1 00:00:00,000 --> 00:00:01,497 [SQUEAKING] 2 00:00:01,497 --> 00:00:03,493 [RUSTLING] 3 00:00:03,493 --> 00:00:06,986 [CLICKING] 4 00:00:09,915 --> 00:00:11,290 MATTHEW VANDER HEIDEN: So today I 5 00:00:11,290 --> 00:00:16,420 want to continue our discussion of amino acid metabolism. 6 00:00:16,420 --> 00:00:18,340 And before we do that, I just want 7 00:00:18,340 --> 00:00:22,080 to come back for a few minutes and revisit the urea 8 00:00:22,080 --> 00:00:25,510 cycle and the Krebs bicycle that we 9 00:00:25,510 --> 00:00:28,340 discussed at the very end of the last lecture. 10 00:00:28,340 --> 00:00:30,910 I only want to do that because it-- 11 00:00:30,910 --> 00:00:33,260 a lot going on with this cycle. 12 00:00:33,260 --> 00:00:36,070 It can appear on the surface to be confusing, 13 00:00:36,070 --> 00:00:39,050 the molecules are hard to draw. 14 00:00:39,050 --> 00:00:41,410 And so I just wanted to draw it neatly here 15 00:00:41,410 --> 00:00:46,660 for you one last time and go through it again. 16 00:00:46,660 --> 00:00:51,790 And so remember, if we start from the amino acid arginine, 17 00:00:51,790 --> 00:00:55,600 arginine can be converted into the non-proteinogenic amino 18 00:00:55,600 --> 00:01:00,160 acid ornithine, and in the process, release urea. 19 00:01:00,160 --> 00:01:04,209 That ornithine can then be in the mitochondria converted 20 00:01:04,209 --> 00:01:09,520 to citrulline, another non-proteinogenic amino acid. 21 00:01:09,520 --> 00:01:12,190 By picking up a carbon and a nitrogen 22 00:01:12,190 --> 00:01:16,030 from this molecule, carbamoyl phosphate, which 23 00:01:16,030 --> 00:01:19,840 is generated from CO2/bicarbonate, as well 24 00:01:19,840 --> 00:01:24,880 as ammonia and to phosphorylations with ATP 25 00:01:24,880 --> 00:01:26,530 to get carbamoyl carbon phosphate, 26 00:01:26,530 --> 00:01:29,350 that's added to ornithine to get citrulline. 27 00:01:29,350 --> 00:01:33,880 That citrulline and then combine with the amino acid aspertate 28 00:01:33,880 --> 00:01:36,730 to give this molecule, argininosuccinate. 29 00:01:36,730 --> 00:01:39,910 So arginine plus a succinate on it. 30 00:01:39,910 --> 00:01:45,640 And then loss of fumarate leaves you with arginine. 31 00:01:45,640 --> 00:01:48,610 That fumarate a can, of course, go through the TCA cycle 32 00:01:48,610 --> 00:01:52,600 to regenerate malate, oxaloacetate, ultimately pick 33 00:01:52,600 --> 00:01:57,370 up nitrogen on oxaloacetate is that alpha-keto acid, 34 00:01:57,370 --> 00:02:00,190 is transaminated to aspertate, of course 35 00:02:00,190 --> 00:02:02,830 getting that nitrogen from glutamate 36 00:02:02,830 --> 00:02:04,960 to alpha-ketoglutarate. 37 00:02:04,960 --> 00:02:07,570 And glutamate, of course, can get its nitrogen 38 00:02:07,570 --> 00:02:13,300 either by transamination with another amino acid 39 00:02:13,300 --> 00:02:15,310 to an alpha-keto acid, converting 40 00:02:15,310 --> 00:02:17,020 alpha-ketoglutarate to glutamate, 41 00:02:17,020 --> 00:02:21,070 or glutamate can be generated by this redox reaction 42 00:02:21,070 --> 00:02:24,760 where it picks up on ammonia via the enzyme glutamate 43 00:02:24,760 --> 00:02:26,740 dehydrogenase. 44 00:02:26,740 --> 00:02:31,750 So, you'll notice in this cycle that ultimately the arginine, 45 00:02:31,750 --> 00:02:35,890 the urea group-- what is released as urea from arginine, 46 00:02:35,890 --> 00:02:39,310 comes from the carbamoyl phosphate. 47 00:02:39,310 --> 00:02:41,800 So that's one of these nitrogens that 48 00:02:41,800 --> 00:02:44,770 was picked up in the synthesis of carbamoyl phosphate. 49 00:02:44,770 --> 00:02:47,380 And the other one comes from aspertate, 50 00:02:47,380 --> 00:02:49,210 which, of course, can come from ammonia 51 00:02:49,210 --> 00:02:53,050 via glutamate dehydrogenase and transamination, 52 00:02:53,050 --> 00:02:56,380 or from transamination from nitrogen picked up 53 00:02:56,380 --> 00:03:01,900 from any other amino acid to ultimately end up on aspertate. 54 00:03:01,900 --> 00:03:04,300 You'll notice that there's redox balance 55 00:03:04,300 --> 00:03:06,860 across this whole cycle. 56 00:03:06,860 --> 00:03:09,430 And so there's a NAD that's required 57 00:03:09,430 --> 00:03:12,010 to reconvert the malate to oxaloacetate to run 58 00:03:12,010 --> 00:03:13,570 this half of the reaction. 59 00:03:13,570 --> 00:03:15,880 But of course, if we pick up an ammonia, 60 00:03:15,880 --> 00:03:19,900 we also have a redox reaction involved 61 00:03:19,900 --> 00:03:22,930 in the glutamate dehydrogenase reaction. 62 00:03:22,930 --> 00:03:26,650 You'll see that ATP is also-- 63 00:03:26,650 --> 00:03:28,370 quite a bit of ATP is needed. 64 00:03:28,370 --> 00:03:31,900 You need 2 ATP to generate each carbamoyl phosphate, 65 00:03:31,900 --> 00:03:35,947 as well as 2 ATP equivalents to generate argininosuccinate, 66 00:03:35,947 --> 00:03:38,530 because remember, if you go back to your notes from last time, 67 00:03:38,530 --> 00:03:41,770 you'll see that ATP to AMP plus pyrophosphate 68 00:03:41,770 --> 00:03:45,700 was part of the citrulline and aspertate generating 69 00:03:45,700 --> 00:03:47,830 argininosuccinate reaction. 70 00:03:47,830 --> 00:03:50,110 And the last thing is that CO2 is 71 00:03:50,110 --> 00:03:51,640 required to run the urea cycle. 72 00:03:51,640 --> 00:03:53,930 That's where the carbon in urea comes from. 73 00:03:53,930 --> 00:03:56,170 And that CO2 is, of course, picked up 74 00:03:56,170 --> 00:03:59,920 in the generation of carbamoyl phosphate. 75 00:03:59,920 --> 00:04:05,920 Now, I think sometimes we can fall into the misconception 76 00:04:05,920 --> 00:04:08,680 when we talk about these that all cells generate urea. 77 00:04:08,680 --> 00:04:10,040 That's not true. 78 00:04:10,040 --> 00:04:13,150 So remember, different organisms use different strategies 79 00:04:13,150 --> 00:04:16,779 to excrete nitrogen. So in us as humans, the liver 80 00:04:16,779 --> 00:04:20,320 and the kidney would run the recycle as I have drawn it here 81 00:04:20,320 --> 00:04:23,470 as a way to ultimately produce urea that 82 00:04:23,470 --> 00:04:25,390 gets excreted in the blood-- 83 00:04:25,390 --> 00:04:28,900 I mean, sorry, in the urine, whereas most tissues 84 00:04:28,900 --> 00:04:31,930 in our body would simply ship off 85 00:04:31,930 --> 00:04:35,200 excess nitrogen from the catabolism of amino acids 86 00:04:35,200 --> 00:04:38,500 to the liver and the kidney by generating either glutamate 87 00:04:38,500 --> 00:04:41,990 or glutamine in the reactions that we talked about last time, 88 00:04:41,990 --> 00:04:45,640 and then those organs would deal with-- use the urea cycle 89 00:04:45,640 --> 00:04:49,300 to produce urea and get rid of excess nitrogen. 90 00:04:49,300 --> 00:04:50,950 But of course, there's other animals 91 00:04:50,950 --> 00:04:54,970 that will use other strategies secreted as ammonia directly 92 00:04:54,970 --> 00:04:58,000 or produce the purine uric acid, which, of course, 93 00:04:58,000 --> 00:05:02,830 we'll talk about next time, how one can interconnect 94 00:05:02,830 --> 00:05:07,180 all this amino acid nitrogen metabolism with nucleic acid 95 00:05:07,180 --> 00:05:09,880 nitrogen metabolism. 96 00:05:09,880 --> 00:05:14,050 I just want to stress that this glutamate dehydrogenase 97 00:05:14,050 --> 00:05:18,340 reaction is a really key reaction that 98 00:05:18,340 --> 00:05:23,510 is necessary to get nitrogen in and out of the system. 99 00:05:23,510 --> 00:05:27,130 And once you get nitrogen in and out of the system, 100 00:05:27,130 --> 00:05:30,370 you can then use these transamination reactions 101 00:05:30,370 --> 00:05:33,760 to move nitrogens around between amino acids 102 00:05:33,760 --> 00:05:37,150 and alpha-keto acids using pyridoxal phosphate as we 103 00:05:37,150 --> 00:05:40,830 discussed last time. 104 00:05:40,830 --> 00:05:47,260 This is shown up above also as the bicycle reaction. 105 00:05:47,260 --> 00:05:49,620 And again, just stresses that you sort of 106 00:05:49,620 --> 00:05:54,090 are running the urea cycle on the right, this other TCA-- 107 00:05:54,090 --> 00:05:56,520 modified TCA cycle, if you will, on the left, 108 00:05:56,520 --> 00:06:00,720 and ultimately illustrates how you pick up those nitrogens 109 00:06:00,720 --> 00:06:06,600 and CO2 to generate urea. 110 00:06:06,600 --> 00:06:08,820 But, of course, if we're going to talk 111 00:06:08,820 --> 00:06:11,850 about how you would make amino acids, which is really 112 00:06:11,850 --> 00:06:14,460 the topic of today, how you break down 113 00:06:14,460 --> 00:06:16,680 and synthesize the carbon skeletons 114 00:06:16,680 --> 00:06:19,830 of different amino acids, well, obviously here's 115 00:06:19,830 --> 00:06:21,000 arginine metabolism. 116 00:06:21,000 --> 00:06:22,560 You can imagine that you could use 117 00:06:22,560 --> 00:06:25,980 the same reactions to produce or break down arginine, 118 00:06:25,980 --> 00:06:29,100 and that is what happens. 119 00:06:29,100 --> 00:06:32,640 But I also want to talk about the remaining amino acids. 120 00:06:32,640 --> 00:06:34,770 In the remaining amino acids, it's 121 00:06:34,770 --> 00:06:37,350 really about how do we deal with the carbon 122 00:06:37,350 --> 00:06:39,600 skeleton, the alpha-keto acids. 123 00:06:39,600 --> 00:06:42,240 And of course, these are linked via 124 00:06:42,240 --> 00:06:48,190 this pyridoxal phosphate-driven transamination reaction. 125 00:06:48,190 --> 00:06:52,270 Now, I don't have time to in this course 126 00:06:52,270 --> 00:06:56,590 to go through how each amino acid carbon skeleton is 127 00:06:56,590 --> 00:06:59,110 produced and broken down. 128 00:06:59,110 --> 00:07:02,410 We'll discuss some major themes. 129 00:07:02,410 --> 00:07:04,810 However, if I don't cover your favorite amino acid, 130 00:07:04,810 --> 00:07:06,940 because of course, all people should 131 00:07:06,940 --> 00:07:11,230 have a favorite amino acid, you can look up the pathways 132 00:07:11,230 --> 00:07:13,900 to make it or break it down, and I 133 00:07:13,900 --> 00:07:16,030 promise that if you paid attention 134 00:07:16,030 --> 00:07:19,420 through the whole class, you have the skills to understand 135 00:07:19,420 --> 00:07:24,080 that particular pathway even if we don't study it in class. 136 00:07:24,080 --> 00:07:27,250 So I want to remind you that in general 137 00:07:27,250 --> 00:07:30,700 for amino acid catabolism-- 138 00:07:37,460 --> 00:07:38,637 and this is in general. 139 00:07:38,637 --> 00:07:39,970 Of course, there are exceptions. 140 00:07:39,970 --> 00:07:44,350 Arginine would behave as I just described for the urea cycle. 141 00:07:44,350 --> 00:07:52,140 But for most amino acids, you start with transamination. 142 00:07:57,700 --> 00:07:59,130 So what does that give you? 143 00:07:59,130 --> 00:08:03,900 That gives the nitrogen to alpha-ketoglutarate 144 00:08:03,900 --> 00:08:06,510 to generate glutamate. 145 00:08:06,510 --> 00:08:09,780 And so that glutamate can then be shipped off 146 00:08:09,780 --> 00:08:11,730 to generate ammonia if you're a fish, 147 00:08:11,730 --> 00:08:16,230 generate urea if you're a human, et cetera. 148 00:08:16,230 --> 00:08:18,420 And what does that leave you with? 149 00:08:18,420 --> 00:08:25,980 That leaves you with a alpha-keto acid related 150 00:08:25,980 --> 00:08:34,280 to the amino acid that can then be oxidized to CO2 using 151 00:08:34,280 --> 00:08:38,120 various pathways-- burn it and get energy, just like we've 152 00:08:38,120 --> 00:08:43,370 described for carbohydrates and fatty acids, or, of course, 153 00:08:43,370 --> 00:08:50,560 in some cases produce glucose or some other molecule that 154 00:08:50,560 --> 00:08:53,710 can then be used to support gluconeogenesis in the liver, 155 00:08:53,710 --> 00:08:56,110 keep glucose high in our blood. 156 00:08:56,110 --> 00:09:02,410 And so that's generally how most amino acids are stabilized. 157 00:09:02,410 --> 00:09:04,210 It's very clear how this works. 158 00:09:04,210 --> 00:09:06,910 If we start with some of the more obvious ones-- 159 00:09:06,910 --> 00:09:11,200 so we talked last time about how alanine, the amino acid, 160 00:09:11,200 --> 00:09:12,530 is related-- 161 00:09:12,530 --> 00:09:15,100 so transamination, get the alpha-keto acid. 162 00:09:15,100 --> 00:09:19,870 That alpha-keto acid is pyruvate, aspertate. 163 00:09:19,870 --> 00:09:22,905 Amino acid undergoes transamination. 164 00:09:22,905 --> 00:09:25,660 The alpha-keto acid is oxaloacetate. 165 00:09:25,660 --> 00:09:31,060 Glutamate undergoes transamination. 166 00:09:31,060 --> 00:09:33,410 alpha-keto acid is alpha-ketoglutarate. 167 00:09:33,410 --> 00:09:36,430 It's very clear how all of these can end up 168 00:09:36,430 --> 00:09:45,630 in the TCA cycle or gluconeogenesis for The cell 169 00:09:45,630 --> 00:09:51,540 to either oxidize for energy or to produce something 170 00:09:51,540 --> 00:09:54,733 like glucose that can be used elsewhere. 171 00:09:54,733 --> 00:09:56,400 Now of course, there's other amino acids 172 00:09:56,400 --> 00:09:58,150 out there that we've already talked about. 173 00:09:58,150 --> 00:10:01,230 So remember asparagine, very similar to aspertate. 174 00:10:01,230 --> 00:10:05,490 Glutamine similar to glutamate. 175 00:10:05,490 --> 00:10:08,980 So those were the ammonia group on the side chain. 176 00:10:08,980 --> 00:10:11,280 We can simply remove those. 177 00:10:11,280 --> 00:10:15,870 Should be clear how to then get those into the TCA 178 00:10:15,870 --> 00:10:17,870 cycle or gluconeogenesis. 179 00:10:17,870 --> 00:10:20,040 A little bit of metabolic trivia. 180 00:10:20,040 --> 00:10:21,930 Humans, we actually don't have an enzyme 181 00:10:21,930 --> 00:10:23,310 to break down asparagine. 182 00:10:23,310 --> 00:10:26,170 Other organisms do. 183 00:10:26,170 --> 00:10:28,350 And then the other one that we alluded to last time 184 00:10:28,350 --> 00:10:37,090 was proline, which is cyclized and oxidized glutamate. 185 00:10:37,090 --> 00:10:41,040 And so I'll just illustrate here quickly how 186 00:10:41,040 --> 00:10:46,500 proline can be metabolized just so you can see this. 187 00:10:54,860 --> 00:10:59,770 So here's the amino acid proline. 188 00:10:59,770 --> 00:11:03,730 And so proline, to show you, if we 189 00:11:03,730 --> 00:11:09,070 do oxidation of this carbon-nitrogen bond, 190 00:11:09,070 --> 00:11:14,200 so that utilizes these an electron acceptor. 191 00:11:14,200 --> 00:11:16,870 That electron acceptor happens to be 192 00:11:16,870 --> 00:11:20,740 FAD being reduced to FADH2. 193 00:11:20,740 --> 00:11:30,920 That generates this molecule. 194 00:11:30,920 --> 00:11:34,850 We can then add water across that double bond. 195 00:11:53,420 --> 00:11:58,180 Now we can open up the ring like this. 196 00:12:19,220 --> 00:12:21,320 So just opened up the ring. 197 00:12:21,320 --> 00:12:27,350 Now I'm going to oxidize this aldehyde to the acid. 198 00:12:27,350 --> 00:12:30,470 So if I do that, something else has to be reduced. 199 00:12:30,470 --> 00:12:38,330 That something else can be NAD+ or NADP+ depending 200 00:12:38,330 --> 00:12:39,860 on the enzyme. 201 00:12:39,860 --> 00:12:43,700 There's enzymes that use either NAD or NADP to make 202 00:12:43,700 --> 00:12:48,390 NADPH or NADH respectively. 203 00:12:48,390 --> 00:13:11,890 And then what I'm left with is this amino acid glutamate. 204 00:13:11,890 --> 00:13:15,010 And so that's how I turn proline into glutamate. 205 00:13:15,010 --> 00:13:19,510 Two additional oxidation steps generating 206 00:13:19,510 --> 00:13:22,600 FADH2 and NAD or NADPH. 207 00:13:22,600 --> 00:13:26,410 And so that's how you would derive energy 208 00:13:26,410 --> 00:13:32,013 from the catabolism of proline, by feeding it into glutamate, 209 00:13:32,013 --> 00:13:33,805 which can then, of course, be transaminated 210 00:13:33,805 --> 00:13:35,980 to alpha-ketoglutarate, and the rest of the carbon 211 00:13:35,980 --> 00:13:38,900 enter the TCA cycle. 212 00:13:38,900 --> 00:13:39,560 OK. 213 00:13:39,560 --> 00:13:45,620 So that covers 1, 2, 3, 4, 5, 6 amino acids. 214 00:13:45,620 --> 00:13:48,780 7 if you count arginine that we talked about 215 00:13:48,780 --> 00:13:50,390 with the urea cycle. 216 00:13:50,390 --> 00:13:55,020 That leaves 13 additional amino acids. 217 00:13:55,020 --> 00:13:57,860 Many of them are first transaminated to the alpha-keto 218 00:13:57,860 --> 00:14:01,400 acid, and then ultimately use-- 219 00:14:01,400 --> 00:14:04,460 the carbon skeleton can be used to generate 220 00:14:04,460 --> 00:14:07,700 another intermediate that's either involved 221 00:14:07,700 --> 00:14:10,880 in the TCA cycle or glycolysis. 222 00:14:10,880 --> 00:14:13,040 And shown here on the slide is basically 223 00:14:13,040 --> 00:14:15,110 just a figure from a textbook that 224 00:14:15,110 --> 00:14:18,950 contains all of the various-- 225 00:14:18,950 --> 00:14:21,390 all of the 20 amino acids from protein 226 00:14:21,390 --> 00:14:27,800 and what they generate either in the TCA cycle or up here. 227 00:14:27,800 --> 00:14:30,530 So you can see here [INAUDIBLE] oxaloacetate, fumarate 228 00:14:30,530 --> 00:14:32,930 succinyl-CoA, alpha-ketoglutarate, acetyl-CoA 229 00:14:32,930 --> 00:14:35,300 pyruvate, acetyl acetate. 230 00:14:35,300 --> 00:14:37,340 Which, of course, as we saw last time, 231 00:14:37,340 --> 00:14:40,610 can be used to generate 2 acetyl-CoA 232 00:14:40,610 --> 00:14:44,840 or be used to generate the ketone body beta-hydroxy 233 00:14:44,840 --> 00:14:46,300 butyrate. 234 00:14:46,300 --> 00:14:50,770 Now, obviously if you can generate any of these things, 235 00:14:50,770 --> 00:14:54,610 we already know the pathways about how you can oxidize them, 236 00:14:54,610 --> 00:14:58,600 or, in some cases, how you can turn them into glucose. 237 00:14:58,600 --> 00:15:01,030 But now I want to return to this idea 238 00:15:01,030 --> 00:15:05,290 that we've come to a bunch of different times 239 00:15:05,290 --> 00:15:08,830 that really comes down to this fact of what we talked about 240 00:15:08,830 --> 00:15:14,560 with the TCA cycle, how the TCA cycle can't net do anaplerosis 241 00:15:14,560 --> 00:15:16,450 from two carbon units. 242 00:15:16,450 --> 00:15:22,210 That is, you can't turn acetyl-CoA or acetoacetate, 243 00:15:22,210 --> 00:15:24,820 because that's just two acetylcholine molecules, 244 00:15:24,820 --> 00:15:28,000 into anything that can generate glucose. 245 00:15:28,000 --> 00:15:30,130 that We don't have the glyoxylate cycle. 246 00:15:30,130 --> 00:15:32,980 Organisms that have the glyoxylate cycle can do this, 247 00:15:32,980 --> 00:15:35,530 but we as humans cannot do that. 248 00:15:35,530 --> 00:15:39,100 Now, many of our amino acids can be 249 00:15:39,100 --> 00:15:43,405 used to produce things like fumarate, succinyl-CoA, 250 00:15:43,405 --> 00:15:44,770 oxaloacetate. 251 00:15:44,770 --> 00:15:48,550 All of that stuff can easily be turned into glucose. 252 00:15:48,550 --> 00:15:55,660 And so if we starve ourselves or go on a low-carbohydrate diet, 253 00:15:55,660 --> 00:15:59,590 well, what happens is, our liver will break down amino acids 254 00:15:59,590 --> 00:16:02,920 and use those amino acids to make glucose, 255 00:16:02,920 --> 00:16:05,620 but we can only make glucose from amino acids 256 00:16:05,620 --> 00:16:08,380 if those amino acids are broken down 257 00:16:08,380 --> 00:16:12,280 into something that's not acetyl-CoA or acetoacetate 258 00:16:12,280 --> 00:16:15,640 because we don't have a glyoxylate cycle. 259 00:16:15,640 --> 00:16:18,460 Just remember I mentioned a couple lectures 260 00:16:18,460 --> 00:16:20,920 ago when we talked about the ketogenic diet, 261 00:16:20,920 --> 00:16:25,030 a true ketogenic diet isn't just low carbohydrates, 262 00:16:25,030 --> 00:16:28,600 it's also low protein because your liver will turn 263 00:16:28,600 --> 00:16:31,360 that protein back into glucose. 264 00:16:31,360 --> 00:16:33,520 And so if you really want to be ketotic, 265 00:16:33,520 --> 00:16:38,080 you have to limit both glucose and-- 266 00:16:38,080 --> 00:16:42,190 both sugars and proteins, because fat, of course, 267 00:16:42,190 --> 00:16:43,977 will only be broken into two carbon units, 268 00:16:43,977 --> 00:16:45,560 and you can't turn those into glucose, 269 00:16:45,560 --> 00:16:49,270 so you instead turn them into ketones. 270 00:16:49,270 --> 00:16:53,620 Now, not all amino acid skeletons, 271 00:16:53,620 --> 00:16:55,600 though, can be used to make something 272 00:16:55,600 --> 00:16:57,700 that can generate glucose. 273 00:16:57,700 --> 00:17:00,270 Some can only make stuff-- 274 00:17:00,270 --> 00:17:02,620 acetyl-CoA, acetoacetate-- that can 275 00:17:02,620 --> 00:17:05,680 be used to generate ketones. 276 00:17:05,680 --> 00:17:10,690 And so this defines another way to classify amino acids, 277 00:17:10,690 --> 00:17:23,444 is so-called glucogenic amino acids or ketogenic amino acids. 278 00:17:27,150 --> 00:17:30,410 And this is a direct consequence of what those amino acid carbon 279 00:17:30,410 --> 00:17:32,540 skeletons are broken into. 280 00:17:32,540 --> 00:17:36,830 And so a glucogenic amino acid is really 281 00:17:36,830 --> 00:17:51,590 any amino acid where the product of breakdown 282 00:17:51,590 --> 00:17:57,250 is greater than 2 carbons that is not acetyl-CoA. 283 00:18:00,590 --> 00:18:07,950 Whereas ketogenic amino acid is an amino acid 284 00:18:07,950 --> 00:18:23,010 where the product of breakdown is acetyl-CoA. 285 00:18:25,790 --> 00:18:33,290 And I should mention, or acetoacetate, 286 00:18:33,290 --> 00:18:37,890 because acetoacetate, as we saw, is 2 acetyl-CoAs. 287 00:18:43,640 --> 00:18:47,720 So acetyl-CoA, acetoacetate can be turned into the ketone body 288 00:18:47,720 --> 00:18:51,358 beta-hydroxybutyrate, an alternative fuel for the brain. 289 00:18:51,358 --> 00:18:53,150 If you break down an amino acid and all you 290 00:18:53,150 --> 00:18:55,520 get is acetyl-CoA or acetoacetate, 291 00:18:55,520 --> 00:19:02,270 you can't turn that carbon skeleton back into glucose; 292 00:19:02,270 --> 00:19:05,090 therefore, it's a ketogenic amino acid. 293 00:19:05,090 --> 00:19:08,690 All other amino acids that generate oxaloacetate, 294 00:19:08,690 --> 00:19:11,990 succinyl-CoA, whatever, something greater 295 00:19:11,990 --> 00:19:16,490 than 2 carbons, not acetyl-CoA, it can then 296 00:19:16,490 --> 00:19:18,410 be turned into glucose, therefore, it's 297 00:19:18,410 --> 00:19:22,590 a glucogenic amino acids. 298 00:19:22,590 --> 00:19:25,700 Now if we come back over here to our slide 299 00:19:25,700 --> 00:19:28,490 and you look at the various amino acids, 300 00:19:28,490 --> 00:19:32,600 most of the amino acids are turned into something that 301 00:19:32,600 --> 00:19:34,070 can be turned into glucose. 302 00:19:34,070 --> 00:19:39,710 And so most amino acids are so-called glucogenic. 303 00:19:39,710 --> 00:19:45,860 However, there's a few amino acids that are ketogenic, 304 00:19:45,860 --> 00:19:48,080 and there's some amino acids that are 305 00:19:48,080 --> 00:19:50,540 both glucogenic and ketogenic. 306 00:19:50,540 --> 00:19:53,330 And so if you look here through the slide, what you'll 307 00:19:53,330 --> 00:19:56,360 find is that tyrosine and isoleucine-- so there's 308 00:19:56,360 --> 00:19:58,850 isoleucine, here's tyrosine. 309 00:19:58,850 --> 00:20:03,560 So they're turned into ketones, but they can also be-- 310 00:20:03,560 --> 00:20:05,690 here's tyrosine, here's isoleucine-- 311 00:20:05,690 --> 00:20:07,375 can also be turned into something 312 00:20:07,375 --> 00:20:08,750 that can be used to make glucose, 313 00:20:08,750 --> 00:20:14,060 and so they're referred to as both glucogenic and ketogenic. 314 00:20:14,060 --> 00:20:17,060 Now, as I said before, we don't have time 315 00:20:17,060 --> 00:20:21,470 to go through how to break down all of the amino acids, 316 00:20:21,470 --> 00:20:25,190 but I will take you through how you break down the three 317 00:20:25,190 --> 00:20:28,170 branched chain amino acids. 318 00:20:28,170 --> 00:20:29,912 And I will do that because, first of all, 319 00:20:29,912 --> 00:20:31,370 it will illustrate that you already 320 00:20:31,370 --> 00:20:33,380 know a lot about metabolism. 321 00:20:33,380 --> 00:20:35,720 You'll see that how these are broken down 322 00:20:35,720 --> 00:20:40,050 is just variations on pathways that we've already discussed. 323 00:20:40,050 --> 00:20:41,960 And so it really drives home the fact 324 00:20:41,960 --> 00:20:44,120 that the complexity of metabolism 325 00:20:44,120 --> 00:20:48,470 is really just nature repurposing relatively 326 00:20:48,470 --> 00:20:51,110 few reactions over and over and over again 327 00:20:51,110 --> 00:20:54,740 in a way that ultimately builds complexity and diversity, 328 00:20:54,740 --> 00:20:57,890 but in the end, is actually quite 329 00:20:57,890 --> 00:21:01,820 consistent across the whole thing. 330 00:21:01,820 --> 00:21:05,840 And you'll also see examples of how amino acid skeleton 331 00:21:05,840 --> 00:21:10,760 breakdown can end up either as glucogenic or ketogenic, 332 00:21:10,760 --> 00:21:14,600 and that's because of the various branched chain 333 00:21:14,600 --> 00:21:15,580 amino acids. 334 00:21:15,580 --> 00:21:21,530 So there's, of course, leucine, valine, and isoleucine. 335 00:21:21,530 --> 00:21:25,760 So those are the three branched chain amino acids. 336 00:21:25,760 --> 00:21:31,730 You'll see the leucine is ketogenic, 337 00:21:31,730 --> 00:21:40,840 valine is glucogenic, and isoleucine, as I just said, 338 00:21:40,840 --> 00:21:45,680 is both ketogenic and glucogenic. 339 00:21:50,500 --> 00:21:54,190 So three very amino acids. 340 00:21:54,190 --> 00:21:56,260 In genetic terms, very conservative 341 00:21:56,260 --> 00:21:57,850 substitutions within a protein. 342 00:22:00,610 --> 00:22:02,950 Very related structures. 343 00:22:02,950 --> 00:22:06,880 However, the way they're broken down, in the case of leucine, 344 00:22:06,880 --> 00:22:09,460 generates only things that are ketogenic; 345 00:22:09,460 --> 00:22:11,590 valine generates things that are glucogenic; 346 00:22:11,590 --> 00:22:13,630 and isoleucine generates both. 347 00:22:13,630 --> 00:22:20,170 And so we'll go through each of these and see how that happens. 348 00:22:20,170 --> 00:22:21,520 So let's start with leucine. 349 00:22:25,770 --> 00:22:28,186 So leucine is a-- 350 00:22:28,186 --> 00:22:33,990 I said above is a ketogenic amino acid. 351 00:22:33,990 --> 00:22:38,820 And so leucine, like many amino acids, 352 00:22:38,820 --> 00:22:41,760 starts break down by transamination. 353 00:22:41,760 --> 00:22:46,470 So this transamination will, of course, take the nitrogen 354 00:22:46,470 --> 00:22:50,970 from leucine, an alpha-keto acid, alpha-ketoglutarate, 355 00:22:50,970 --> 00:22:56,610 generate glutamate, as well as the alpha-keto acid of leucine, 356 00:22:56,610 --> 00:22:59,190 which, just to remind you leucine looks like, 357 00:22:59,190 --> 00:23:00,165 looks like this. 358 00:23:11,680 --> 00:23:16,680 So this is the side chain over here of leucine. 359 00:23:16,680 --> 00:23:19,410 Here's the alpha-keto acid related to leucine. 360 00:23:19,410 --> 00:23:21,540 If I take this alpha-keto group, turn it 361 00:23:21,540 --> 00:23:23,640 into an amino group, that's leucine. 362 00:23:23,640 --> 00:23:28,800 So this is the alpha-keto acid related to leucine. 363 00:23:28,800 --> 00:23:32,700 So the next step of leucine breakdown 364 00:23:32,700 --> 00:23:36,930 involves oxidative decarboxylation 365 00:23:36,930 --> 00:23:40,060 of this alpha-keto acid. 366 00:23:40,060 --> 00:23:43,140 So if you remember, we've seen this reaction before. 367 00:23:43,140 --> 00:23:47,220 We did it in pyruvate to generate acetaldehyde, 368 00:23:47,220 --> 00:23:49,260 an ethanol metabolism. 369 00:23:49,260 --> 00:23:50,850 We did it in-- 370 00:23:50,850 --> 00:23:52,950 well, we did alpha decarboxylation there, 371 00:23:52,950 --> 00:23:55,710 and then we did oxidative alpha decarboxylation 372 00:23:55,710 --> 00:23:58,440 when we turn pyruvate into acetyl-CoA. 373 00:23:58,440 --> 00:24:00,690 And we turned alpha-ketoglutarate 374 00:24:00,690 --> 00:24:02,400 into succinyl-CoA. 375 00:24:02,400 --> 00:24:05,190 Well, that exact reaction, which we 376 00:24:05,190 --> 00:24:07,140 saw with pyruvate decarboxylation, 377 00:24:07,140 --> 00:24:09,330 as well as what we saw with alpha-ketoglutarate 378 00:24:09,330 --> 00:24:13,470 dehydrogenase generating acetyl-CoA and succinyl-CoA 379 00:24:13,470 --> 00:24:18,540 is what happens here for the alpha-keto acids produced 380 00:24:18,540 --> 00:24:22,470 from breakdown of leucine and other branched chain 381 00:24:22,470 --> 00:24:23,880 amino acids. 382 00:24:23,880 --> 00:24:26,790 And so if you look back in your notes, 383 00:24:26,790 --> 00:24:29,510 we went through the mechanism of this in detail. 384 00:24:29,510 --> 00:24:37,450 Remember, this involved edition of CoA, loss of CO2, 385 00:24:37,450 --> 00:24:41,020 it's an oxidation reaction. 386 00:24:41,020 --> 00:24:44,700 So remember, the electrons needed to go somewhere, 387 00:24:44,700 --> 00:24:48,560 and so they ended up going to NADH. 388 00:24:48,560 --> 00:24:49,510 So that's oxidized. 389 00:24:49,510 --> 00:24:52,150 NAD+ is reduced to NADH. 390 00:24:52,150 --> 00:24:56,740 And remember, this involved that mini-electron transport chain 391 00:24:56,740 --> 00:25:04,870 with FAD, lipoic acid, and TPP+. 392 00:25:04,870 --> 00:25:08,980 And in the end, that releases the CO2 393 00:25:08,980 --> 00:25:21,860 and you end up with this branched chain acyl-CoA. 394 00:25:24,550 --> 00:25:28,360 So same reaction is PDH, alpha-ketoglutarate, 395 00:25:28,360 --> 00:25:29,890 dehydrogenase. 396 00:25:29,890 --> 00:25:31,750 Just like those two reactions, remember, 397 00:25:31,750 --> 00:25:35,150 that had an E1, an E2, and an E3 subunit. 398 00:25:35,150 --> 00:25:38,050 So this actually uses the exact same E2 and E3 399 00:25:38,050 --> 00:25:40,000 subunit as those reactions. 400 00:25:40,000 --> 00:25:42,040 The E1 subunit is, of course, different 401 00:25:42,040 --> 00:25:47,200 because it's unique to the branched chain amino acids, 402 00:25:47,200 --> 00:25:48,860 whereas in pyruvate dehydrogenase, 403 00:25:48,860 --> 00:25:50,860 to be unique to pyruvate and alpha-ketoglutarate 404 00:25:50,860 --> 00:25:53,830 dehydrogenase, you need the alpha-ketoglutarate. 405 00:25:53,830 --> 00:25:59,860 In this case, this enzyme is called BCKDH for Branched Chain 406 00:25:59,860 --> 00:26:04,900 Keto Acid Dehydrogenase, and allows 407 00:26:04,900 --> 00:26:09,880 the oxidative decarboxylation to generate this branched chain 408 00:26:09,880 --> 00:26:12,640 acyl-CoA. 409 00:26:12,640 --> 00:26:17,890 Now this branched chain acyl-CoA looks a lot like a fatty acid, 410 00:26:17,890 --> 00:26:20,770 and in fact, it's metabolized very much like we 411 00:26:20,770 --> 00:26:23,260 would do fatty acid oxidation. 412 00:26:23,260 --> 00:26:27,550 So what's the first step in beta oxidation of fatty acids? 413 00:26:27,550 --> 00:26:30,910 Well, we would introduce a double bond here. 414 00:26:30,910 --> 00:26:35,770 And so that's exactly what happens next. 415 00:26:35,770 --> 00:26:40,700 So this would be a membrane-bound FAD 416 00:26:40,700 --> 00:26:43,850 containing enzyme, part of the electron transport chain. 417 00:26:43,850 --> 00:26:47,883 Going to oxidize that carbon-carbon bond. 418 00:26:47,883 --> 00:26:48,800 There's that generate. 419 00:26:59,860 --> 00:27:00,730 All right. 420 00:27:00,730 --> 00:27:03,182 Now, if we are doing fatty acid oxidation, 421 00:27:03,182 --> 00:27:05,140 we would, of course, add water across the bond. 422 00:27:05,140 --> 00:27:07,210 We'll do that in a minute. 423 00:27:07,210 --> 00:27:10,190 Before that happens, the next step, though, 424 00:27:10,190 --> 00:27:13,750 is that to facilitate ultimately break down of this, 425 00:27:13,750 --> 00:27:16,360 we're going to end up adding our carboxyl group 426 00:27:16,360 --> 00:27:18,080 to the end of the molecule. 427 00:27:18,080 --> 00:27:21,260 So if we're going to add CO2 to the end of the molecule, 428 00:27:21,260 --> 00:27:22,710 how would we do that? 429 00:27:22,710 --> 00:27:26,540 Well, we've seen that reaction many times before as well. 430 00:27:26,540 --> 00:27:30,760 So if we're going to add a CO2 group, 431 00:27:30,760 --> 00:27:34,010 that's going to come from biotin. 432 00:27:34,010 --> 00:27:39,890 So the next enzyme would have biotin in the active site that 433 00:27:39,890 --> 00:27:42,210 can pick up a CO2. 434 00:27:42,210 --> 00:27:45,080 How does it pick up the CO2? 435 00:27:45,080 --> 00:27:53,820 Well, it picks up the CO2 via bicarbonate plus ATP, 436 00:27:53,820 --> 00:27:56,910 and that's going to go to-- 437 00:27:56,910 --> 00:27:59,670 that's going to phosphorylate the bicarbonate. 438 00:27:59,670 --> 00:28:03,840 And then when we transfer that phosphorylated bicarbonate 439 00:28:03,840 --> 00:28:08,250 onto biotin, we'll release the PI, then the CO2 from biotin 440 00:28:08,250 --> 00:28:12,270 can be added to carboxylate. 441 00:28:12,270 --> 00:28:14,580 That molecule, just like we've saw before 442 00:28:14,580 --> 00:28:17,580 with other carboxylation reactions, 443 00:28:17,580 --> 00:28:25,820 and that will generate this intermediate. 444 00:28:42,070 --> 00:28:43,900 This intermediate here. 445 00:28:43,900 --> 00:28:44,410 OK. 446 00:28:44,410 --> 00:28:45,620 So no new chemistry. 447 00:28:45,620 --> 00:28:48,640 You've seen all this many times before. 448 00:28:48,640 --> 00:28:50,290 Now we're going to continue with-- 449 00:28:50,290 --> 00:28:53,920 what we would do is if we were breaking this down-- 450 00:28:53,920 --> 00:28:56,300 oxidizing it as a fatty acid. 451 00:28:56,300 --> 00:29:01,150 And so now we're going to add water across that double bond. 452 00:29:21,550 --> 00:29:22,050 OK. 453 00:29:22,050 --> 00:29:25,490 Now we added water across that double bond. 454 00:29:25,490 --> 00:29:36,220 And then now we're just going to do this reaction, which 455 00:29:36,220 --> 00:29:48,300 will generate from this side of the molecule an acetyl-CoA. 456 00:29:51,750 --> 00:29:55,980 And if you look on the other side of the molecule, what we 457 00:29:55,980 --> 00:30:09,490 are left with is acetoacetate. 458 00:30:23,270 --> 00:30:34,130 Acetoacetate can be broken down into two acetyl-CoAs. 459 00:30:34,130 --> 00:30:38,150 If I break it in half, add CoA to each one of them 460 00:30:38,150 --> 00:30:41,840 by reactions I showed you before as well, or, of course, 461 00:30:41,840 --> 00:30:46,520 we can reduce this ketone to the alcohol 462 00:30:46,520 --> 00:30:52,610 and make the ketone body beta-hydroxy butyrate. 463 00:30:52,610 --> 00:30:56,260 You can look that up from the end of the last lecture. 464 00:30:56,260 --> 00:31:00,040 But in the end, this is how one can break down 465 00:31:00,040 --> 00:31:01,930 the leucine skeleton. 466 00:31:01,930 --> 00:31:04,450 You get a acetyl-CoA or acetoacetate. 467 00:31:04,450 --> 00:31:07,690 Can't generate glucose from any of those molecules as humans 468 00:31:07,690 --> 00:31:09,520 because we don't have a glyoxylate cycle. 469 00:31:09,520 --> 00:31:13,990 Therefore, leucine is a ketogenic amino acid. 470 00:31:13,990 --> 00:31:15,590 All right. 471 00:31:15,590 --> 00:31:16,550 Valine. 472 00:31:16,550 --> 00:31:17,510 Let's look at valine. 473 00:31:23,490 --> 00:31:29,040 So valine is glucogenic despite the fact 474 00:31:29,040 --> 00:31:31,770 that it's very similar to leucine 475 00:31:31,770 --> 00:31:35,310 and broken down in a way that's very similar to leucine. 476 00:31:35,310 --> 00:31:37,030 So, how do we break it down? 477 00:31:37,030 --> 00:31:41,190 So first step, transamination. 478 00:31:41,190 --> 00:31:43,620 Nitrogen from valine to alpha-ketoglutarate 479 00:31:43,620 --> 00:31:48,180 to generate glutamate, and as well as the branched 480 00:31:48,180 --> 00:31:52,845 chain alpha-keto acid that's related to valine. 481 00:32:04,110 --> 00:32:06,900 So that's the alpha-keto acid related to valine. 482 00:32:06,900 --> 00:32:10,260 One carbon shorter than side chain, one 483 00:32:10,260 --> 00:32:14,050 carbon shorter than leucine. 484 00:32:14,050 --> 00:32:19,940 Just like we did with leucine, we're 485 00:32:19,940 --> 00:32:23,780 going to metabolize the alpha-keto acid 486 00:32:23,780 --> 00:32:26,870 with the branched chain keto acid dehydrogenase. 487 00:32:26,870 --> 00:32:28,730 Same reaction. 488 00:32:28,730 --> 00:32:31,640 Oxidative decarboxylation here. 489 00:32:31,640 --> 00:32:37,280 That releases CO2, adds CoA. 490 00:32:37,280 --> 00:32:42,740 Reaction involves also NAD+ to NADH. 491 00:32:42,740 --> 00:32:48,230 Requires lipoic acid, TPP+, FAD, just like we described before. 492 00:32:48,230 --> 00:32:51,990 I'm not going to draw out all the pieces of it again, 493 00:32:51,990 --> 00:33:06,830 but we're going to end up with the branched chain acyl-CoA. 494 00:33:06,830 --> 00:33:09,500 Metabolize this branched chain acyl-CoA 495 00:33:09,500 --> 00:33:11,490 as if it's a fatty acid. 496 00:33:11,490 --> 00:33:16,700 And so first step, oxidize this carbon-carbon bond. 497 00:33:16,700 --> 00:33:20,700 That electrons go to FAD, make FADH2. 498 00:33:33,860 --> 00:33:41,335 This product, add water across that double bond. 499 00:34:00,250 --> 00:34:03,940 Water across that double bond. 500 00:34:03,940 --> 00:34:10,300 Next, if we oxidize this alcohol twice-- 501 00:34:10,300 --> 00:34:13,239 so oxidize it once, we'll get the aldehyde. 502 00:34:13,239 --> 00:34:16,659 Oxidize it again, we can get the carboxylic acid. 503 00:34:19,730 --> 00:34:31,989 And so oxidizing twice means NAD+ times 2 and NADH times 2. 504 00:34:31,989 --> 00:34:34,795 And now that becomes the acid. 505 00:34:52,389 --> 00:34:53,639 OK. 506 00:34:53,639 --> 00:34:58,480 So same molecule, but now this alcohol becomes an acid. 507 00:34:58,480 --> 00:35:01,900 I drew it that way on purpose. 508 00:35:01,900 --> 00:35:03,570 If you look back in your notes, this 509 00:35:03,570 --> 00:35:13,930 is methyl methylmalonyl-CoA, which 510 00:35:13,930 --> 00:35:21,220 we saw before in our discussion of odd chain fatty acid 511 00:35:21,220 --> 00:35:23,560 metabolism. 512 00:35:23,560 --> 00:35:30,950 And you'll remember that there was this B12-dependent reaction 513 00:35:30,950 --> 00:35:37,220 where I can basically swap the positions of this proton 514 00:35:37,220 --> 00:35:41,880 and this thioester group here. 515 00:35:41,880 --> 00:35:43,250 This is not aero-pushing. 516 00:35:43,250 --> 00:35:48,890 This B12-dependent reaction that I described 517 00:35:48,890 --> 00:35:55,460 before where I can rearrange methylmalonyl-CoA 518 00:35:55,460 --> 00:36:13,897 to make this molecule, which is succinyl-CoA. 519 00:36:16,700 --> 00:36:21,320 Succinyl-CoA oxidized in the TCA cycle, generate ATP, 520 00:36:21,320 --> 00:36:24,770 but also can use it as a substrate anaplerosis 521 00:36:24,770 --> 00:36:27,810 for the TCA cycle, so it can be used to generate glucose. 522 00:36:27,810 --> 00:36:33,020 And so that's why valine is a glucogenic amino acid. 523 00:36:33,020 --> 00:36:34,550 All right. 524 00:36:34,550 --> 00:36:41,930 Last branched chain amino acid is isoleucine. 525 00:36:41,930 --> 00:36:48,684 So isoleucine is both ketogenic and glucogenic. 526 00:36:53,980 --> 00:36:56,960 So let's see how that happens. 527 00:36:56,960 --> 00:36:59,260 So if we start with isoleucine, first we 528 00:36:59,260 --> 00:37:01,420 undergo transformation. 529 00:37:01,420 --> 00:37:03,550 alpha-ketoglutarate to glutamate, 530 00:37:03,550 --> 00:37:19,670 and you get the branched chain alpha-keto acid. 531 00:37:19,670 --> 00:37:24,620 So that's isoleucine as an alpha-keto acid rather than 532 00:37:24,620 --> 00:37:26,480 an amino acid. 533 00:37:26,480 --> 00:37:31,530 Next step, do the alpha decarboxylation 534 00:37:31,530 --> 00:37:36,610 with branched keto acid dehydrogenase. 535 00:37:36,610 --> 00:37:42,760 That removes that CO2, oxidizes that carbon to the acid, 536 00:37:42,760 --> 00:37:57,680 and we end up with this branched chain acyl-CoA. 537 00:37:57,680 --> 00:38:00,140 Same first steps as we saw before. 538 00:38:00,140 --> 00:38:03,425 Metabolize that as if it's a fatty acid. 539 00:38:07,850 --> 00:38:10,400 So oxidize that carbon-carbon bond. 540 00:38:21,410 --> 00:38:25,325 Add water across the double bond. 541 00:38:44,410 --> 00:38:45,070 OK. 542 00:38:45,070 --> 00:38:47,500 Get this intermediate. 543 00:38:47,500 --> 00:38:54,690 Now oxidize this alcohol to the ketone. 544 00:38:54,690 --> 00:39:00,660 Electrons go to an NAD+, which is reduced to NADH. 545 00:39:18,470 --> 00:39:36,450 Now we can use CoA to take off this end of the molecule here, 546 00:39:36,450 --> 00:39:47,140 which is acetyl-CoA, hence ketogenic. 547 00:39:47,140 --> 00:40:04,330 The remainder of the molecule is this three-carbon acyl-CoA. 548 00:40:04,330 --> 00:40:07,040 We saw this from odd chain fatty acid metabolism. 549 00:40:07,040 --> 00:40:09,370 This is propionyl-CoA. 550 00:40:12,430 --> 00:40:19,420 Remember, to deal with that, we can add CO2. 551 00:40:19,420 --> 00:40:26,645 So that, of course, requires biotin, and ATP. 552 00:40:26,645 --> 00:40:30,460 So remember, we had CO2 to this molecule. 553 00:40:30,460 --> 00:40:32,100 That gives us methyl-- 554 00:40:32,100 --> 00:40:34,600 not going to draw it all out for the sake of time, 555 00:40:34,600 --> 00:40:36,520 but that gives us methylmalonyl-CoA. 556 00:40:39,940 --> 00:40:42,370 Methylmalonyl-CoA shown up there, 557 00:40:42,370 --> 00:40:45,910 so it's adding CO2 to this molecule. 558 00:40:45,910 --> 00:40:53,460 And then we can do the vitamin B12 rearrangement 559 00:40:53,460 --> 00:40:57,900 to get succinyl-CoA. 560 00:40:57,900 --> 00:41:00,570 And so that can be turned into glucose. 561 00:41:00,570 --> 00:41:03,720 And so it generates an acetyl-CoA and a succinyl-CoA, 562 00:41:03,720 --> 00:41:08,830 isoleucine is both glucogenic and ketogenic. 563 00:41:08,830 --> 00:41:15,390 And so a little tedious to go through how you break down all 564 00:41:15,390 --> 00:41:17,640 three of those branched chain amino acids, 565 00:41:17,640 --> 00:41:19,830 but it really illustrates that it's just 566 00:41:19,830 --> 00:41:22,560 variations on the same chemistry that we've 567 00:41:22,560 --> 00:41:26,610 seen before with fatty acid metabolism, TCA cycle 568 00:41:26,610 --> 00:41:31,230 reactions, that ultimately generate intermediates that 569 00:41:31,230 --> 00:41:35,880 can be fed into the TCA cycle, oxidized further to CO2, 570 00:41:35,880 --> 00:41:41,040 generate ATP, generate NADH, electron transport chain, 571 00:41:41,040 --> 00:41:44,880 oxidative phosphorylation, supply the cell with energy 572 00:41:44,880 --> 00:41:46,740 to do various kinds of work. 573 00:41:46,740 --> 00:41:50,730 Or can be turned into a ketone if you're a human 574 00:41:50,730 --> 00:41:52,000 and you start with acetyl-- 575 00:41:52,000 --> 00:41:54,720 and what you get is acetyl-CoA or acetoacetate. 576 00:41:54,720 --> 00:41:56,790 Or even into glucose if you start 577 00:41:56,790 --> 00:42:00,120 with something like succinyl-CoA that 578 00:42:00,120 --> 00:42:03,060 can be turned back into glucose by the liver, 579 00:42:03,060 --> 00:42:05,130 defining the difference between the glucogenic 580 00:42:05,130 --> 00:42:08,450 and the ketogenic amino acids. 581 00:42:08,450 --> 00:42:09,740 All right. 582 00:42:09,740 --> 00:42:15,290 Now going through branched chain amino acid metabolism 583 00:42:15,290 --> 00:42:19,940 also allows transition into a discussion 584 00:42:19,940 --> 00:42:32,620 of another topic which are the so-called inborn 585 00:42:32,620 --> 00:42:36,430 errors of metabolism. 586 00:42:39,900 --> 00:42:43,860 So what's an inborn error of metabolism? 587 00:42:43,860 --> 00:42:48,450 Well, sometimes individuals are born 588 00:42:48,450 --> 00:42:51,750 that have deficiencies in enzymes 589 00:42:51,750 --> 00:42:56,560 that are necessary to carry out some function of metabolism. 590 00:42:56,560 --> 00:43:01,500 Some aspect of the biochemistry we've been learning about. 591 00:43:01,500 --> 00:43:05,490 Now you can imagine that some of these genetic deficiencies, 592 00:43:05,490 --> 00:43:09,570 if it's somewhere smack in the middle of central carbon 593 00:43:09,570 --> 00:43:11,580 metabolism and you can't generate energy, 594 00:43:11,580 --> 00:43:13,950 it's not going to be compatible with life. 595 00:43:13,950 --> 00:43:15,540 But it turns out that some of them 596 00:43:15,540 --> 00:43:19,740 are quite compatible with life, like deficiency 597 00:43:19,740 --> 00:43:23,250 in branched chain keto acid dehydrogenase. 598 00:43:23,250 --> 00:43:34,950 So BCKDH deficiency is something that children are sometimes 599 00:43:34,950 --> 00:43:40,470 born with, and this deficiency results in a disorder 600 00:43:40,470 --> 00:43:44,310 called maple syrup urine disease. 601 00:43:47,920 --> 00:43:50,100 So it's called maple syrup urine disease 602 00:43:50,100 --> 00:43:53,940 because the unit smells like maple syrup, 603 00:43:53,940 --> 00:43:57,870 but effectively what this is is this is a disorder where 604 00:43:57,870 --> 00:44:00,210 there's a deficiency in the activity of branched 605 00:44:00,210 --> 00:44:02,490 chain keto acid dehydrogenase. 606 00:44:02,490 --> 00:44:06,120 That means the cells can't break down 607 00:44:06,120 --> 00:44:07,980 branched chain amino acids. 608 00:44:07,980 --> 00:44:13,320 They end up generating some otherwise side toxic product. 609 00:44:13,320 --> 00:44:16,860 Some of it ends up in the urine, smells like maple syrup. 610 00:44:16,860 --> 00:44:20,850 But it also can result in damage to the CNS 611 00:44:20,850 --> 00:44:28,990 and problems with thinking, mental retardation, et cetera. 612 00:44:28,990 --> 00:44:32,880 And so it can be quite devastating to have 613 00:44:32,880 --> 00:44:36,090 loss of this enzyme, which prevents you from breaking down 614 00:44:36,090 --> 00:44:40,050 branched chain amino acids, a so-called inborn error 615 00:44:40,050 --> 00:44:42,220 of metabolism. 616 00:44:42,220 --> 00:44:45,210 Now this is a relatively rare disease. 617 00:44:45,210 --> 00:44:46,590 All of these are. 618 00:44:46,590 --> 00:44:49,590 But if you go to medical school, these 619 00:44:49,590 --> 00:44:51,960 are questions because they lend themselves 620 00:44:51,960 --> 00:44:57,690 to questions that often show up on various board-type exams. 621 00:44:57,690 --> 00:45:00,750 And so it's good to know that deficiencies 622 00:45:00,750 --> 00:45:05,830 of some of these enzymes can result in diseases. 623 00:45:05,830 --> 00:45:09,240 So maple syrup urine disease caused by an inability 624 00:45:09,240 --> 00:45:11,760 to break down branched chain amino acids because you're 625 00:45:11,760 --> 00:45:14,850 deficient in the enzyme branched chain amino acid-- 626 00:45:14,850 --> 00:45:17,730 or branched keto acid dehydrogenase, 627 00:45:17,730 --> 00:45:19,950 which catalyzes the stuff I showed you up there 628 00:45:19,950 --> 00:45:24,750 in the breakdown of all three branched chain amino acids. 629 00:45:24,750 --> 00:45:26,610 By no means is this the only one. 630 00:45:26,610 --> 00:45:31,560 Often these are associated with amino acid breakdown. 631 00:45:31,560 --> 00:45:34,180 And so two of the other more common-- 632 00:45:34,180 --> 00:45:38,070 all of these are very rare, but relatively more common ones 633 00:45:38,070 --> 00:45:40,320 is a disease called alkaptonuria. 634 00:45:45,240 --> 00:45:46,950 So what's alkaptonuria? 635 00:45:46,950 --> 00:45:48,630 Well, that's missing an enzyme-- 636 00:45:52,430 --> 00:46:01,150 so enzyme deficiency in tryptophan metabolism. 637 00:46:05,820 --> 00:46:14,780 And another one is fennel phenylketonuria, 638 00:46:14,780 --> 00:46:25,570 which is an enzyme deficiency in phenylalanine metabolism. 639 00:46:28,710 --> 00:46:33,810 Branched chain amino acids are very common, but tryptophan, 640 00:46:33,810 --> 00:46:36,820 phenylalanine, two of the more rare amino acids, 641 00:46:36,820 --> 00:46:40,350 it turns out these are two of the amino acid breakdown 642 00:46:40,350 --> 00:46:45,030 deficiencies that have less severe phenotypes, 643 00:46:45,030 --> 00:46:49,080 and so they're somewhat-- 644 00:46:49,080 --> 00:46:54,250 more people walking around with those conditions. 645 00:46:54,250 --> 00:46:56,890 If any of you have had children or someday 646 00:46:56,890 --> 00:46:59,500 when you have children, what will happen 647 00:46:59,500 --> 00:47:02,350 is that you will notice that when babies are born, 648 00:47:02,350 --> 00:47:04,810 one of the first things that's done with infants 649 00:47:04,810 --> 00:47:07,000 is they have a blood test sent out. 650 00:47:07,000 --> 00:47:09,640 They do a little heel stick, collect some blood, 651 00:47:09,640 --> 00:47:11,620 and send it to the state lab where 652 00:47:11,620 --> 00:47:15,130 they test for various inborn errors of metabolism. 653 00:47:15,130 --> 00:47:19,120 What they're looking for is things like phenylketonuria, 654 00:47:19,120 --> 00:47:21,677 maple syrup urine disease, et cetera. 655 00:47:21,677 --> 00:47:23,260 Why do they want to find these things? 656 00:47:23,260 --> 00:47:27,820 Well, it's because if you have too much of the product, 657 00:47:27,820 --> 00:47:30,760 too much phenylalanine, too much tryptophan, too much branched 658 00:47:30,760 --> 00:47:33,250 chain amino acid, and you can't break them down, 659 00:47:33,250 --> 00:47:35,920 it's not the lack of the ability to break them down 660 00:47:35,920 --> 00:47:38,030 that's necessarily the problem. 661 00:47:38,030 --> 00:47:40,540 The problem is is that the inability to break them down 662 00:47:40,540 --> 00:47:42,910 leads to overwhelming a system building up 663 00:47:42,910 --> 00:47:45,790 of toxic intermediates that damage the brain. 664 00:47:45,790 --> 00:47:48,910 And so by doing these newborn screening panels, 665 00:47:48,910 --> 00:47:51,460 it's greatly enhanced the management of these things, 666 00:47:51,460 --> 00:47:54,310 because often you can control the symptoms 667 00:47:54,310 --> 00:47:55,810 by dietary intervention. 668 00:47:55,810 --> 00:47:58,300 Simply limiting the phenylalanine 669 00:47:58,300 --> 00:48:01,900 or the branched chain amino acid or the tryptophan intake 670 00:48:01,900 --> 00:48:05,510 in the diet is a treatment for these diseases, 671 00:48:05,510 --> 00:48:08,980 and so therefore, if you know about them early, 672 00:48:08,980 --> 00:48:11,200 limiting exposure to those things 673 00:48:11,200 --> 00:48:16,210 limits the exposure to the toxic breakdown products that 674 00:48:16,210 --> 00:48:20,560 can't be metabolized because of the deficiency, and therefore, 675 00:48:20,560 --> 00:48:24,730 limits the effects on the brain. 676 00:48:24,730 --> 00:48:29,440 If you drink diet soda and you look at the side of your diet 677 00:48:29,440 --> 00:48:34,270 soda can, what's written on the side of it is phenylketonurics, 678 00:48:34,270 --> 00:48:36,310 contains phenylalanine. 679 00:48:36,310 --> 00:48:37,660 Why is that written there? 680 00:48:37,660 --> 00:48:40,840 Well, because if you happen to be a phenylketonuric, 681 00:48:40,840 --> 00:48:44,410 you shouldn't drink diet soda. 682 00:48:44,410 --> 00:48:44,950 Why? 683 00:48:44,950 --> 00:48:47,290 Because the artificial sweetener in there contains 684 00:48:47,290 --> 00:48:49,630 phenylalanine, and so this would give you 685 00:48:49,630 --> 00:48:52,300 a big dose of phenylalanine, and if you can't break down 686 00:48:52,300 --> 00:48:53,990 phenylalanine, that's a problem. 687 00:48:53,990 --> 00:48:57,460 So it's a warning to the people in the population who 688 00:48:57,460 --> 00:49:01,420 happen to have phenylketonuria not to drink diet soda. 689 00:49:05,150 --> 00:49:06,650 All right. 690 00:49:06,650 --> 00:49:09,350 Now, I want to say a few other things 691 00:49:09,350 --> 00:49:15,740 about amino acid metabolism, only because these things will 692 00:49:15,740 --> 00:49:21,380 come up for you as you go through other aspects 693 00:49:21,380 --> 00:49:22,415 of biology. 694 00:49:28,040 --> 00:49:34,720 And that is that amino acids are very versatile starting points 695 00:49:34,720 --> 00:49:38,440 to build all kinds of hormones and neurotransmitters 696 00:49:38,440 --> 00:49:40,540 and bioactive molecules. 697 00:49:40,540 --> 00:49:42,610 So I know some people-- 698 00:49:42,610 --> 00:49:45,950 some of the MIT students in the class are course 9. 699 00:49:45,950 --> 00:49:51,880 That's the brain and cognitive science. 700 00:49:51,880 --> 00:49:53,530 Classes you take, you'll learn a lot 701 00:49:53,530 --> 00:49:55,030 about different neurotransmitters. 702 00:49:55,030 --> 00:49:57,820 Well, one of the canonical neurotransmitters 703 00:49:57,820 --> 00:49:59,260 is an amino acid itself. 704 00:49:59,260 --> 00:50:02,020 It's the amino acid glutamate. 705 00:50:02,020 --> 00:50:04,782 So obviously that's important for the brain to work. 706 00:50:04,782 --> 00:50:06,490 But what are the other neurotransmitters? 707 00:50:06,490 --> 00:50:10,860 Well, there's things like dopamine, 708 00:50:10,860 --> 00:50:17,125 epinephrine, norepinephrine. 709 00:50:22,590 --> 00:50:25,800 These are all bioactive molecules, 710 00:50:25,800 --> 00:50:27,510 have to come from somewhere. 711 00:50:27,510 --> 00:50:30,570 Well, it turns out all of these ultimately come 712 00:50:30,570 --> 00:50:35,610 from the metabolism of tyrosine, which, of course, can also 713 00:50:35,610 --> 00:50:39,120 come from the metabolism of phenylalanine. 714 00:50:39,120 --> 00:50:41,250 And so don't have time to go into it, 715 00:50:41,250 --> 00:50:43,620 but you can look up the pathways to generate 716 00:50:43,620 --> 00:50:47,560 these various neurotransmitters from tyrosine 717 00:50:47,560 --> 00:50:50,370 if you're interested. 718 00:50:50,370 --> 00:50:52,500 What's the other big neurotransmitter? 719 00:50:52,500 --> 00:50:54,390 Well, it's acetylcholine. 720 00:50:58,560 --> 00:50:59,850 What's acetylcholine? 721 00:50:59,850 --> 00:51:01,240 Well, let's break it down. 722 00:51:01,240 --> 00:51:07,490 Well, it's an acetyl group, so that comes from acetyl-CoA. 723 00:51:07,490 --> 00:51:11,030 And choline-- and what's choline? 724 00:51:11,030 --> 00:51:16,310 Well, choline comes from, ultimately as I showed you-- 725 00:51:16,310 --> 00:51:21,770 alluded to before, ethanolamine, and ethanolamine 726 00:51:21,770 --> 00:51:24,050 comes from serine. 727 00:51:24,050 --> 00:51:25,910 We'll come back to this later. 728 00:51:25,910 --> 00:51:29,195 And so serine metabolism, as well acetyl-CoA, 729 00:51:29,195 --> 00:51:31,820 is how you get acetylcholine. 730 00:51:31,820 --> 00:51:36,290 It's also choline the phospholipids and ethanolamine 731 00:51:36,290 --> 00:51:39,250 for the phospholipids. 732 00:51:39,250 --> 00:51:42,400 If you're not into the brain but into other aspects 733 00:51:42,400 --> 00:51:46,270 pathophysiology-- so thyroid hormone, 734 00:51:46,270 --> 00:51:48,280 very common thing that many people 735 00:51:48,280 --> 00:51:51,400 need replacement of, very important to manage physiology 736 00:51:51,400 --> 00:51:52,360 in our body. 737 00:51:52,360 --> 00:51:59,360 Thyroid hormone also comes from thyroxine. 738 00:51:59,360 --> 00:52:09,230 Melanin, the pigment that makes our skin different shades, 739 00:52:09,230 --> 00:52:15,070 melanin, the skin pigment, it is basically 740 00:52:15,070 --> 00:52:17,950 produced from dopamine-- 741 00:52:17,950 --> 00:52:20,920 or actually, a dopamine metabolite. 742 00:52:20,920 --> 00:52:24,430 So dopamine precursor. 743 00:52:24,430 --> 00:52:29,210 Which comes from tyrosine as well. 744 00:52:29,210 --> 00:52:31,480 And so if you're interested in any 745 00:52:31,480 --> 00:52:33,190 of these particular molecules, of course, 746 00:52:33,190 --> 00:52:36,190 you can look up in the book and you'll see how they're made, 747 00:52:36,190 --> 00:52:38,740 and I promise, you have the ability to understand it, 748 00:52:38,740 --> 00:52:42,820 it's repurposing some reactions that we've already seen. 749 00:52:42,820 --> 00:52:44,650 There's some unique ones in there 750 00:52:44,650 --> 00:52:46,810 like melanin synthesis is actually parts 751 00:52:46,810 --> 00:52:49,150 of it are non-enzymatic, even. 752 00:52:49,150 --> 00:52:53,780 But this-- I like to mention this because obviously we 753 00:52:53,780 --> 00:52:56,300 don't have time to study and discuss 754 00:52:56,300 --> 00:52:59,390 the entire complexity of the metabolic map, 755 00:52:59,390 --> 00:53:03,770 but really, you understand the basics, the central parts 756 00:53:03,770 --> 00:53:07,280 of it, and it's the same reactions repurposed out 757 00:53:07,280 --> 00:53:09,410 in different directions that allows 758 00:53:09,410 --> 00:53:11,930 this complexity and this diversity of metabolism, 759 00:53:11,930 --> 00:53:15,140 making all of these different biomolecules that 760 00:53:15,140 --> 00:53:18,020 are necessary for the cells to do things, and, of course, 761 00:53:18,020 --> 00:53:21,500 you can go look these up if you're interested in any 762 00:53:21,500 --> 00:53:23,510 of them specifically. 763 00:53:23,510 --> 00:53:26,000 And regardless, you should have some appreciation 764 00:53:26,000 --> 00:53:28,520 of how these things all interconnect 765 00:53:28,520 --> 00:53:32,500 with the other pathways that we've talked about. 766 00:53:32,500 --> 00:53:33,100 All right. 767 00:53:38,480 --> 00:53:39,890 All right. 768 00:53:39,890 --> 00:53:44,690 So now I want to turn to amino acid synthesis 769 00:53:44,690 --> 00:53:50,060 and say a few words about how amino acids are built. 770 00:53:50,060 --> 00:53:54,450 So of course, we've covered some of these already, 771 00:53:54,450 --> 00:53:57,500 and as a very general statement, many of them 772 00:53:57,500 --> 00:53:59,300 are made by transamination. 773 00:53:59,300 --> 00:54:02,330 So first you build the alpha-keto acid, 774 00:54:02,330 --> 00:54:07,490 and then you transaminate that alpha-keto acid from glutamate 775 00:54:07,490 --> 00:54:11,280 to generate the amino acid. 776 00:54:11,280 --> 00:54:16,220 Now of course, the pathways that you use to make amino acids 777 00:54:16,220 --> 00:54:17,990 are not the same as the pathways that you 778 00:54:17,990 --> 00:54:20,700 use to break down amino acids. 779 00:54:20,700 --> 00:54:23,850 So again, if you paid attention for the entire course, 780 00:54:23,850 --> 00:54:28,280 it should be clear for both thermodynamic energetic reasons 781 00:54:28,280 --> 00:54:31,310 that you can't have the same pathways to build and break 782 00:54:31,310 --> 00:54:36,500 stuff down because all pathways delta G has to be less than 0. 783 00:54:36,500 --> 00:54:38,990 So we saw this with glucose and fatty acids. 784 00:54:38,990 --> 00:54:41,760 We can repurpose-- some steps can be the same, 785 00:54:41,760 --> 00:54:46,070 but the ones that allow the energetic driving have 786 00:54:46,070 --> 00:54:49,790 to be different because you have to couple one direction 787 00:54:49,790 --> 00:54:52,490 to energy consumption and the other one 788 00:54:52,490 --> 00:54:54,733 could be spontaneous if it releases energy, 789 00:54:54,733 --> 00:54:56,150 and you have to have pathways that 790 00:54:56,150 --> 00:54:59,310 can work in either direction. 791 00:54:59,310 --> 00:55:03,950 But, in general, if you can build an alpha-keto acid 792 00:55:03,950 --> 00:55:08,180 like oxaloacetic acid or alpha-ketoglutarate 793 00:55:08,180 --> 00:55:11,990 or pyruvate, well, obviously we can 794 00:55:11,990 --> 00:55:16,082 transaminate all of these things to get the amino acid. 795 00:55:16,082 --> 00:55:17,540 So alpha-ketoglutarate to glutamate 796 00:55:17,540 --> 00:55:19,670 can also be from glutamate dehydrogenase. 797 00:55:19,670 --> 00:55:22,010 That's how you can get new nitrogen into the system. 798 00:55:22,010 --> 00:55:23,720 And that way we can generate aspartame 799 00:55:23,720 --> 00:55:29,870 glutamate and alanine, and aspertate into asparagine, 800 00:55:29,870 --> 00:55:33,470 asparagine by adding the ammonia to it. 801 00:55:33,470 --> 00:55:35,210 That would be a very similar reaction 802 00:55:35,210 --> 00:55:37,550 to glutamate into glutamine. 803 00:55:37,550 --> 00:55:40,550 That's glutamate synthase, asparagine synthase. 804 00:55:40,550 --> 00:55:43,520 Same mechanism describe glutamate synthase last time 805 00:55:43,520 --> 00:55:44,930 to make glutamine. 806 00:55:44,930 --> 00:55:48,560 And of course, proline, as I showed you earlier, 807 00:55:48,560 --> 00:55:53,870 is cyclized, and in this case, oxidized-- 808 00:55:53,870 --> 00:55:58,220 or sorry, cyclized then reduced glutamate. 809 00:55:58,220 --> 00:56:02,920 And then-- so that's six of the amino acids. 810 00:56:02,920 --> 00:56:07,150 We covered arginine earlier, that seven. 811 00:56:07,150 --> 00:56:11,680 And so 13 other amino acids. 812 00:56:11,680 --> 00:56:14,350 Here's another figure from a book just showing 813 00:56:14,350 --> 00:56:20,590 the starting material to make all of the various amino acids. 814 00:56:20,590 --> 00:56:23,120 Obviously we know how to make oxaloacetate, 815 00:56:23,120 --> 00:56:26,530 phosphoenolpyruvate, erythrose 4-phosphate, pyruvate, 816 00:56:26,530 --> 00:56:28,750 ribose 5-phosphate, 3-phosphoglycerate, 817 00:56:28,750 --> 00:56:30,280 and alpha-ketoglutarate. 818 00:56:30,280 --> 00:56:33,190 And so generation of those by the pathways 819 00:56:33,190 --> 00:56:36,340 we've already talked about then allows those molecules 820 00:56:36,340 --> 00:56:38,830 to be shunted into pathways to generate 821 00:56:38,830 --> 00:56:42,590 all of the various amino acids. 822 00:56:42,590 --> 00:56:45,580 Now I want to reiterate, humans, we 823 00:56:45,580 --> 00:56:48,100 can't make all 20 amino acids. 824 00:56:48,100 --> 00:56:49,090 Animals can't do that. 825 00:56:49,090 --> 00:56:51,160 Many organisms, of course, can. 826 00:56:51,160 --> 00:56:55,030 We lost the ability to make nine of our amino acids, 827 00:56:55,030 --> 00:56:58,720 and in fact, if you count the two conditional ones, really 828 00:56:58,720 --> 00:57:02,110 11 of amino acids, even though we can turn phenylalanine 829 00:57:02,110 --> 00:57:05,320 into tyrosine, we still need a source of phenylalanine 830 00:57:05,320 --> 00:57:06,530 to do so. 831 00:57:06,530 --> 00:57:10,510 And so each of these nine or 11, depending on how you count it, 832 00:57:10,510 --> 00:57:14,628 essential amino acids must be eaten in the diet. 833 00:57:14,628 --> 00:57:16,420 So there are obviously pathways to do them, 834 00:57:16,420 --> 00:57:20,890 we just don't have the enzymes in humans to do it. 835 00:57:20,890 --> 00:57:24,370 And then the other ones we do retain. 836 00:57:24,370 --> 00:57:26,620 You can obviously look up the pathway 837 00:57:26,620 --> 00:57:28,960 that's used by whatever organism to make 838 00:57:28,960 --> 00:57:31,690 your favorite amino acid. 839 00:57:31,690 --> 00:57:36,655 Today what I want to discuss is how we will make-- 840 00:57:39,740 --> 00:57:46,100 today I want to discuss how we will make serine and glycine, 841 00:57:46,100 --> 00:57:49,730 because it turns out, serine and s metabolism 842 00:57:49,730 --> 00:57:53,490 play a key role in other pathways, 843 00:57:53,490 --> 00:57:55,700 including nucleotide synthesis which we 844 00:57:55,700 --> 00:57:59,630 will cover in the next lecture. 845 00:57:59,630 --> 00:58:02,150 Serine glycine metabolism also is a way 846 00:58:02,150 --> 00:58:06,920 to make one carbon units that are more reduced than CO2. 847 00:58:06,920 --> 00:58:11,180 And these will be critical for one-carbon transfer reactions 848 00:58:11,180 --> 00:58:17,230 that you'll encounter throughout other aspects of biology. 849 00:58:17,230 --> 00:58:23,860 So, serine and glycine, very important amino acids. 850 00:58:23,860 --> 00:58:26,010 And so just to be clear about this, 851 00:58:26,010 --> 00:58:30,420 so it turns out serine-glycine metabolism, 852 00:58:30,420 --> 00:58:32,470 important for nucleotides among carbon units, 853 00:58:32,470 --> 00:58:33,770 we'll see that a lot. 854 00:58:33,770 --> 00:58:38,270 But serine and glycine also used to make phospholipid head 855 00:58:38,270 --> 00:58:38,770 groups. 856 00:58:56,100 --> 00:58:58,530 Nucleotides, one-carbon units we're going to talk about. 857 00:58:58,530 --> 00:59:00,240 I want you to appreciate, you also 858 00:59:00,240 --> 00:59:03,580 need serine to make phospholipid head groups. 859 00:59:03,580 --> 00:59:04,750 So what do I mean by that? 860 00:59:04,750 --> 00:59:06,960 Well, of course, there's phosphatidylserine. 861 00:59:10,710 --> 00:59:15,840 Obviously that's serine is the head group, and so serine-- 862 00:59:15,840 --> 00:59:17,970 the amino acid is required for that. 863 00:59:17,970 --> 00:59:22,220 But also used to generate ethanolamine. 864 00:59:25,800 --> 00:59:28,740 So what is ethanolamine? 865 00:59:28,740 --> 00:59:40,420 Well again, just to remind you of this, 866 00:59:40,420 --> 00:59:44,620 so here is the amino acid serine. 867 00:59:44,620 --> 00:59:48,160 So, to generate ethanolamine, it's 868 00:59:48,160 --> 00:59:53,260 decarbonization of serine to do that. 869 00:59:53,260 --> 00:59:56,810 So loss of this CO2. 870 00:59:56,810 --> 00:59:58,810 This is a reaction I don't have time to go into, 871 00:59:58,810 --> 00:59:59,602 you can look it up. 872 00:59:59,602 --> 01:00:03,310 It is another repurposing of pyridoxal phosphate. 873 01:00:03,310 --> 01:00:09,110 And that generates this molecule, 874 01:00:09,110 --> 01:00:11,670 which is ethanolamine. 875 01:00:11,670 --> 01:00:17,760 That ends up head group on phosphatidylethanolamine. 876 01:00:17,760 --> 01:00:21,030 And if I want to turn it into choline, 877 01:00:21,030 --> 01:00:24,540 either for acetylcholine as a neurotransmitter 878 01:00:24,540 --> 01:00:27,540 or for phosphatidylcholine as a head group, 879 01:00:27,540 --> 01:00:35,310 it's basically adding 3 methyl groups 880 01:00:35,310 --> 01:00:39,810 onto this nitrogen of ethanolamine. 881 01:00:39,810 --> 01:00:46,680 And so those three methyl groups, 882 01:00:46,680 --> 01:00:50,910 that's a carbon that's more reduced than CO2. 883 01:00:50,910 --> 01:00:52,890 That's a so-called one carbon unit. 884 01:00:52,890 --> 01:00:58,320 It turns out, as you'll see, those also come from serine. 885 01:00:58,320 --> 01:01:01,140 Last thing is serine is necessary to make 886 01:01:01,140 --> 01:01:04,500 head groups for a class of lipids called sphingolipids. 887 01:01:07,380 --> 01:01:13,680 There's a-- sphingosine is another amino alcohol that 888 01:01:13,680 --> 01:01:16,890 is generated from serine and ends up being the head 889 01:01:16,890 --> 01:01:18,930 group for sphingolipids. 890 01:01:18,930 --> 01:01:22,080 Especially if you're interested in the immune system 891 01:01:22,080 --> 01:01:24,880 of the brain, these end up being important molecules. 892 01:01:24,880 --> 01:01:26,730 And so you can look up how they're 893 01:01:26,730 --> 01:01:29,820 related to serine, but just appreciate that for now 894 01:01:29,820 --> 01:01:30,630 that they-- 895 01:01:30,630 --> 01:01:33,840 another important downstream thing that's 896 01:01:33,840 --> 01:01:36,780 generated from serine metabolism. 897 01:01:36,780 --> 01:01:40,290 Also illustrating how amino acids 898 01:01:40,290 --> 01:01:41,790 can be very important to generate 899 01:01:41,790 --> 01:01:44,560 lots of other biomolecules. 900 01:01:44,560 --> 01:01:45,490 OK. 901 01:01:45,490 --> 01:01:49,390 So, how do we make serine? 902 01:01:49,390 --> 01:01:51,910 Well, if we go over here, you'll see 903 01:01:51,910 --> 01:01:56,500 that serine is downstream of 3-phosphoglycerate 904 01:01:56,500 --> 01:01:58,490 from glycolysis. 905 01:01:58,490 --> 01:02:00,580 So what's 3-phosphoglycerate? 906 01:02:12,340 --> 01:02:17,830 OK, here's 3-phosphoglycerate from glycolysis, or the product 907 01:02:17,830 --> 01:02:20,710 of rubisco if you like. 908 01:02:20,710 --> 01:02:23,330 So photosynthesis. 909 01:02:23,330 --> 01:02:27,610 So there's 3-phosphoglycerate. 910 01:02:27,610 --> 01:02:33,220 So if I oxidize this alcohol to ketone, 911 01:02:33,220 --> 01:02:34,900 electrons have to go somewhere. 912 01:02:34,900 --> 01:02:39,577 NAD+ reduced to NADH, I get this intermediate. 913 01:02:46,410 --> 01:02:52,680 It's phosphohydroxypyruvate So pyruvate with a phospho on it, 914 01:02:52,680 --> 01:02:55,110 hydroxypyruvate. 915 01:02:55,110 --> 01:03:01,330 This molecule can undergo a transamination reaction. 916 01:03:01,330 --> 01:03:04,410 So pick up nitrogen from glutamate, 917 01:03:04,410 --> 01:03:06,180 make the alpha-keto acid. 918 01:03:06,180 --> 01:03:26,290 Take this alpha-keto acid and generate phosphoserine. 919 01:03:26,290 --> 01:03:30,040 The amino acid that's phosphorylated, phosphoserine. 920 01:03:30,040 --> 01:03:33,790 And then all I need to do is dephosphorylate it, 921 01:03:33,790 --> 01:03:37,400 and I end up with the amino acid serine. 922 01:03:37,400 --> 01:03:38,730 Cool. 923 01:03:38,730 --> 01:03:40,320 All right. 924 01:03:40,320 --> 01:03:43,020 To make glycine from serine-- 925 01:03:43,020 --> 01:03:48,030 so remember, glycine is one basically the amino acid 926 01:03:48,030 --> 01:03:49,690 with no side chain on it. 927 01:03:49,690 --> 01:03:53,970 So I need to remove this carbon and the alcohol. 928 01:03:53,970 --> 01:03:57,170 So I'll just redraw serine this way. 929 01:04:05,570 --> 01:04:08,420 So that's redrawing serine. 930 01:04:08,420 --> 01:04:12,830 Need to lose that group to get glycine. 931 01:04:12,830 --> 01:04:19,800 This is helped along by pyridoxal phosphate. 932 01:04:19,800 --> 01:04:34,290 So a reminder, this is pyridoxal phosphate. 933 01:05:56,260 --> 01:05:56,760 OK. 934 01:05:56,760 --> 01:06:00,420 So this is exactly what we drew, is the first steps 935 01:06:00,420 --> 01:06:03,300 in transamination. 936 01:06:03,300 --> 01:06:09,600 Except if instead of basically going like this, 937 01:06:09,600 --> 01:06:18,240 I do this to break this carbon-carbon bond, 938 01:06:18,240 --> 01:06:19,480 what do I get? 939 01:06:19,480 --> 01:06:24,630 Well, I release a one-carbon unit. 940 01:06:24,630 --> 01:06:28,470 In this case, it's the one-carbon unit 941 01:06:28,470 --> 01:06:30,420 as formaldehyde. 942 01:06:33,800 --> 01:06:37,190 The one-carbon aldehyde, formaldehyde. 943 01:06:37,190 --> 01:07:05,420 And generate this intermediate. 944 01:07:54,410 --> 01:08:03,340 And it's just exactly what we showed before for resolving 945 01:08:03,340 --> 01:08:05,950 the transamination. 946 01:08:18,380 --> 01:08:33,890 And I am left with glycine, as well as I regenerated pyridoxal 947 01:08:33,890 --> 01:08:39,060 phosphate for the next catalytic cycle of the enzyme. 948 01:08:39,060 --> 01:08:41,840 And so illustrates the flexibility 949 01:08:41,840 --> 01:08:43,370 of pyridoxal phosphate. 950 01:08:43,370 --> 01:08:48,380 In this case, helping convert serine into glycine 951 01:08:48,380 --> 01:08:54,140 and a one-carbon unit shown here as formaldehyde. 952 01:08:54,140 --> 01:08:58,430 Now the enzyme that carries out this reaction 953 01:08:58,430 --> 01:09:05,510 is an enzyme called SHMT, which stands 954 01:09:05,510 --> 01:09:11,277 for serine hydroxymethyltransferase. 955 01:09:23,060 --> 01:09:25,700 Serine hydroxymethyltransferase. 956 01:09:25,700 --> 01:09:31,370 And it actually doesn't release the formaldehyde directly. 957 01:09:31,370 --> 01:09:34,609 Instead, it transfers that formaldehyde 958 01:09:34,609 --> 01:09:40,460 to an important one-carbon donor for many one-carbon reactions 959 01:09:40,460 --> 01:09:44,760 that is called folate species or folic acid. 960 01:09:44,760 --> 01:09:48,590 So remember, if we transferred CO2 in a carboxylation 961 01:09:48,590 --> 01:09:51,080 reaction, we use a cofactor biotin. 962 01:09:51,080 --> 01:09:53,720 Biotin's useful to transfer CO2. 963 01:09:53,720 --> 01:09:56,720 But if we're going to do something like transfer 964 01:09:56,720 --> 01:10:00,830 the methyl groups shown up there for choline synthesis, that's 965 01:10:00,830 --> 01:10:03,650 transferring carbon that's more reduced than CO2, 966 01:10:03,650 --> 01:10:05,570 and you don't use biotin for that. 967 01:10:05,570 --> 01:10:08,990 Instead, you use a cofactor called 968 01:10:08,990 --> 01:10:14,930 folate that's derived from the vitamin folic acid. 969 01:10:14,930 --> 01:10:20,990 So folic acid, very important vitamin. 970 01:10:20,990 --> 01:10:25,760 It's the primary thing that's included in prenatal vitamins. 971 01:10:25,760 --> 01:10:26,630 Why is that? 972 01:10:26,630 --> 01:10:30,560 Because deficiency in folic acid was shown a while back 973 01:10:30,560 --> 01:10:33,240 to cause neural tube defects-- 974 01:10:33,240 --> 01:10:36,740 so developmental defects where the neural tube does not close. 975 01:10:36,740 --> 01:10:39,650 This leads to things like spina bifida. 976 01:10:39,650 --> 01:10:43,190 One of the real successes of public health intervention 977 01:10:43,190 --> 01:10:47,510 was the recognition of this and fortifying various cereals 978 01:10:47,510 --> 01:10:49,160 with folic acid. 979 01:10:49,160 --> 01:10:53,060 And doing so has greatly reduced the incidence 980 01:10:53,060 --> 01:10:57,980 of these birth defects involving folate deficiency. 981 01:10:57,980 --> 01:11:00,950 Folate deficiency's also a common cause of anemia. 982 01:11:00,950 --> 01:11:03,350 And so folic acid is a vitamin that lots of people 983 01:11:03,350 --> 01:11:05,570 take for that reason. 984 01:11:05,570 --> 01:11:09,140 And in fact, folic acid, also very important in the history 985 01:11:09,140 --> 01:11:10,402 of cancer treatment. 986 01:11:10,402 --> 01:11:12,110 And if you want to learn more about that, 987 01:11:12,110 --> 01:11:17,240 take 745, which is offered in the fall. 988 01:11:17,240 --> 01:11:18,590 All right. 989 01:11:18,590 --> 01:11:22,970 So, folic acid is a complex molecule 990 01:11:22,970 --> 01:11:31,670 that is converted in cells to a molecule called THF, which 991 01:11:31,670 --> 01:11:33,866 stands for tetrahydrofolate. 992 01:11:38,930 --> 01:11:46,040 So I'll draw out folic acid for you and tetrahydrofolate. 993 01:12:37,210 --> 01:12:38,140 OK. 994 01:12:38,140 --> 01:12:43,210 So, this here is folic acid. 995 01:12:43,210 --> 01:12:46,360 The folic acid molecule is tetrahydrofolate. 996 01:12:46,360 --> 01:12:51,100 It has a peptide bond here to a glutamate molecule, 997 01:12:51,100 --> 01:12:54,190 and it's actually a polyglutamate tail that 998 01:12:54,190 --> 01:12:56,950 is there to trap it in cells. 999 01:12:56,950 --> 01:13:08,390 It's this central part of the molecule here 1000 01:13:08,390 --> 01:13:11,540 that actually carries the one-carbon unit. 1001 01:13:11,540 --> 01:13:15,230 And so the way that the nitrogens are numbered, 1002 01:13:15,230 --> 01:13:17,100 this is nitrogen-5. 1003 01:13:17,100 --> 01:13:18,920 This is nitrogen-10. 1004 01:13:18,920 --> 01:13:20,840 That will be important in a minute. 1005 01:13:20,840 --> 01:13:26,340 But it's really this sort of central part here 1006 01:13:26,340 --> 01:13:29,820 of the molecule that I will draw over and over again 1007 01:13:29,820 --> 01:13:35,690 as the one-carbon unit-carrying species. 1008 01:13:35,690 --> 01:13:37,790 To show how this works, it's easier 1009 01:13:37,790 --> 01:13:42,380 if I start off by showing how it can pick up a more 1010 01:13:42,380 --> 01:13:44,700 oxidized one-carbon unit. 1011 01:13:44,700 --> 01:13:51,950 So the one-carbon carboxylic acid is this, that's formate. 1012 01:13:51,950 --> 01:14:03,190 And so if I phosphorylate formic acid, 1013 01:14:03,190 --> 01:14:06,985 this formic acid can then be picked up by the-- 1014 01:14:22,620 --> 01:14:27,990 so here's that carrying part of the one-carbon-- 1015 01:14:27,990 --> 01:14:31,620 the box part of tetrahydrofolate. 1016 01:14:31,620 --> 01:14:44,120 And so this can pick up formic acid like this. 1017 01:15:04,920 --> 01:15:05,420 OK. 1018 01:15:05,420 --> 01:15:07,550 So that gives us this molecule, which 1019 01:15:07,550 --> 01:15:15,070 is called N10-formyltetrahydrofolate, 1020 01:15:15,070 --> 01:15:16,960 THF. 1021 01:15:16,960 --> 01:15:21,800 I can create a ring out of this molecule. 1022 01:15:28,545 --> 01:15:29,045 This. 1023 01:15:50,572 --> 01:15:51,080 OK. 1024 01:15:51,080 --> 01:16:03,505 And if I remove water from this ring, we draw it like this. 1025 01:16:22,730 --> 01:16:23,230 OK. 1026 01:16:23,230 --> 01:16:34,480 This is called N5,N10-methenyl THF. 1027 01:16:34,480 --> 01:16:57,480 And if I reduce that molecule, it's NADPH. 1028 01:16:57,480 --> 01:17:07,545 So hydride ion. 1029 01:17:22,180 --> 01:17:23,260 OK. 1030 01:17:23,260 --> 01:17:38,880 Then I end up with this molecule, 1031 01:17:38,880 --> 01:17:50,240 which is N5,N10-methylene THF. 1032 01:17:50,240 --> 01:18:11,990 And if I further reduce this molecule, 1033 01:18:11,990 --> 01:18:26,580 then I end up with this molecule, 1034 01:18:26,580 --> 01:18:36,270 which is N5-methyl THF. 1035 01:18:36,270 --> 01:18:41,850 Appears incredibly complex what's going on here, 1036 01:18:41,850 --> 01:18:45,060 but I went through this, because what I want you to realize 1037 01:18:45,060 --> 01:18:48,180 is that each of these species are simply 1038 01:18:48,180 --> 01:18:51,600 tetrahydrofolate carrying a one-carbon unit 1039 01:18:51,600 --> 01:18:55,050 in a different oxidation state. 1040 01:18:55,050 --> 01:19:00,660 So this N10 formyl THF is carrying formic acid, 1041 01:19:00,660 --> 01:19:02,850 the one-carbon acid. 1042 01:19:02,850 --> 01:19:07,710 I can reduce it to N5,N10-methylene THF. 1043 01:19:07,710 --> 01:19:11,610 That's carrying the one-carbon aldehyde, formaldehyde. 1044 01:19:11,610 --> 01:19:13,260 Or I could reduce it further. 1045 01:19:13,260 --> 01:19:22,770 This is carrying the one-carbon methyl group as N5-methyl THF. 1046 01:19:22,770 --> 01:19:26,730 And it turns out that this allows a lot of flexibility 1047 01:19:26,730 --> 01:19:29,490 in carrying out one-carbon reactions. 1048 01:19:29,490 --> 01:19:33,690 Here is a same thing written from a textbook. 1049 01:19:33,690 --> 01:19:37,530 The direction-- the order is shown a little bit differently, 1050 01:19:37,530 --> 01:19:39,270 the molecules are rotated. 1051 01:19:39,270 --> 01:19:41,550 And it includes a couple other species 1052 01:19:41,550 --> 01:19:43,812 that are added in for histodine metabolism. 1053 01:19:43,812 --> 01:19:45,270 But if you look at this, you'll see 1054 01:19:45,270 --> 01:19:48,390 it's exactly what I just drawn where 1055 01:19:48,390 --> 01:19:50,670 you get these key species. 1056 01:19:50,670 --> 01:19:58,830 Where N5-methyl THF is effectively 1057 01:19:58,830 --> 01:20:00,970 carrying a methyl group. 1058 01:20:00,970 --> 01:20:03,090 So a one-carbon methyl donor. 1059 01:20:03,090 --> 01:20:17,490 N5,N10-methylene THF is carrying the formaldehyde. 1060 01:20:17,490 --> 01:20:32,610 And N10-formyl THF is carrying the formate group 1061 01:20:32,610 --> 01:20:35,250 to donate as a one-carbon unit. 1062 01:20:35,250 --> 01:20:38,490 This will be the donor, ultimately, for things 1063 01:20:38,490 --> 01:20:40,590 like choline synthesis. 1064 01:20:40,590 --> 01:20:44,190 Formaldehyde-- and N5,N10-methylene and formyl THF 1065 01:20:44,190 --> 01:20:47,370 will be important in nucleic acid synthesis and we'll see 1066 01:20:47,370 --> 01:20:49,330 that next time. 1067 01:20:49,330 --> 01:20:54,240 And so now if we go back to our SHMT reaction, 1068 01:20:54,240 --> 01:21:00,170 I can show you how these things really work. 1069 01:21:00,170 --> 01:21:11,960 And so here's a THF molecule. 1070 01:21:11,960 --> 01:21:23,040 And so here is the intermediate in serine-glycine conversion 1071 01:21:23,040 --> 01:21:36,890 found to pyridoxal phosphate, et cetera. 1072 01:21:36,890 --> 01:21:45,630 And that will release glycine and eventually PLP. 1073 01:21:45,630 --> 01:21:49,180 So glycine and PLP can be generated from that. 1074 01:21:49,180 --> 01:21:55,680 And what ends up here on the folate is-- 1075 01:22:24,980 --> 01:22:35,670 which is N5,N10-methylene THF. 1076 01:22:35,670 --> 01:22:40,140 And if I take this and I oxidize it, 1077 01:22:40,140 --> 01:22:44,070 I can take the aldehyde to the acid. 1078 01:22:44,070 --> 01:22:45,870 So oxidation. 1079 01:22:45,870 --> 01:22:48,630 NAD+ is reduced to NADH. 1080 01:22:48,630 --> 01:22:54,990 Now I get an N10-formyl THF. 1081 01:22:54,990 --> 01:23:03,000 And if instead I reduce it, so electrons from NADPH go 1082 01:23:03,000 --> 01:23:04,290 to NADP+. 1083 01:23:04,290 --> 01:23:07,110 So NADPH gets oxidized, electrons go there. 1084 01:23:07,110 --> 01:23:14,250 And then I get an N5-methyl THF. 1085 01:23:14,250 --> 01:23:17,730 This gives me a donor of methyl groups. 1086 01:23:17,730 --> 01:23:22,250 This gives me a donor of formyl groups. 1087 01:23:22,250 --> 01:23:23,420 All right. 1088 01:23:23,420 --> 01:23:25,880 Very last thing I want to talk about today 1089 01:23:25,880 --> 01:23:32,540 is we'll talk a lot about how we use the more oxidized species 1090 01:23:32,540 --> 01:23:35,120 next time to generate nucleotides, 1091 01:23:35,120 --> 01:23:37,880 but I want to say a few words about how these methyl 1092 01:23:37,880 --> 01:23:41,810 groups are used to be involved in methylation 1093 01:23:41,810 --> 01:23:45,590 reactions, things like choline synthesis shown up 1094 01:23:45,590 --> 01:23:50,750 there, but also not just choline synthesis. 1095 01:23:50,750 --> 01:23:57,110 Also can be used for reactions involved in, say, epigenetics. 1096 01:23:57,110 --> 01:23:59,390 And so for those of you who will never 1097 01:23:59,390 --> 01:24:01,640 think about biochemistry again after taking 1098 01:24:01,640 --> 01:24:04,310 this class but we'll take-- 1099 01:24:04,310 --> 01:24:06,560 think about genetics, you'll certainly 1100 01:24:06,560 --> 01:24:08,630 know the gene expression is controlled 1101 01:24:08,630 --> 01:24:13,070 by methylation of DNA and histones and things like that. 1102 01:24:13,070 --> 01:24:15,630 Those methyl groups have to come from somewhere, 1103 01:24:15,630 --> 01:24:20,240 and they come ultimately from these methylation reactions, 1104 01:24:20,240 --> 01:24:22,610 the serine there. 1105 01:24:22,610 --> 01:24:24,770 Now I don't have time to go through all 1106 01:24:24,770 --> 01:24:27,300 of one-carbon metabolism. 1107 01:24:27,300 --> 01:24:29,120 This is very complex. 1108 01:24:29,120 --> 01:24:31,010 But it turns out the one-carbon donor 1109 01:24:31,010 --> 01:24:34,832 for most methylation reactions isn't N5-methyl THF, 1110 01:24:34,832 --> 01:24:37,040 even though that's where the methyl group comes from. 1111 01:24:37,040 --> 01:24:39,080 It's actually this molecule. 1112 01:25:02,490 --> 01:25:05,720 So this here is the amino acid methionine. 1113 01:25:15,760 --> 01:25:20,260 And if I put it here onto an adenine, what I end up with 1114 01:25:20,260 --> 01:25:35,610 is this molecule called S-adenosylmethionine or SAM. 1115 01:25:35,610 --> 01:25:38,520 This methyl group on SAM is very labile. 1116 01:25:38,520 --> 01:25:44,040 And so it is the universal methyl donor 1117 01:25:44,040 --> 01:25:46,380 to be used in methylation reactions, 1118 01:25:46,380 --> 01:25:50,640 choline synthesis, epigenetic methylation of DNA or histones, 1119 01:25:50,640 --> 01:25:52,110 whatever. 1120 01:25:52,110 --> 01:25:54,510 And if you transfer that methyl group off, 1121 01:25:54,510 --> 01:26:09,920 you're left with this non-proteinogenic amino acid 1122 01:26:09,920 --> 01:26:12,710 that's called homocysteine. 1123 01:26:12,710 --> 01:26:22,070 And that homocysteine is here onto an adenine 1124 01:26:22,070 --> 01:26:36,280 to make S-adenosylhomocysteine, which is abbreviated as SAH. 1125 01:26:36,280 --> 01:26:43,990 SAH picks up-- needs to regenerate SAM. 1126 01:26:43,990 --> 01:26:46,480 Methyl group has to come from somewhere. 1127 01:26:46,480 --> 01:26:54,010 This comes from N5-methyl THF. 1128 01:26:54,010 --> 01:26:56,710 Of course, generates THF. 1129 01:26:56,710 --> 01:27:01,180 And then THF can pick up another methyl group, ultimately 1130 01:27:01,180 --> 01:27:04,180 from serine-to-glycine conversion and reduction 1131 01:27:04,180 --> 01:27:08,680 with NADH to make N5-methyl THF. 1132 01:27:08,680 --> 01:27:11,710 I show here on the slide, here's just 1133 01:27:11,710 --> 01:27:13,900 a picture of one-carbon metabolism 1134 01:27:13,900 --> 01:27:16,030 that I took from a review article. 1135 01:27:16,030 --> 01:27:19,330 And so here's SAM metabolism. 1136 01:27:19,330 --> 01:27:21,730 Lots and lots of complicated reactions 1137 01:27:21,730 --> 01:27:24,490 that are linked to cystine metabolism and polyamine 1138 01:27:24,490 --> 01:27:26,208 metabolism. 1139 01:27:26,208 --> 01:27:28,000 Obviously don't have time to get into this, 1140 01:27:28,000 --> 01:27:30,370 but I want you to appreciate that this happens, where 1141 01:27:30,370 --> 01:27:32,980 SAM and SAH come from, how they're involved 1142 01:27:32,980 --> 01:27:36,010 in one-carbon metabolism, because this will come up 1143 01:27:36,010 --> 01:27:38,950 again in your future endeavors if you do something 1144 01:27:38,950 --> 01:27:40,840 with biology. 1145 01:27:40,840 --> 01:27:41,470 All right. 1146 01:27:41,470 --> 01:27:46,370 Final topic next time is nucleic acid metabolism, 1147 01:27:46,370 --> 01:27:48,910 and then we will have covered all 1148 01:27:48,910 --> 01:27:51,190 of the basics of metabolism. 1149 01:27:51,190 --> 01:27:52,740 Thanks.