much phenylalanine, not allowing the phenylalanine 00:09:53.550 --> 00:09:54.900 to build up too much. 00:09:54.900 --> 00:09:57.480 But I don't know if any of you have lately 00:09:57.480 --> 00:09:59.520 grabbed a can of Coca-Cola that's 00:09:59.520 --> 00:10:02.070 got aspartame as a sweetener. 00:10:02.070 --> 00:10:05.580 It turns out that sweetener, NutraSweet rather, 00:10:05.580 --> 00:10:07.810 is a dipeptide. 00:10:07.810 --> 00:10:08.580 See? 00:10:08.580 --> 00:10:10.800 But it contains phenylalanine. 00:10:10.800 --> 00:10:15.600 So if you drink a ton of diet drinks that include NutraSweet, 00:10:15.600 --> 00:10:17.910 you are actually bombing yourself 00:10:17.910 --> 00:10:20.440 with high levels of phenylalanine 00:10:20.440 --> 00:10:21.960 that the body can't deal with. 00:10:21.960 --> 00:10:24.150 So people who have phenylketonuria, 00:10:24.150 --> 00:10:28.440 i.e. a defect in that enzyme, shouldn't be drinking or using 00:10:28.440 --> 00:10:30.360 NutraSweet type sweeteners. 00:10:30.360 --> 00:10:32.310 Because they actually give you too much 00:10:32.310 --> 00:10:36.390 phenylalanine at once, that you can mitigate the levels of. 00:10:36.390 --> 00:10:40.050 So I want to just tell you about these genetic disorders. 00:10:40.050 --> 00:10:43.980 There's a fairly decent set that are tested for at birth. 00:10:43.980 --> 00:10:46.080 But the ones that are tested are for ones 00:10:46.080 --> 00:10:49.140 that you can make dietary modifications or lifestyle 00:10:49.140 --> 00:10:53.110 modifications and mitigate the symptoms. 00:10:53.110 --> 00:10:56.190 And so that's a very important thing to know. 00:10:56.190 --> 00:10:59.760 You're not tested for things you don't know how to fix, 00:10:59.760 --> 00:11:02.430 because that wouldn't be appropriate. 00:11:02.430 --> 00:11:06.770 All right, any questions about that? 00:11:06.770 --> 00:11:07.441 Yeah. 00:11:07.441 --> 00:11:10.312 STUDENT: [INAUDIBLE] 00:11:10.312 --> 00:11:10.937 PROFESSOR: Yes. 00:11:10.937 --> 00:11:12.340 STUDENT: [INAUDIBLE] 00:11:12.340 --> 00:11:14.890 PROFESSOR: Oh, you know, that was me being clunky with-- 00:11:14.890 --> 00:11:16.694 of course you guys notice everything. 00:11:19.420 --> 00:11:21.133 This morning, I was making-- 00:11:21.133 --> 00:11:22.300 all right, let's go forward. 00:11:22.300 --> 00:11:25.600 One, two, and that and that. 00:11:25.600 --> 00:11:27.370 I know exactly what you're talking about. 00:11:27.370 --> 00:11:30.100 This little curb down, yeah that's 00:11:30.100 --> 00:11:33.520 me shaking when I'm doing the ChemDraw drawing. 00:11:33.520 --> 00:11:35.350 It should be flat. 00:11:35.350 --> 00:11:36.760 But thank you for noticing that. 00:11:36.760 --> 00:11:39.910 Just so that's not ambiguity, there should not be-- there 00:11:39.910 --> 00:11:42.280 could be, actually, a little dip when substrates bind 00:11:42.280 --> 00:11:42.850 to enzymes. 00:11:42.850 --> 00:11:44.630 But I didn't mean to imply it. 00:11:44.630 --> 00:11:45.730 OK, anything else? 00:11:49.590 --> 00:11:54.610 OK, so what I want to talk about now is the equilibrium problem. 00:11:54.610 --> 00:11:55.580 And what is that? 00:12:05.660 --> 00:12:16.560 So if we have reactions that are endergonic-- 00:12:16.560 --> 00:12:18.600 so we have one of these situations 00:12:18.600 --> 00:12:22.140 where we have a substrate going to a product that's 00:12:22.140 --> 00:12:22.845 higher energy. 00:12:25.360 --> 00:12:29.100 What that means is, at equilibrium between substrate 00:12:29.100 --> 00:12:32.820 and product, which is defined by the delta G, 00:12:32.820 --> 00:12:36.990 you have substrate going to product. 00:12:36.990 --> 00:12:40.120 But mostly, you've got a lot of substrate 00:12:40.120 --> 00:12:42.010 there, which is the amount of each 00:12:42.010 --> 00:12:44.890 of these is defined by this energy difference. 00:12:44.890 --> 00:12:45.700 OK. 00:12:45.700 --> 00:12:49.310 So how do we survive with these kinds of transformations 00:12:49.310 --> 00:12:52.780 when we really want the flux for an enzyme 00:12:52.780 --> 00:12:55.780 to be in the forward direction? 00:12:55.780 --> 00:12:59.450 Because if we need the product, we need to move things forward. 00:12:59.450 --> 00:13:02.680 So nature deals with this by coupling reactions 00:13:02.680 --> 00:13:04.220 to other reactions. 00:13:04.220 --> 00:13:07.510 So it finds ways around the equilibrium problem 00:13:07.510 --> 00:13:10.810 by, for example, putting a series of reactions. 00:13:10.810 --> 00:13:16.330 For example, let's go from A to B to C. 00:13:16.330 --> 00:13:21.940 So these are three intermediates catalyzed by enzyme 1, 00:13:21.940 --> 00:13:23.210 enzyme 2. 00:13:23.210 --> 00:13:24.250 OK. 00:13:24.250 --> 00:13:28.360 And let's just say this has an unfavorable delta G. 00:13:28.360 --> 00:13:35.910 So we don't make-- we have a lot of A. We have very little B. 00:13:35.910 --> 00:13:37.440 And then what happens? 00:13:37.440 --> 00:13:38.940 How are we going to-- and then let's 00:13:38.940 --> 00:13:43.710 just say, for example, this reaction is favorable. 00:13:43.710 --> 00:13:44.490 So let's see. 00:13:44.490 --> 00:13:47.950 The delta G here is positive. 00:13:47.950 --> 00:13:51.690 The delta G here is negative. 00:13:51.690 --> 00:13:55.030 So by plus VE, I mean positive and negative. 00:13:55.030 --> 00:13:59.500 So this is a favorable reaction, whereas this 00:13:59.500 --> 00:14:01.630 is an unfavorable reaction. 00:14:01.630 --> 00:14:04.990 How does putting two reactions adjacent 00:14:04.990 --> 00:14:07.900 to each other happening on the same substrate 00:14:07.900 --> 00:14:10.210 and moving through help that situation? 00:14:12.830 --> 00:14:13.910 Yeah. 00:14:13.910 --> 00:14:18.658 STUDENT: [INAUDIBLE] 00:14:18.658 --> 00:14:19.450 PROFESSOR: Perfect. 00:14:19.450 --> 00:14:24.490 So the answer here is that, as you take whatever B you have 00:14:24.490 --> 00:14:28.140 and turn it into C, A has to-- 00:14:28.140 --> 00:14:32.650 A1 has to make more B. So you solve the equilibrium problem 00:14:32.650 --> 00:14:35.650 in that way to a certain extent by just opening the tap 00:14:35.650 --> 00:14:37.430 at the other end of the series. 00:14:37.430 --> 00:14:40.750 And nature organizes a ton of reactions in sequential 00:14:40.750 --> 00:14:44.570 pathways to get around these kinds of problems. 00:14:44.570 --> 00:14:47.400 So this is done by coupling reactions. 00:14:53.700 --> 00:14:55.720 And so there are some reactions that 00:14:55.720 --> 00:14:59.380 are highly favorable, highly exothermic, 00:14:59.380 --> 00:15:02.260 where you can really sort of guarantee flux 00:15:02.260 --> 00:15:03.580 through that enzyme. 00:15:03.580 --> 00:15:07.800 A lot of these enzymes are ATP dependent. 00:15:10.890 --> 00:15:12.930 They use and burn ATP. 00:15:12.930 --> 00:15:14.850 So you get a lot of energy out. 00:15:14.850 --> 00:15:17.640 And they drive the flux through enzyme one, 00:15:17.640 --> 00:15:20.890 by enzyme to being an exergonic reaction, 00:15:20.890 --> 00:15:22.590 while the enzyme one is and endergonic. 00:15:22.590 --> 00:15:24.240 So flux is guaranteed. 00:15:24.240 --> 00:15:28.620 And a lot of pathways sort of set up to be in this way 00:15:28.620 --> 00:15:31.200 with this coupling of the chemistries. 00:15:33.900 --> 00:15:35.530 What else? 00:15:35.530 --> 00:15:43.590 So what we find is that enzymes, first of all, 00:15:43.590 --> 00:15:50.890 work in pathways where they are co-located in certain places. 00:15:50.890 --> 00:15:57.810 They may be, for example, co-localized 00:15:57.810 --> 00:16:00.030 to certain organelles in a human cell. 00:16:00.030 --> 00:16:03.090 They may be co-localized in the mitochondria 00:16:03.090 --> 00:16:07.390 or in some organelle. 00:16:07.390 --> 00:16:10.260 And we'll talk more about organelles and mitochondria 00:16:10.260 --> 00:16:11.390 later. 00:16:11.390 --> 00:16:14.435 They could be co-localized at a membrane. 00:16:17.870 --> 00:16:20.540 And so you ensure that the enzymes are together 00:16:20.540 --> 00:16:22.640 by putting them in the same place. 00:16:22.640 --> 00:16:25.520 And then nature also evolves ways 00:16:25.520 --> 00:16:28.760 where the enzymes physically interact with each other, 00:16:28.760 --> 00:16:31.670 either covalently or non-covalently. 00:16:31.670 --> 00:16:35.720 So they could be associated in the pathway 00:16:35.720 --> 00:16:39.320 by some kind of non-covalent interaction. 00:16:39.320 --> 00:16:48.390 Or you may actually link enzymes to make them single species. 00:16:48.390 --> 00:16:53.820 So if this is enzyme one and this is enzyme two, 00:16:53.820 --> 00:17:00.840 here you have an enzyme one, enzyme two single 00:17:00.840 --> 00:17:04.613 long polypeptide chain that has two domains. 00:17:04.613 --> 00:17:06.780 They can't get away from each other, because they're 00:17:06.780 --> 00:17:08.400 joined covalently. 00:17:08.400 --> 00:17:10.619 And they catalyze sequential reactions. 00:17:10.619 --> 00:17:13.410 This just doesn't happen with just three enzymes. 00:17:13.410 --> 00:17:15.869 It can happen with 10 enzymes or more. 00:17:15.869 --> 00:17:18.990 So there are very clever ways to ensure the flux 00:17:18.990 --> 00:17:21.990 occurs through pathways. 00:17:21.990 --> 00:17:22.490 OK. 00:17:26.609 --> 00:17:30.210 But don't forget, all along, that each of these enzymes 00:17:30.210 --> 00:17:32.730 is responsible for a single transformation. 00:17:32.730 --> 00:17:34.080 That's important. 00:17:34.080 --> 00:17:37.470 There's another phenomenon that having flux through pathways 00:17:37.470 --> 00:17:44.130 is very useful for, is to deal with toxic intermediates. 00:17:49.980 --> 00:17:52.390 Because that makes it very advantageous, 00:17:52.390 --> 00:17:54.920 again, to couple reactions. 00:17:54.920 --> 00:17:59.205 So let's say product B is toxic. 00:18:02.230 --> 00:18:04.100 We don't want it hanging around much. 00:18:04.100 --> 00:18:07.500 We don't want it released from an enzyme to go do damage 00:18:07.500 --> 00:18:09.160 somewhere in the cell. 00:18:09.160 --> 00:18:11.760 So having flux through a pathway basically 00:18:11.760 --> 00:18:14.160 ensures the B never gets out of the game. 00:18:14.160 --> 00:18:16.500 It just goes straight to enzyme two. 00:18:16.500 --> 00:18:20.250 So that's another physical advantage of those processes 00:18:20.250 --> 00:18:22.290 being linked together. 00:18:22.290 --> 00:18:28.050 And finally, the process also ensures a very nice opportunity 00:18:28.050 --> 00:18:29.760 to do regulation. 00:18:29.760 --> 00:18:32.490 So here we on this slide, I show you 00:18:32.490 --> 00:18:35.700 this sort of mega mess of metabolic pathways 00:18:35.700 --> 00:18:36.450 in physiology. 00:18:36.450 --> 00:18:39.090 That there would be the Krebs cycle. 00:18:39.090 --> 00:18:42.570 But all the metabolic pathways that are all interlinked. 00:18:42.570 --> 00:18:45.720 And many of these pathways will be co-locali-- 00:18:45.720 --> 00:18:49.800 steps in these pathways will be co-localized as clusters. 00:18:49.800 --> 00:18:55.050 And so that deal tells you how we can solve the equilibrium 00:18:55.050 --> 00:18:57.510 problem by linking enzymes-- 00:18:57.510 --> 00:18:59.400 the flux through pathways. 00:18:59.400 --> 00:19:03.240 And one of the best examples is in aerobic glycolysis, 00:19:03.240 --> 00:19:04.890 where in the early steps, they're 00:19:04.890 --> 00:19:07.110 not energetically favorable. 00:19:07.110 --> 00:19:11.220 You use ATP to start to break down glucose. 00:19:11.220 --> 00:19:13.110 Then you get to a certain intermediate 00:19:13.110 --> 00:19:16.530 where it's conversion to a smaller molecule 00:19:16.530 --> 00:19:19.780 generates ATP with very favorable reactions. 00:19:19.780 --> 00:19:24.360 So glycolysis is a really great example of this. 00:19:24.360 --> 00:19:27.210 Now the other thing that I just want to describe to you 00:19:27.210 --> 00:19:32.060 is the issue of feedback. 00:19:32.060 --> 00:19:36.920 And I've described this here on this slide. 00:19:36.920 --> 00:19:39.010 And so we'll talk about it on this slide. 00:19:39.010 --> 00:19:42.330 So if we are working with a pathway 00:19:42.330 --> 00:19:47.340 that goes through multiple steps to make an end product, five 00:19:47.340 --> 00:19:49.420 steps, three steps or whatever. 00:19:49.420 --> 00:19:50.990 And you've made too much of that. 00:19:50.990 --> 00:19:52.740 You've already made a lot of that product. 00:19:52.740 --> 00:19:54.690 And you don't need anymore. 00:19:54.690 --> 00:19:59.130 Nature also has in place a regulatory mechanism 00:19:59.130 --> 00:20:02.310 to feedback and stop flux through the pathway. 00:20:02.310 --> 00:20:04.350 You don't just stop all the enzymes. 00:20:04.350 --> 00:20:07.510 You find a way to stop the first enzyme. 00:20:07.510 --> 00:20:12.150 So this is a very important paradigm in biochemistry. 00:20:12.150 --> 00:20:14.400 And that's called negative feedback. 00:20:14.400 --> 00:20:17.910 So I'm showing you it here just in a very simple cartoon 00:20:17.910 --> 00:20:21.630 form in the isoleucine biosynthesis pathway. 00:20:21.630 --> 00:20:24.150 That's one of the hydrophobic amino acids. 00:20:24.150 --> 00:20:27.120 This is an intermediate that is on its way 00:20:27.120 --> 00:20:31.530 from this amino acid that is polar but not charged, 00:20:31.530 --> 00:20:32.400 threonine. 00:20:32.400 --> 00:20:35.280 So threonine gets converted to isoleucine. 00:20:35.280 --> 00:20:37.950 We need threonine to make isoleucine. 00:20:37.950 --> 00:20:40.280 But once we got a lot of isoleucine, 00:20:40.280 --> 00:20:45.510 it binds to the very first enzyme in the pathway and acts 00:20:45.510 --> 00:20:49.860 as an allosteric regulator that dampens activity. 00:20:49.860 --> 00:20:52.050 So in this case, I just want to point out 00:20:52.050 --> 00:20:56.490 to you that I'm showing a very common way we notate things. 00:20:56.490 --> 00:21:00.840 When we are talking about inhibiting a reaction, 00:21:00.840 --> 00:21:02.160 we draw it like this. 00:21:06.700 --> 00:21:10.060 We align and then align to the so the arrow, 00:21:10.060 --> 00:21:12.800 see which means you've stopped the activity. 00:21:12.800 --> 00:21:14.750 So you'll see this again and again. 00:21:14.750 --> 00:21:17.300 You're going to see it a lot in signaling pathways, 00:21:17.300 --> 00:21:19.190 because things often feedback. 00:21:19.190 --> 00:21:22.640 So another thing that nature ensures, in addition 00:21:22.640 --> 00:21:24.590 to not building up toxic products 00:21:24.590 --> 00:21:26.720 and dealing with equilibria, is that you 00:21:26.720 --> 00:21:29.360 don't want a ton of enzymes working to make something 00:21:29.360 --> 00:21:30.920 you don't need anymore. 00:21:30.920 --> 00:21:33.470 So you might as well take the end product 00:21:33.470 --> 00:21:35.870 and use it to stop the first enzyme. 00:21:35.870 --> 00:21:38.940 As that in product becomes scarce, 00:21:38.940 --> 00:21:40.910 it dissociates from the first enzyme. 00:21:40.910 --> 00:21:43.170 And it turns the pathway back on again. 00:21:43.170 --> 00:21:47.350 And I think that's a really neat way of making that happen. 00:21:47.350 --> 00:21:49.640 And also, in these cases, the enzymes 00:21:49.640 --> 00:21:51.200 have to be clustered as a group. 00:21:51.200 --> 00:21:54.080 Because you wouldn't get those local concentrations 00:21:54.080 --> 00:21:57.790 to be so advantageous if the enzymes weren't co-localized. 00:21:57.790 --> 00:21:59.600 So does that make sense? 00:21:59.600 --> 00:22:03.050 If they weren't in a really near location, the enzyme that 00:22:03.050 --> 00:22:06.230 present produces isoleucine, that isoleucine 00:22:06.230 --> 00:22:09.140 couldn't bind back to the first enzyme in the pathway 00:22:09.140 --> 00:22:12.290 if they were in different compartments of the cell. 00:22:12.290 --> 00:22:16.050 OK, everyone good with that? 00:22:16.050 --> 00:22:17.050 Good. 00:22:17.050 --> 00:22:19.080 All right. 00:22:19.080 --> 00:22:23.020 OK, so now we are moving on to carbohydrates. 00:22:41.340 --> 00:22:44.490 It's a pretty strange word, carbohydrate. 00:22:44.490 --> 00:22:47.360 But actually, it relates to early findings 00:22:47.360 --> 00:22:51.300 that glucose is a carbohydrate. 00:22:51.300 --> 00:22:53.820 And its molecular formula is C6H12O6. 00:22:56.850 --> 00:23:00.790 So they called it a hydrate of carbon 00:23:00.790 --> 00:23:04.060 before when they knew the elemental composition but they 00:23:04.060 --> 00:23:05.980 didn't know anything about the structure. 00:23:05.980 --> 00:23:09.610 There's a lot of carbohydrates that don't obey this rule. 00:23:09.610 --> 00:23:13.760 But that's where the name comes from, a hydrate of carbon. 00:23:13.760 --> 00:23:17.170 All right now carbohydrates account 00:23:17.170 --> 00:23:20.540 for-- what did I have here? 00:23:20.540 --> 00:23:25.970 25% of the mass of macromolecules, so 00:23:25.970 --> 00:23:27.470 a good amount. 00:23:27.470 --> 00:23:30.170 They are very, very important, carbohydrates 00:23:30.170 --> 00:23:31.700 in central metabolism. 00:23:31.700 --> 00:23:35.450 We use carbohydrates as a source of energy. 00:23:35.450 --> 00:23:37.880 But also, carbohydrates are a part 00:23:37.880 --> 00:23:42.320 of storage of energy in the form of polymeric structures, 00:23:42.320 --> 00:23:43.770 that I'll describe to you. 00:23:43.770 --> 00:23:47.210 There are different ones in plants and in humans. 00:23:47.210 --> 00:23:51.620 One is glycogen. One is cellulose. 00:23:51.620 --> 00:23:55.280 But carbohydrates have an increasingly important role 00:23:55.280 --> 00:23:58.580 in the extracellular matrix in these polymers that 00:23:58.580 --> 00:24:02.990 are wrapped around your cells and also as signaling entities 00:24:02.990 --> 00:24:05.460 both inside and outside the cell. 00:24:05.460 --> 00:24:07.370 So we used to think of carbohydrates 00:24:07.370 --> 00:24:10.190 and straight away connect this with metabolism. 00:24:10.190 --> 00:24:12.710 But the story is far greater than that. 00:24:12.710 --> 00:24:14.720 And I'll try to explain to you why. 00:24:14.720 --> 00:24:17.180 And it's because of the richness of functional groups 00:24:17.180 --> 00:24:18.830 in a carbohydrate. 00:24:18.830 --> 00:24:24.910 So the simplest carbohydrate, before I go up there, 00:24:24.910 --> 00:24:27.280 is a three carbon molecule. 00:24:30.810 --> 00:24:33.840 This would actually be called glyceraldehyde. 00:24:33.840 --> 00:24:36.220 But don't worry about that other name for it. 00:24:36.220 --> 00:24:39.730 It's a three carbon carbohydrate. 00:24:45.190 --> 00:24:50.120 And this molecule would be called a triose. 00:24:50.120 --> 00:24:53.345 So we've got a couple of new-- a new suffix. 00:24:56.680 --> 00:24:59.530 Because anything that is a carbohydrate 00:24:59.530 --> 00:25:02.140 ends with the suffix "ose," not to be 00:25:02.140 --> 00:25:05.840 confused with the suffix "ase," which is an enzyme. 00:25:05.840 --> 00:25:08.310 So look carefully whether it's an "a" or "o," because it's 00:25:08.310 --> 00:25:10.990 the difference between a big protein that catalyzes 00:25:10.990 --> 00:25:13.270 a reaction and a carbohydrate. 00:25:13.270 --> 00:25:16.090 So a triose would be a carbohydrate 00:25:16.090 --> 00:25:17.740 with three carbons. 00:25:17.740 --> 00:25:20.070 They have an aldehyde. 00:25:20.070 --> 00:25:23.020 Or let's just say they have a carbonyl functionality. 00:25:25.720 --> 00:25:31.570 So remember, there would be lone pair electrons on those OHs, 00:25:31.570 --> 00:25:33.490 similarly on these. 00:25:33.490 --> 00:25:36.700 And remember, that each of these vertices 00:25:36.700 --> 00:25:39.660 corresponds to a carbon. 00:25:39.660 --> 00:25:44.620 It's some-- the way you recognize carbohydrates is most 00:25:44.620 --> 00:25:45.910 commonly-- 00:25:45.910 --> 00:25:53.020 is that they are rich in carbon dash OH 00:25:53.020 --> 00:25:54.818 bonds, which are hydroxyls. 00:25:57.746 --> 00:26:00.610 Which makes them polar molecules, 00:26:00.610 --> 00:26:04.630 likely to be highly solvated in water and very different 00:26:04.630 --> 00:26:08.320 for from the compounds that are rich in just CH bonds that 00:26:08.320 --> 00:26:10.460 don't have such opportunities. 00:26:10.460 --> 00:26:13.660 So if you see a molecule and it's got a bunch of CHs 00:26:13.660 --> 00:26:16.440 but not a bunch of OHs, it's probably a lipid. 00:26:16.440 --> 00:26:19.810 If you see a compound that's rich in OHs, 00:26:19.810 --> 00:26:22.420 it's likely to be a carbohydrate. 00:26:22.420 --> 00:26:24.790 The story gets a little bit more interesting 00:26:24.790 --> 00:26:28.060 as we move up to some of the different carbohydrates, which 00:26:28.060 --> 00:26:29.560 I've shown you there on that screen. 00:26:29.560 --> 00:26:32.110 And I'm going to go forward to talk about those. 00:26:32.110 --> 00:26:37.240 Because this triose is important in primary metabolism. 00:26:37.240 --> 00:26:40.030 We break down carbon carbohydrates 00:26:40.030 --> 00:26:44.740 that have six sugars to small carbohydrates that have three-- 00:26:44.740 --> 00:26:46.600 excuse me, carbohydrates that have 00:26:46.600 --> 00:26:49.850 six carbons to carbohydrates that have three carbons. 00:26:49.850 --> 00:26:52.990 And that's where these three carbon entities crop up. 00:26:52.990 --> 00:26:58.810 But I want to focus you in on two sets of carbohydrates, 00:26:58.810 --> 00:27:00.860 the hexoses and the pentoses. 00:27:04.750 --> 00:27:09.010 So we immediately know they're carbohydrates, right? 00:27:09.010 --> 00:27:10.600 "Ose." 00:27:10.600 --> 00:27:15.110 The hexoses obviously have six carbons. 00:27:15.110 --> 00:27:18.170 And the pentoses have five carbons. 00:27:18.170 --> 00:27:21.050 And these are the most important of the carbohydrates. 00:27:21.050 --> 00:27:23.810 Yes, there are carbohydrates with four carbons. 00:27:23.810 --> 00:27:27.230 And then there were ones with seven, eight, nine carbons. 00:27:27.230 --> 00:27:28.730 But these are the ones will totally 00:27:28.730 --> 00:27:31.550 focus on in 7016, because these are 00:27:31.550 --> 00:27:34.550 very important in different biopolymers. 00:27:34.550 --> 00:27:39.220 And the hexoses are important components, for example, 00:27:39.220 --> 00:27:50.570 of cellulose and glycogen. But where are the pentose carbons? 00:27:50.570 --> 00:27:53.320 And why are they so important? 00:27:53.320 --> 00:27:55.962 Actually, I need to draw this is its straight chain version. 00:27:55.962 --> 00:27:57.170 Because I'll drive you crazy. 00:28:07.580 --> 00:28:11.420 So this sugar here is a pentose, one, two, three, four, 00:28:11.420 --> 00:28:15.890 five carbons, a bunch of OHs, aldehyde at one end. 00:28:15.890 --> 00:28:20.002 Commonly, carbohydrates will fold up into a cyclic structure 00:28:20.002 --> 00:28:20.960 through an equilibrium. 00:28:20.960 --> 00:28:23.660 I won't worry you too much with the chemistry. 00:28:23.660 --> 00:28:28.240 But I'm just going to show you that structure. 00:28:28.240 --> 00:28:30.600 It looks like this, a five-membered ring. 00:28:33.370 --> 00:28:37.260 The interconversion of these two is an equilibrium process. 00:28:37.260 --> 00:28:41.860 And those carbohydrates are incredibly important where? 00:28:41.860 --> 00:28:44.930 Yeah, nucleic acids. 00:28:44.930 --> 00:28:48.880 So your phosphodiester backbone is 00:28:48.880 --> 00:28:54.820 attached to sugars that are attached a bit to purines 00:28:54.820 --> 00:28:55.510 and pyrimidines. 00:28:55.510 --> 00:28:57.520 And we'll see those structures later. 00:28:57.520 --> 00:29:02.050 But an absolutely essential feature of that polymer 00:29:02.050 --> 00:29:04.960 is the five-membered ring carbohydrates 00:29:04.960 --> 00:29:11.770 that are known as ribose, which is what that guy is, 00:29:11.770 --> 00:29:21.160 and two deoxyribose, where one of the hydroxyls 00:29:21.160 --> 00:29:23.840 is actually a hydrogen. It's not a hydroxyl. 00:29:23.840 --> 00:29:27.070 And it's this one. 00:29:27.070 --> 00:29:31.140 So instead of being an OH, it's an H. 00:29:31.140 --> 00:29:32.700 And we number carbohydrates. 00:29:32.700 --> 00:29:34.860 And I'll reinforce this much more 00:29:34.860 --> 00:29:38.370 when we talk about carbohydrate, about nucleic acids. 00:29:38.370 --> 00:29:39.890 There's a numbering system. 00:29:39.890 --> 00:29:43.230 So two deoxyribose is in your DNA. 00:29:46.920 --> 00:29:51.980 And ribose itself is in your RNA. 00:29:51.980 --> 00:29:54.835 OK, so obviously, we need to worry about carbohydrates 00:29:54.835 --> 00:29:56.210 and learn a little bit about them 00:29:56.210 --> 00:29:58.260 based on that key criterion. 00:29:58.260 --> 00:30:02.330 OK, let's move now to the hexoses. 00:30:02.330 --> 00:30:05.660 I'm not going to make you keep drawing hexoses and things. 00:30:05.660 --> 00:30:08.090 I'm going to just tell you a little bit about them 00:30:08.090 --> 00:30:10.220 with respect to their structures. 00:30:10.220 --> 00:30:16.070 So I've shown you on the board the cyclic form of a pentose. 00:30:16.070 --> 00:30:18.352 This is the linear form and the cyclic form. 00:30:18.352 --> 00:30:19.310 Let me write that down. 00:30:25.060 --> 00:30:28.450 And by the way, in your DNA, it's always in the cyclic form. 00:30:28.450 --> 00:30:30.310 It's not in the linear form. 00:30:30.310 --> 00:30:34.720 And the hexoses also have a linear and a cyclic form. 00:30:34.720 --> 00:30:38.320 And I show you that equilibrium for glucose. 00:30:38.320 --> 00:30:40.210 You see six carbons. 00:30:40.210 --> 00:30:41.530 I've got them numbered. 00:30:41.530 --> 00:30:45.220 And they form favorably into the six-membered ring. 00:30:45.220 --> 00:30:47.470 This is the cyclic form of glucose. 00:30:47.470 --> 00:30:49.870 This is the linear form of glucose. 00:30:49.870 --> 00:30:53.080 When glucose associates into polymers, 00:30:53.080 --> 00:30:56.890 it becomes these things like cellulose or glycogen. 00:30:56.890 --> 00:30:59.920 And it depends a lot on the linkages in those polymers 00:30:59.920 --> 00:31:02.000 to define which one it is. 00:31:02.000 --> 00:31:07.120 Now, as I mentioned, carbohydrates aren't always 00:31:07.120 --> 00:31:09.430 just a series of OH groups. 00:31:09.430 --> 00:31:12.518 There's sometimes other functionality. 00:31:12.518 --> 00:31:14.185 So I'm just going to quickly draw those. 00:31:17.030 --> 00:31:22.310 And if you've got them on your handouts, 00:31:22.310 --> 00:31:24.640 you can play along with me here. 00:31:29.230 --> 00:31:36.010 So sometimes, there's an NH2 there. 00:31:36.010 --> 00:31:39.850 That's called glucose amine, very creatively. 00:31:39.850 --> 00:31:46.840 Sometimes that NH2 is converted to an amide, 00:31:46.840 --> 00:31:48.430 like that bond in a peptide. 00:31:48.430 --> 00:31:51.310 So it's glucose amide. 00:31:51.310 --> 00:31:54.640 And sometimes-- so you can draw these on your handout, 00:31:54.640 --> 00:31:57.070 because the six-membered rings are there. 00:31:57.070 --> 00:31:59.790 This stays as an OH. 00:31:59.790 --> 00:32:04.600 But this OH here is at a different oxidation state. 00:32:04.600 --> 00:32:06.310 Don't worry about that terminology. 00:32:06.310 --> 00:32:09.920 But what's important, it's glucuronic acid. 00:32:09.920 --> 00:32:13.690 So it can be negatively charged, positively charged, neutral. 00:32:13.690 --> 00:32:17.380 So there are variations on a lot of our hexoses, 00:32:17.380 --> 00:32:20.380 basically meaning this carbohydrate molecular formula 00:32:20.380 --> 00:32:21.340 doesn't work anymore. 00:32:21.340 --> 00:32:23.290 But the term has stuck. 00:32:23.290 --> 00:32:26.920 So there's quite a variety of different carbohydrates 00:32:26.920 --> 00:32:28.510 with slight differences. 00:32:28.510 --> 00:32:31.840 And the intriguing thing is that the carbohydrates 00:32:31.840 --> 00:32:35.710 that you and I use in all of our physiologic processes 00:32:35.710 --> 00:32:37.780 are much simpler than the carbohydrates 00:32:37.780 --> 00:32:39.450 that bacteria use. 00:32:39.450 --> 00:32:42.250 There is an expansion of like 10 to the 2 or 10 00:32:42.250 --> 00:32:46.690 to the 3 in the variety of sugars that bacteria use. 00:32:46.690 --> 00:32:49.280 And that's definitely a story for another day. 00:32:49.280 --> 00:32:53.170 So let me now move on to thinking about carbohydrates 00:32:53.170 --> 00:32:56.770 not as the monomers that you metabolize, 00:32:56.770 --> 00:32:58.720 but rather as the polymers that are 00:32:58.720 --> 00:33:01.930 involved in many other different types of processes. 00:33:01.930 --> 00:33:03.760 And when we think about the polymers, 00:33:03.760 --> 00:33:06.850 we want to think about how their polymers differ 00:33:06.850 --> 00:33:11.290 from the polymers of nucleic acids or proteins. 00:33:11.290 --> 00:33:14.260 Because this will tell you why carbohydrates 00:33:14.260 --> 00:33:16.630 are so complicated. 00:33:16.630 --> 00:33:21.190 When you take a bunch of amino acids and make a polymer, 00:33:21.190 --> 00:33:23.630 it's a linear polymer. 00:33:23.630 --> 00:33:25.940 Every unit is joined to the next by a name. 00:33:25.940 --> 00:33:27.330 There's no branching there. 00:33:27.330 --> 00:33:28.990 It's just a linear polymer. 00:33:28.990 --> 00:33:31.960 So the diversity is not enormous. 00:33:31.960 --> 00:33:33.190 Or-- it's pretty enormous. 00:33:33.190 --> 00:33:34.960 But it's not as big as it could be 00:33:34.960 --> 00:33:38.380 if it were a branch polymer with different types of side chains. 00:33:38.380 --> 00:33:42.740 We will see next week that the polymers of the nucleic acids-- 00:33:42.740 --> 00:33:44.130 here's the basic structure. 00:33:44.130 --> 00:33:45.910 There's the ribose, by the way. 00:33:45.910 --> 00:33:49.770 The R could be an OH or an H attached to a base of purine 00:33:49.770 --> 00:33:52.070 or pyrimidine-- you don't need to know that yet; 00:33:52.070 --> 00:33:53.260 you'll know it next week-- 00:33:53.260 --> 00:33:54.730 and then to a phosphate. 00:33:54.730 --> 00:33:58.398 But those again, are linear polymers. 00:33:58.398 --> 00:33:59.440 You don't have branching. 00:33:59.440 --> 00:34:02.020 You just have a single continuous chain. 00:34:02.020 --> 00:34:04.330 The crazy thing about sugars is they can 00:34:04.330 --> 00:34:06.680 branch from any of those OHs. 00:34:06.680 --> 00:34:11.500 So there's much more diversity of structure and function 00:34:11.500 --> 00:34:13.750 wrapped in the carbohydrates, which makes 00:34:13.750 --> 00:34:16.070 them real trouble to study. 00:34:16.070 --> 00:34:20.270 OK, I want to now introduce you to another feature. 00:34:20.270 --> 00:34:22.659 The other thing is, when we join amino acids 00:34:22.659 --> 00:34:27.190 or we join nucleic acid building blocks, nucleosides, 00:34:27.190 --> 00:34:30.130 there's no difference in the shapes that we can form. 00:34:30.130 --> 00:34:31.870 We don't have variety there. 00:34:31.870 --> 00:34:35.679 But in sugars, we can make different kinds of linkages 00:34:35.679 --> 00:34:39.909 depending on how two OH groups in a sugar are joined. 00:34:39.909 --> 00:34:43.520 So for example, if you join two glucoses, 00:34:43.520 --> 00:34:46.790 in this kind of linkage, that would give you maltose. 00:34:46.790 --> 00:34:50.837 But if you join two glucoses in that kind of linkage, 00:34:50.837 --> 00:34:51.920 it would give you lactose. 00:34:51.920 --> 00:34:54.139 And those are different compounds. 00:34:54.139 --> 00:34:58.060 They serve different types of physiologic roles. 00:34:58.060 --> 00:35:02.750 And there are enzymes that will make these bonds and then 00:35:02.750 --> 00:35:05.850 enzymes that will break these bonds. 00:35:05.850 --> 00:35:11.040 There is a common disorder that people have as they grow older. 00:35:11.040 --> 00:35:16.190 The enzyme that breaks the lactose bond the gets 00:35:16.190 --> 00:35:16.790 turned off. 00:35:16.790 --> 00:35:18.210 It doesn't work anymore. 00:35:18.210 --> 00:35:20.510 And that's the enzyme, lactose. 00:35:20.510 --> 00:35:24.710 So when people are intolerant to sugars-- 00:35:24.710 --> 00:35:27.170 lactose is the sugar in milk. 00:35:27.170 --> 00:35:29.150 And they can't digest dairy products. 00:35:29.150 --> 00:35:31.460 Because lactase doesn't work anymore. 00:35:31.460 --> 00:35:32.690 Or you can take supplements. 00:35:32.690 --> 00:35:36.230 So that's how that relates to physiology. 00:35:36.230 --> 00:35:38.990 The reaction between two glucoses 00:35:38.990 --> 00:35:42.590 to make the disaccharide is actually a condensation. 00:35:42.590 --> 00:35:45.470 Because when you join that bond, you kick out 00:35:45.470 --> 00:35:47.750 water as a side product. 00:35:47.750 --> 00:35:51.360 Or when you break that bond, you release water. 00:35:51.360 --> 00:35:54.500 So this is another one of the condensation reactions. 00:35:54.500 --> 00:35:56.690 So underline that on the slide. 00:35:56.690 --> 00:35:58.940 Because condensation means a reaction 00:35:58.940 --> 00:36:02.150 that precedes and produces you a molecule of water. 00:36:08.030 --> 00:36:10.610 And this just sums up the lactase problem, 00:36:10.610 --> 00:36:13.790 where you can digest lactose, the milk sugar. 00:36:13.790 --> 00:36:15.980 OK, so those are monomers. 00:36:15.980 --> 00:36:19.550 Now let's think about polymers and complex structures 00:36:19.550 --> 00:36:20.870 of sugars. 00:36:20.870 --> 00:36:22.580 And I put these all on the slides, 00:36:22.580 --> 00:36:25.800 because it's just impossible for you to keep drawing them. 00:36:25.800 --> 00:36:28.535 And I'm just going to give you sort of one of my pet peeves. 00:36:31.070 --> 00:36:34.670 I draw sugars like this. 00:36:34.670 --> 00:36:39.020 A lot of other people draw sugars like that. 00:36:41.700 --> 00:36:42.660 And I don't like that. 00:36:42.660 --> 00:36:44.350 Because this is what they look like. 00:36:44.350 --> 00:36:46.530 So if you see this and you go, I haven't 00:36:46.530 --> 00:36:49.740 seen sugars looking like that before, it's 00:36:49.740 --> 00:36:55.830 because this is the way to draw them that actually represents 00:36:55.830 --> 00:36:56.580 their shape. 00:36:56.580 --> 00:36:59.100 So if it's unusual format to you, 00:36:59.100 --> 00:37:02.050 I'm not going to ask you to construct these. 00:37:02.050 --> 00:37:05.310 I just want you to be familiar with looking at them like this 00:37:05.310 --> 00:37:06.750 rather than like this. 00:37:06.750 --> 00:37:11.210 Because, to me, that's the best way to render them. 00:37:11.210 --> 00:37:12.960 OK, so polymers of sugar. 00:37:12.960 --> 00:37:14.790 I just mentioned to you, there are 00:37:14.790 --> 00:37:18.300 polymers of sugars that are important to storage. 00:37:18.300 --> 00:37:21.270 So when we have excess glucose, we 00:37:21.270 --> 00:37:26.520 store glucose as glycogen. It's often stored in the liver. 00:37:26.520 --> 00:37:28.140 And later on in the semester, we'll 00:37:28.140 --> 00:37:31.410 see how a bolt of adrenaline sets 00:37:31.410 --> 00:37:34.560 all the processes in motion to chew up glycogen, 00:37:34.560 --> 00:37:37.860 to release more glucose so you can have a lot of energy 00:37:37.860 --> 00:37:39.600 quickly. 00:37:39.600 --> 00:37:44.280 So in that polymer, the sugars are linked in a different way. 00:37:44.280 --> 00:37:48.060 The common polymer in plants and, in fact, 00:37:48.060 --> 00:37:51.360 accounts for a massive proportion of the biomass, 00:37:51.360 --> 00:37:53.670 is a different polymer of glucose 00:37:53.670 --> 00:37:56.640 where the linkages are beta-- 00:37:56.640 --> 00:37:58.240 we would call this a beta linkage. 00:37:58.240 --> 00:37:59.520 But that's the way it looks. 00:37:59.520 --> 00:38:01.200 And that would be cellulose. 00:38:01.200 --> 00:38:02.910 And it's a linear polymer. 00:38:02.910 --> 00:38:07.290 Coming down here, glycogen is often a branched polymer 00:38:07.290 --> 00:38:10.760 with different kinds of linkages with different aspects 00:38:10.760 --> 00:38:12.220 or different shapes. 00:38:12.220 --> 00:38:16.110 So the glycogen that we store and can break down 00:38:16.110 --> 00:38:20.790 in order to produce glucose to make energy is glycogen. 00:38:20.790 --> 00:38:23.940 We cannot break down cellulose. 00:38:23.940 --> 00:38:26.610 We don't digest plant cellulose, because we 00:38:26.610 --> 00:38:28.560 don't have those enzymes, which is 00:38:28.560 --> 00:38:30.750 why we don't get nutritional value out 00:38:30.750 --> 00:38:35.190 of the cellulose the same way we can put forces in action 00:38:35.190 --> 00:38:36.970 to break down glucose. 00:38:36.970 --> 00:38:42.180 So the way those bonds look is absolutely critical for how 00:38:42.180 --> 00:38:45.750 you can use the energy that's within them by using enzymes 00:38:45.750 --> 00:38:46.890 to break those bonds. 00:38:49.830 --> 00:38:52.700 OK, so in general-- 00:38:52.700 --> 00:38:53.940 I've just said that. 00:38:53.940 --> 00:38:59.100 Glucose can be stored a cellulose or as glycogen. 00:38:59.100 --> 00:39:04.500 The process of photosynthesis converts energy and sunlight 00:39:04.500 --> 00:39:08.190 into glucose. 00:39:08.190 --> 00:39:11.160 And then you can make the polymers of glucose. 00:39:11.160 --> 00:39:13.410 And what I'm showing you here in these polymers 00:39:13.410 --> 00:39:15.720 is a simplified view. 00:39:15.720 --> 00:39:18.900 I want to introduce to you one other term. 00:39:18.900 --> 00:39:20.250 And that term is glycan. 00:39:23.960 --> 00:39:26.640 And that basically refers to something 00:39:26.640 --> 00:39:29.580 that is more than one sugar, one carbohydrate. 00:39:35.398 --> 00:39:37.190 I was looking at the videos of my lectures. 00:39:37.190 --> 00:39:39.120 I realized my handwriting is horrible. 00:39:39.120 --> 00:39:41.450 So I'm really trying very hard to make it a little bit 00:39:41.450 --> 00:39:42.740 neater today. 00:39:42.740 --> 00:39:46.070 So glycan is just the name for a polymer of sugars. 00:39:46.070 --> 00:39:50.880 But they can also be called polysaccharides. 00:39:56.550 --> 00:39:59.340 But glycan now is the commonly accepted term 00:39:59.340 --> 00:40:00.610 for a lot of sugars. 00:40:00.610 --> 00:40:03.180 Now, I told you about energy storage. 00:40:03.180 --> 00:40:05.370 I've told you about simple disaccharides 00:40:05.370 --> 00:40:07.680 and monosaccharides and metabolism. 00:40:07.680 --> 00:40:09.570 But what I want to do now is give you 00:40:09.570 --> 00:40:13.380 a little overview of all the different places where 00:40:13.380 --> 00:40:15.138 sugars feature in a cell. 00:40:15.138 --> 00:40:16.680 Because I think it's really important 00:40:16.680 --> 00:40:20.670 to realize that sugars form a great sort of set 00:40:20.670 --> 00:40:23.640 of molecules for communication. 00:40:23.640 --> 00:40:25.200 So I'm going to go around this sort 00:40:25.200 --> 00:40:27.860 of funny looking square cell. 00:40:27.860 --> 00:40:29.670 And this would be a eukaryotic cell, 00:40:29.670 --> 00:40:31.230 because it's got a nucleus. 00:40:31.230 --> 00:40:33.150 And there are different compartments. 00:40:33.150 --> 00:40:36.510 So within the cell, the cell sits 00:40:36.510 --> 00:40:39.300 in what's known as an extracellular matrix. 00:40:39.300 --> 00:40:42.930 It's a mesh work of sugar polymers 00:40:42.930 --> 00:40:44.980 that actually is important for the cells 00:40:44.980 --> 00:40:48.180 and important for trapping signals that come from cells 00:40:48.180 --> 00:40:49.720 and go to other cells. 00:40:49.720 --> 00:40:53.940 So those are all predominantly made up of carbohydrate. 00:40:53.940 --> 00:40:55.740 The next thing to look at is that there 00:40:55.740 --> 00:40:58.880 are proteins within the cell. 00:40:58.880 --> 00:41:03.120 They can become modified with a sugar and go to the nucleus 00:41:03.120 --> 00:41:04.420 or leave the nucleus. 00:41:04.420 --> 00:41:08.340 So there is a type of signaling that is based on adding a sugar 00:41:08.340 --> 00:41:10.500 or taking it off a protein. 00:41:10.500 --> 00:41:13.950 We'll see later in the semester how also phosphorylation 00:41:13.950 --> 00:41:17.070 does a lot of functions that look like that. 00:41:17.070 --> 00:41:20.340 There are sugars that are displayed on the cell surface 00:41:20.340 --> 00:41:21.450 polymers. 00:41:21.450 --> 00:41:23.610 And that's where signaling becomes important. 00:41:23.610 --> 00:41:26.490 Because sugars may be attached to lipids. 00:41:26.490 --> 00:41:28.980 You remember, we've talked about phospholipids 00:41:28.980 --> 00:41:30.630 being part of the membrane. 00:41:30.630 --> 00:41:33.810 Sugars can be attached to lipids that sit in the membrane 00:41:33.810 --> 00:41:34.650 and face out. 00:41:34.650 --> 00:41:37.650 And it's how cell-cell communication 00:41:37.650 --> 00:41:39.930 occurs in some instances. 00:41:39.930 --> 00:41:42.960 Or they may be attached to proteins 00:41:42.960 --> 00:41:45.940 that are also displayed on the surface of the cell. 00:41:45.940 --> 00:41:48.390 So this tells you a little bit about where 00:41:48.390 --> 00:41:52.110 we put these sugars is what's responsible for communication. 00:41:52.110 --> 00:41:55.560 Because they're on the surface of the cell with their sides 00:41:55.560 --> 00:41:58.360 out. 00:41:58.360 --> 00:42:00.490 And then the final thing I want to talk about 00:42:00.490 --> 00:42:02.270 is the blood group system. 00:42:02.270 --> 00:42:05.770 So a lot of you may be aware of blood groups. 00:42:05.770 --> 00:42:08.860 There are four principal blood groups. 00:42:08.860 --> 00:42:12.850 The differences between the blood in a A, B, AB and O blood 00:42:12.850 --> 00:42:16.720 groups are differences in just the sugars that are attached 00:42:16.720 --> 00:42:18.440 to the surface of the cell. 00:42:18.440 --> 00:42:19.960 So let me describe those. 00:42:19.960 --> 00:42:22.360 And then we'll talk about blood groups and things that 00:42:22.360 --> 00:42:27.250 are being done to enhance the supplies of red blood cells 00:42:27.250 --> 00:42:28.590 in cases of emergency. 00:42:28.590 --> 00:42:31.420 I have a nice little video I'm hoping to get to. 00:42:31.420 --> 00:42:33.310 So on the surface of the cell, you 00:42:33.310 --> 00:42:35.150 might have different sugars. 00:42:35.150 --> 00:42:37.930 This is a trisaccharide. 00:42:37.930 --> 00:42:40.680 All right, you can see one, two, three sugars. 00:42:40.680 --> 00:42:41.940 They have different linkages. 00:42:41.940 --> 00:42:43.710 But you can pick out the sugars. 00:42:43.710 --> 00:42:53.250 And they are joined by a bond called a glycoside bond 00:42:53.250 --> 00:42:54.405 and those join sugars. 00:42:59.700 --> 00:43:02.370 So what do you think the enzyme that cleaves the glycoside is? 00:43:06.362 --> 00:43:08.360 STUDENT: Glycosidase. 00:43:08.360 --> 00:43:10.040 PROFESSOR: Glycosidase. 00:43:10.040 --> 00:43:11.300 You would say glycosidase. 00:43:11.300 --> 00:43:12.530 I would say glycosidase. 00:43:12.530 --> 00:43:13.940 But if they are the same thing. 00:43:16.890 --> 00:43:19.310 And that's going to be pertinent in a minute. 00:43:22.750 --> 00:43:25.970 So remember, if in doubt, guess and stick "ase" 00:43:25.970 --> 00:43:27.970 at the end if I ask you the name of an enzyme, 00:43:27.970 --> 00:43:29.570 because that works pretty well. 00:43:29.570 --> 00:43:31.870 So if you have O blood group, you 00:43:31.870 --> 00:43:36.820 would have exclusively this trisaccharide on your red blood 00:43:36.820 --> 00:43:37.790 cells. 00:43:37.790 --> 00:43:40.060 If you have the A blood group, you 00:43:40.060 --> 00:43:42.550 have an extra sugar attached to that trisaccharide. 00:43:42.550 --> 00:43:47.470 And it's a glucosamide sugar. 00:43:47.470 --> 00:43:53.380 There's an extra carbonyl group on an amide. 00:43:53.380 --> 00:43:56.990 And if you have B blood group, it's gluco-- 00:43:56.990 --> 00:43:57.770 it's a sugar. 00:43:57.770 --> 00:43:59.410 It's actually called galactose. 00:43:59.410 --> 00:44:02.200 That has all OH groups. 00:44:02.200 --> 00:44:05.110 So the differences between if you're O group, 00:44:05.110 --> 00:44:07.590 if you're A group, or if you're B group, 00:44:07.590 --> 00:44:10.270 adjust those differences in sugars. 00:44:10.270 --> 00:44:13.960 And then people who have AB blood group have a composite. 00:44:13.960 --> 00:44:17.890 They have a mixture of the A and the B blood group. 00:44:17.890 --> 00:44:20.824 So do you-- yeah, question. 00:44:20.824 --> 00:44:22.600 STUDENT: [INAUDIBLE] 00:44:22.600 --> 00:44:26.650 PROFESSOR: That's a second marker, 00:44:26.650 --> 00:44:28.450 which we won't talk about. 00:44:28.450 --> 00:44:32.110 So it's A plus another marker that's either 00:44:32.110 --> 00:44:34.060 one type or another type. 00:44:34.060 --> 00:44:36.430 But the AB and O are defined by the sugars. 00:44:36.430 --> 00:44:38.560 Yeah, good question. 00:44:38.560 --> 00:44:42.810 OK, so do people know their blood group? 00:44:42.810 --> 00:44:44.340 It's good to know, frankly. 00:44:44.340 --> 00:44:46.792 Because someone-- you know, you may you cut yourself. 00:44:46.792 --> 00:44:48.750 And someone says, do you know your blood group? 00:44:48.750 --> 00:44:49.542 And you'll go, yes. 00:44:49.542 --> 00:44:51.745 And they'll give you an on-site transfusion. 00:44:51.745 --> 00:44:53.370 I've been watching too much Jack Bauer. 00:44:53.370 --> 00:44:58.950 But, you know, that's a story for another day as well. 00:44:58.950 --> 00:45:01.200 So it turns out that depending on blood groups, 00:45:01.200 --> 00:45:05.500 you can either be a universal donor or a universal acceptor. 00:45:05.500 --> 00:45:07.860 So the people with the O blood group 00:45:07.860 --> 00:45:10.560 can give anyone their blood. 00:45:10.560 --> 00:45:13.380 People with O, A, B, and AB. 00:45:13.380 --> 00:45:17.360 But unfortunately for the poor people with O blood group is 00:45:17.360 --> 00:45:22.080 that they cannot receive blood from blood group A, B, or AB. 00:45:22.080 --> 00:45:23.760 And I wanted to show this. 00:45:23.760 --> 00:45:25.650 And I hope I can get it working. 00:45:25.650 --> 00:45:27.670 Because we have just the right amount of time, 00:45:27.670 --> 00:45:29.820 which makes me really happy. 00:45:29.820 --> 00:45:33.030 Because I don't really program things that well sometimes. 00:45:33.030 --> 00:45:36.340 There was a pay-- there was-- 00:45:36.340 --> 00:45:38.130 the latest American chemist-- 00:45:38.130 --> 00:45:39.380 NARRATOR: --or other disaster. 00:45:39.380 --> 00:45:41.300 Those who are affected by crisis usually 00:45:41.300 --> 00:45:45.740 need four vital things, food, shelter, water and blood. 00:45:45.740 --> 00:45:48.590 In particular, O-type blood, because it can be safely given 00:45:48.590 --> 00:45:49.790 to any patient. 00:45:49.790 --> 00:45:52.250 Now, scientists say they have identified enzymes 00:45:52.250 --> 00:45:55.610 from the human gut that can turn type A and B blood into type 00:45:55.610 --> 00:45:58.310 O up to 30 times more efficiently than previously 00:45:58.310 --> 00:45:59.720 studied enzymes. 00:45:59.720 --> 00:46:01.823 Type A or B blood has specific sugars 00:46:01.823 --> 00:46:02.990 on the outside of its cells. 00:46:02.990 --> 00:46:03.650 PROFESSOR: I just described-- 00:46:03.650 --> 00:46:04.880 NARRATOR: These sugars are recognized 00:46:04.880 --> 00:46:05.932 by the immune system. 00:46:05.932 --> 00:46:07.640 And if they don't match the type of blood 00:46:07.640 --> 00:46:10.880 that's already in an individual, those cells are destroyed. 00:46:10.880 --> 00:46:12.590 Because these sugars are recognized 00:46:12.590 --> 00:46:15.020 by the immune system, they're called antigens. 00:46:15.020 --> 00:46:17.360 Type AB blood has both antigens. 00:46:17.360 --> 00:46:19.100 And type O blood has none. 00:46:19.100 --> 00:46:20.900 The researchers presented these findings 00:46:20.900 --> 00:46:22.790 at the recent American Chemical Society 00:46:22.790 --> 00:46:24.620 National Meeting in Boston. 00:46:24.620 --> 00:46:27.590 Stephen Withers from the University of British Columbia 00:46:27.590 --> 00:46:30.080 has been studying enzymes that remove A or B 00:46:30.080 --> 00:46:32.190 antigens from red blood cells. 00:46:32.190 --> 00:46:33.950 If those antigens can be removed, 00:46:33.950 --> 00:46:37.190 then type A or B can be converted to type O blood. 00:46:37.190 --> 00:46:38.900 To find the enzymes more quickly, 00:46:38.900 --> 00:46:41.690 Withers and a colleague at his institution used a technique 00:46:41.690 --> 00:46:44.330 called metagenomics, which allows scientists 00:46:44.330 --> 00:46:46.880 to sample the genes of millions of microorganisms 00:46:46.880 --> 00:46:49.070 without the need for individual c-- 00:46:49.070 --> 00:46:50.720 PROFESSOR: So that tells you something 00:46:50.720 --> 00:46:55.100 about technology and engineering and understanding structures. 00:46:55.100 --> 00:46:57.810 So it would be really advantageous. 00:46:57.810 --> 00:47:00.590 The stage at which you really need blood supplies 00:47:00.590 --> 00:47:02.600 is to take all the blood in the blood banks 00:47:02.600 --> 00:47:05.720 and turn everything into a universal donor. 00:47:05.720 --> 00:47:08.810 But the blood banks keep these differentiated supplies 00:47:08.810 --> 00:47:09.620 of blood. 00:47:09.620 --> 00:47:13.160 But what if you need something that you can give everyone 00:47:13.160 --> 00:47:14.300 safely? 00:47:14.300 --> 00:47:17.000 And so there are enzymes in the gut. 00:47:17.000 --> 00:47:20.810 There are bacteria in the gut that actually live off 00:47:20.810 --> 00:47:22.790 of sugars that they chop off cells 00:47:22.790 --> 00:47:30.690 in the matrix in the GI system. 00:47:30.690 --> 00:47:32.600 And so what the Withers group did 00:47:32.600 --> 00:47:35.870 was to screen a lot of different enzymes 00:47:35.870 --> 00:47:39.410 from bacteria in the gut and find 00:47:39.410 --> 00:47:42.530 ones that had a really good specificity for removing 00:47:42.530 --> 00:47:43.820 those sugars. 00:47:43.820 --> 00:47:45.740 Then they did protein engineering 00:47:45.740 --> 00:47:48.410 work to make them more efficient, 00:47:48.410 --> 00:47:50.450 thus creating something that was proposed 00:47:50.450 --> 00:47:53.690 a long time ago as could be useful, but now really 00:47:53.690 --> 00:47:54.860 making it useful. 00:47:54.860 --> 00:47:57.380 Because those enzymes are much more efficient. 00:47:57.380 --> 00:48:00.050 They really catalyze reactions at great speed. 00:48:00.050 --> 00:48:03.080 So they're much more efficient engineering enzymes 00:48:03.080 --> 00:48:04.760 to treat your blood cells, to make 00:48:04.760 --> 00:48:08.390 sure you get rid of all the features 00:48:08.390 --> 00:48:12.300 that are characteristic of the A, the B, and the AB antigens. 00:48:12.300 --> 00:48:14.750 Because if you don't do a good job of it, 00:48:14.750 --> 00:48:16.640 then the human immune system will 00:48:16.640 --> 00:48:19.220 recognize the little bits that sneak in 00:48:19.220 --> 00:48:21.780 and start triggering an immune response. 00:48:21.780 --> 00:48:24.770 So the efficiency of the enzymes that cleave those sugars off 00:48:24.770 --> 00:48:26.730 is absolutely paramount. 00:48:26.730 --> 00:48:29.670 And that's what I have for you today. 00:48:29.670 --> 00:48:31.340 I will see you Monday, so don't forget. 00:48:31.340 --> 00:48:34.310 The Pset's due at 3:00. 00:48:34.310 --> 00:48:39.620 Monday, I would like for you to have a preview of the-- 00:48:39.620 --> 00:48:44.822 whoops, come on-- of the DNA reading material. 00:48:44.822 --> 00:48:46.280 I don't know if any of you do this. 00:48:46.280 --> 00:48:48.020 But I think it's really handy. 00:48:48.020 --> 00:48:50.110 So there's just some very little sections 00:48:50.110 --> 00:48:53.600 that will give you a bit of exposure to nucleic acids. 00:48:53.600 --> 00:48:55.730 It'll just make the lecture a little bit more 00:48:55.730 --> 00:48:56.610 kind of familiar. 00:48:56.610 --> 00:48:59.350 But that's what we're up for Monday.