1 00:00:00,090 --> 00:00:02,490 The following content is provided under a Creative 2 00:00:02,490 --> 00:00:04,030 Commons license. 3 00:00:04,030 --> 00:00:06,330 Your support will help MIT OpenCourseWare 4 00:00:06,330 --> 00:00:10,720 continue to offer high-quality educational resources for free. 5 00:00:10,720 --> 00:00:13,320 To make a donation or view additional materials 6 00:00:13,320 --> 00:00:17,280 from hundreds of MIT courses, visit MIT OpenCourseWare 7 00:00:17,280 --> 00:00:18,450 at ocw.mit.edu. 8 00:00:20,970 --> 00:00:22,800 JOHN ESSIGMANN: We're now at storyboard 19, 9 00:00:22,800 --> 00:00:25,680 panel B. In the last lecture, I mentioned 10 00:00:25,680 --> 00:00:28,320 that we're going to be looking at several special cases 11 00:00:28,320 --> 00:00:31,750 with regard to the metabolism of fatty acids. 12 00:00:31,750 --> 00:00:34,710 The first special case concerns the metabolism of fatty acids 13 00:00:34,710 --> 00:00:37,200 that already contain double bond. 14 00:00:37,200 --> 00:00:39,510 You remember from last time that a double bond 15 00:00:39,510 --> 00:00:42,420 with a trans configuration forms naturally 16 00:00:42,420 --> 00:00:44,550 during beta oxidation. 17 00:00:44,550 --> 00:00:47,160 In the special case we're going to look at now, 18 00:00:47,160 --> 00:00:50,340 the double bond has a Cis configuration. 19 00:00:50,340 --> 00:00:52,170 Fatty acids with a Cis-double bond 20 00:00:52,170 --> 00:00:54,150 typically come from membranes. 21 00:00:54,150 --> 00:00:56,280 One of the ways nature plasticizes 22 00:00:56,280 --> 00:00:58,620 our membranes is to make them more fluid 23 00:00:58,620 --> 00:01:01,740 by putting in Cis-double bonds that bend the fatty acid 24 00:01:01,740 --> 00:01:04,470 molecule and reduce stacking. 25 00:01:04,470 --> 00:01:06,870 Ultimately, this reduction in stacking 26 00:01:06,870 --> 00:01:09,930 results in a lowering of the overall melting temperature 27 00:01:09,930 --> 00:01:12,460 of that part of the membrane. 28 00:01:12,460 --> 00:01:15,910 The example I'm going to use is oleyl Coenzyme A. 29 00:01:15,910 --> 00:01:20,140 This fatty acyl Coenzyme A comes from Oleic acid, which 30 00:01:20,140 --> 00:01:24,070 also has the shorthand notation (18:1) delta 9. 31 00:01:24,070 --> 00:01:27,220 That is, there is a double bond nine carbons in 32 00:01:27,220 --> 00:01:28,960 from the carboxylate. 33 00:01:28,960 --> 00:01:31,360 The reaction I've shown in panel B 34 00:01:31,360 --> 00:01:33,970 goes through three rounds of beta oxidation 35 00:01:33,970 --> 00:01:38,410 resulting in a Cis delta three enoyl Coenzyme A. 36 00:01:38,410 --> 00:01:41,620 The enzyme oleyl Coenzyme A isomerase 37 00:01:41,620 --> 00:01:44,980 will then remove the acidic hydrogen from the 2 carbon, 38 00:01:44,980 --> 00:01:47,530 repositioning the double bond, and then 39 00:01:47,530 --> 00:01:50,770 putting that double bond into trans configuration, which 40 00:01:50,770 --> 00:01:54,700 is now amenable to further hydration and beta oxidation. 41 00:01:54,700 --> 00:01:58,330 Overall, the isomerase has taken the Cis-double bond 42 00:01:58,330 --> 00:02:02,470 and repositioned it to make it a trans double bond that is now 43 00:02:02,470 --> 00:02:04,420 able to undergo further oxidation 44 00:02:04,420 --> 00:02:06,615 by the classical beta oxidation pathway. 45 00:02:09,539 --> 00:02:12,620 Let's turn now to panel C of storyboard 19. 46 00:02:12,620 --> 00:02:14,390 The second special case that I'd like 47 00:02:14,390 --> 00:02:16,730 to deal with concerns the way that we metabolize 48 00:02:16,730 --> 00:02:19,490 fatty acids that have an uneven, that is odd, 49 00:02:19,490 --> 00:02:21,620 number of carbons in them. 50 00:02:21,620 --> 00:02:27,000 One example would be the C15 fatty acid Pentadecanoic acid, 51 00:02:27,000 --> 00:02:28,730 which we get from milk fat. 52 00:02:28,730 --> 00:02:32,660 In this case, six rounds of beta oxidation will release six 53 00:02:32,660 --> 00:02:34,400 acetyl Coenzyme A's. 54 00:02:34,400 --> 00:02:37,640 But note that we're left with a 3 carbon residue, 55 00:02:37,640 --> 00:02:41,540 or carboxylic acid called propionyl Coenzyme A. 56 00:02:41,540 --> 00:02:44,210 Nature doesn't like to throw anything away. 57 00:02:44,210 --> 00:02:46,490 It's going to take this three-carbon molecule, 58 00:02:46,490 --> 00:02:49,100 propionyl CoA, that doesn't easily 59 00:02:49,100 --> 00:02:52,700 integrate into any other biochemical pathways. 60 00:02:52,700 --> 00:02:54,980 Nature's going to add a carbon to it, 61 00:02:54,980 --> 00:02:57,470 hence making it into a four-carbon molecule. 62 00:02:57,470 --> 00:02:59,410 As we'll see, that four-carbon molecule 63 00:02:59,410 --> 00:03:03,080 will integrate seamlessly into the TCA cycle. 64 00:03:03,080 --> 00:03:05,390 The conversion of the three-carbon compound 65 00:03:05,390 --> 00:03:07,460 into a four-carbon compound begins 66 00:03:07,460 --> 00:03:11,010 with the enzyme propionyl Coenzyme A carboxylase. 67 00:03:11,010 --> 00:03:13,010 In a few minutes, we'll look at the fine details 68 00:03:13,010 --> 00:03:14,630 of how this enzyme works. 69 00:03:14,630 --> 00:03:17,720 For now, however, what it does is use the cofactor 70 00:03:17,720 --> 00:03:21,440 biotin in order to introduce a carbon dioxide, or CO2, 71 00:03:21,440 --> 00:03:24,560 into the 2 carbon of the propionyl Coenzyme A. 72 00:03:24,560 --> 00:03:27,920 The 2 carbon is the middle carbon of the propionyl group. 73 00:03:27,920 --> 00:03:30,140 This is now a branched molecule that's 74 00:03:30,140 --> 00:03:33,230 called methylmalonyl Coenzyme A. 75 00:03:33,230 --> 00:03:38,150 Next, the molecule is subjected to a carbon chain rearrangement 76 00:03:38,150 --> 00:03:40,600 that takes the branched molecule and linearizes 77 00:03:40,600 --> 00:03:44,720 it to form succinyl Coenzyme A. Succinyl Coenzyme A will then 78 00:03:44,720 --> 00:03:47,540 integrate directly into the TCA cycle 79 00:03:47,540 --> 00:03:52,010 to allow its carbons to be metabolized fully to CO2. 80 00:03:52,010 --> 00:03:54,680 In summary, nature puts a CO2 into 81 00:03:54,680 --> 00:03:59,300 the three-carbon propionyl CoA, forming a four-carbon branch 82 00:03:59,300 --> 00:04:00,380 structure. 83 00:04:00,380 --> 00:04:02,060 Then, in an amazing rearrangement 84 00:04:02,060 --> 00:04:04,190 that we'll look at later, the branched molecule 85 00:04:04,190 --> 00:04:07,040 is made linear, forming succinyl CoA, which 86 00:04:07,040 --> 00:04:09,360 is a TCA cycle intermediate. 87 00:04:09,360 --> 00:04:13,230 So the otherwise useless C-3 molecule, propionyl Coenzyme A 88 00:04:13,230 --> 00:04:16,360 is converted to something of value. 89 00:04:16,360 --> 00:04:18,870 Lastly, let's turn to panel D. I'm 90 00:04:18,870 --> 00:04:21,630 going to deal more with the details of this reaction 91 00:04:21,630 --> 00:04:22,960 in a few minutes. 92 00:04:22,960 --> 00:04:24,480 But for now, what I'd like to say 93 00:04:24,480 --> 00:04:26,790 is that there are many sources of propionyl CoA, 94 00:04:26,790 --> 00:04:30,030 not just from odd chain fatty acids in the diet. 95 00:04:30,030 --> 00:04:33,180 Secondly, the introduction of succinate into the TCA cycle 96 00:04:33,180 --> 00:04:35,460 results in an increase in the amount of carbon 97 00:04:35,460 --> 00:04:37,200 going through the TCA cycle. 98 00:04:37,200 --> 00:04:40,270 That is, this is truly an anapleurotic reaction. 99 00:04:40,270 --> 00:04:41,940 This is a reaction that we can use 100 00:04:41,940 --> 00:04:45,180 to increase the overall rate of carbon metabolism 101 00:04:45,180 --> 00:04:47,750 in the TCA cycle. 102 00:04:47,750 --> 00:04:50,300 We're now going to turn to storyboard 20. 103 00:04:50,300 --> 00:04:52,970 Let's look at panel A. In the last lecture 104 00:04:52,970 --> 00:04:56,210 on fatty acid metabolism, I talked about propionyl CoA 105 00:04:56,210 --> 00:04:58,740 carboxylase, which uses biotin to add 106 00:04:58,740 --> 00:05:01,830 a CO2 moiety to the middle carbon of propionyl Coenzyme 107 00:05:01,830 --> 00:05:06,050 A. This lecture is a chemical interlude, in which we're going 108 00:05:06,050 --> 00:05:09,620 to look at propionyl CoA carboxylase 109 00:05:09,620 --> 00:05:14,390 and several other carboxylases that are used in biochemistry. 110 00:05:14,390 --> 00:05:17,060 One of these is acetate CoA carboxylase. 111 00:05:17,060 --> 00:05:19,400 This carboxylase puts the CO2 group 112 00:05:19,400 --> 00:05:23,180 onto acetyl CoA to make malonyl CoA, which is the precursor 113 00:05:23,180 --> 00:05:27,000 to fatty acids during the fatty acid biosynthesis reactions. 114 00:05:27,000 --> 00:05:29,450 Let's also look at panel B. We're also 115 00:05:29,450 --> 00:05:32,300 going to be looking at pyruvate carboxylase, which 116 00:05:32,300 --> 00:05:36,710 adds a carbonyl group to the pyruvic acid molecule in order 117 00:05:36,710 --> 00:05:38,450 to make oxaloacetate. 118 00:05:38,450 --> 00:05:41,030 This is one of the anaplerotic enzymes that 119 00:05:41,030 --> 00:05:43,760 can increase the quantity of carbon going through the TCA 120 00:05:43,760 --> 00:05:44,450 cycle. 121 00:05:44,450 --> 00:05:46,820 That is, it facilitates anapleurosis 122 00:05:46,820 --> 00:05:49,340 in the biological system. 123 00:05:49,340 --> 00:05:53,270 Let's now look at storyboard 21, panel A. The 124 00:05:53,270 --> 00:05:55,580 carboxylases all use carbon dioxide 125 00:05:55,580 --> 00:05:58,070 as their carboxylating reagent. 126 00:05:58,070 --> 00:06:00,950 CO2 itself is not very soluble in water, 127 00:06:00,950 --> 00:06:03,620 so cells use carbonic anhydrase in order 128 00:06:03,620 --> 00:06:06,440 to hydrate it to form carbonic acid. 129 00:06:06,440 --> 00:06:08,840 The biotin carboxylase subunit will then 130 00:06:08,840 --> 00:06:11,030 phosphorylate the carbonic acid in order 131 00:06:11,030 --> 00:06:13,310 to form a chemically-reactive intermediate 132 00:06:13,310 --> 00:06:17,150 known as carbonyl phosphate or carboxy phosphate. 133 00:06:17,150 --> 00:06:20,600 Now, carbon dioxide by virtue of its structure-- that is, 134 00:06:20,600 --> 00:06:23,870 a carbon with two electronegative oxygens pulling 135 00:06:23,870 --> 00:06:24,530 on it-- 136 00:06:24,530 --> 00:06:27,650 is pre-activated for nucleophilic attack. 137 00:06:27,650 --> 00:06:29,900 And as I said a few minutes ago, CO2 138 00:06:29,900 --> 00:06:33,290 is just not present at high enough concentration 139 00:06:33,290 --> 00:06:35,690 in the cell for it to be able to add effectively 140 00:06:35,690 --> 00:06:37,190 to nucleophiles. 141 00:06:37,190 --> 00:06:40,280 A nucleophile such as the amide nitrogen of biotin 142 00:06:40,280 --> 00:06:42,300 would be an example. 143 00:06:42,300 --> 00:06:45,440 So what the cell does is use ATP to make 144 00:06:45,440 --> 00:06:49,890 carbonyl phosphate, which is a very water-soluble molecule. 145 00:06:49,890 --> 00:06:52,940 It's a very efficient delivery vehicle for carbon dioxide 146 00:06:52,940 --> 00:06:55,490 into the active site of an enzyme. 147 00:06:55,490 --> 00:06:58,610 Now let's look at panel B. The biotin carboxylase 148 00:06:58,610 --> 00:07:00,980 subunit of pyruvate carboxylase has 149 00:07:00,980 --> 00:07:04,790 a biotin cofactor at the end of a 14-Angstrom-long swinging 150 00:07:04,790 --> 00:07:05,810 arm. 151 00:07:05,810 --> 00:07:07,670 This subunit of the enzyme breaks 152 00:07:07,670 --> 00:07:11,490 the bicarbonate phosphate bond and releases carbon dioxide 153 00:07:11,490 --> 00:07:14,080 in high concentration in the active site. 154 00:07:14,080 --> 00:07:18,200 Biotin on the swinging arm then attacks the high concentration 155 00:07:18,200 --> 00:07:22,130 of carbon dioxide in order to become N-carboxy biotin 156 00:07:22,130 --> 00:07:24,120 as shown in this figure. 157 00:07:24,120 --> 00:07:28,130 The N-carboxy biotin takes advantage of its swinging arm 158 00:07:28,130 --> 00:07:31,010 to move away from the active site at which it acquired 159 00:07:31,010 --> 00:07:33,980 the CO2 and then move to a second site 160 00:07:33,980 --> 00:07:37,610 on the enzyme at which the arm releases carbon dioxide, once 161 00:07:37,610 --> 00:07:39,890 again at high concentration. 162 00:07:39,890 --> 00:07:43,220 But this time CO2 is released at high concentration 163 00:07:43,220 --> 00:07:46,400 in the vicinity of the substrate, pyruvate. 164 00:07:46,400 --> 00:07:50,090 Pyruvate, in order to be a good nucleophile to acquire the CO2, 165 00:07:50,090 --> 00:07:54,920 probably exists as shown in the figure as the pyruvate enolate. 166 00:07:54,920 --> 00:07:57,470 Let me review panel B at this point. 167 00:07:57,470 --> 00:07:59,600 Overall, this reaction has resulted 168 00:07:59,600 --> 00:08:02,240 in putting a carboxylic acid residue 169 00:08:02,240 --> 00:08:04,370 on the 3-carbon of pyruvate. 170 00:08:04,370 --> 00:08:07,340 And this results in the formation of oxaloacetate. 171 00:08:07,340 --> 00:08:09,890 Thus, activation of pyruvate carboxylase 172 00:08:09,890 --> 00:08:12,770 will result in taking a molecule of pyruvate 173 00:08:12,770 --> 00:08:15,110 and converting it to oxaloacetate. 174 00:08:15,110 --> 00:08:17,840 This anaplerotic reaction gives the ability 175 00:08:17,840 --> 00:08:19,880 to increase the volume of carbon that's 176 00:08:19,880 --> 00:08:22,430 cycling in the TCA cycle, thus allowing 177 00:08:22,430 --> 00:08:26,420 you to be able to increase their overall rate of respiration. 178 00:08:26,420 --> 00:08:28,700 And as I've said several times in the past, 179 00:08:28,700 --> 00:08:31,910 oxaloacetate is present at rather limiting concentrations 180 00:08:31,910 --> 00:08:33,780 within the mitochondrial matrix. 181 00:08:33,780 --> 00:08:37,820 So this is a very useful biochemical reaction. 182 00:08:37,820 --> 00:08:40,580 At this point, let's move on to story board 22 183 00:08:40,580 --> 00:08:44,360 and look at panel A. Let me loop back now and give some bigger 184 00:08:44,360 --> 00:08:47,690 picture points with regard to carboxylase chemistry. 185 00:08:47,690 --> 00:08:50,520 Pyruvate carboxylase and the other enzymes of this class 186 00:08:50,520 --> 00:08:52,310 have two active sites. 187 00:08:52,310 --> 00:08:55,370 One of them is the biotin carboxylase domain, 188 00:08:55,370 --> 00:08:58,340 where a biotin moiety covalently attached to the enzyme 189 00:08:58,340 --> 00:08:59,930 will acquire CO2. 190 00:08:59,930 --> 00:09:03,080 Let's call this step 1 of the reaction scheme. 191 00:09:03,080 --> 00:09:05,480 Once the biotin on the swinging arm 192 00:09:05,480 --> 00:09:08,510 has been N-carboxylated as in step 1, 193 00:09:08,510 --> 00:09:13,730 the N-carboxy biotin moves to site 2, where the substrate is. 194 00:09:13,730 --> 00:09:17,390 The second site is the biotin transferase domain. 195 00:09:17,390 --> 00:09:20,680 In the example I just used, the substrate was pyruvate. 196 00:09:20,680 --> 00:09:22,460 But it just as easily could have been 197 00:09:22,460 --> 00:09:25,070 another quote unquote "carboxylation substrate," 198 00:09:25,070 --> 00:09:28,100 for example propionyl CoA. 199 00:09:28,100 --> 00:09:30,430 In the case of pyruvate, as we just saw, 200 00:09:30,430 --> 00:09:34,550 it's the pyruvate enolate that becomes carboxylated in site 2 201 00:09:34,550 --> 00:09:37,820 in order to form the final product oxaloacetate. 202 00:09:37,820 --> 00:09:41,360 This carboxylation of substrate is the second and final step 203 00:09:41,360 --> 00:09:43,680 of the overall reaction. 204 00:09:43,680 --> 00:09:47,150 Take a look at panel B. Now let me give you a second example 205 00:09:47,150 --> 00:09:49,160 of carboxylase chemistry. 206 00:09:49,160 --> 00:09:51,140 In this case, our substrate will acetyl 207 00:09:51,140 --> 00:09:55,160 Coenzyme A. We're going to use the same chemistry we described 208 00:09:55,160 --> 00:09:57,440 a minute ago for pyruvate, but in this case 209 00:09:57,440 --> 00:10:00,650 it is another carboxylate-- acetyl CoA carboxylate-- 210 00:10:00,650 --> 00:10:05,450 that picks up the CO2 residue at its carboxy transferase domain. 211 00:10:05,450 --> 00:10:10,010 In step 2, which occurs in the carboxy transferase domain, 212 00:10:10,010 --> 00:10:14,030 the substrate acetyl CoA picks up CO2 on its 2-carbon-- 213 00:10:14,030 --> 00:10:16,070 the one distal to the Coenzyme A group-- 214 00:10:16,070 --> 00:10:20,690 to form the three-carbon product malonyl Coenzyme A. 215 00:10:20,690 --> 00:10:23,000 We'll see later that the carbon dioxide that's 216 00:10:23,000 --> 00:10:26,420 been added to acetyl CoA to form malonyl CoA 217 00:10:26,420 --> 00:10:28,310 is an excellent leaving group. 218 00:10:28,310 --> 00:10:32,690 Malonyl CoA is the fundamental precursor to all fatty acids 219 00:10:32,690 --> 00:10:35,660 through the fatty acid biosynthesis pathway. 220 00:10:35,660 --> 00:10:38,270 Again, we'll see the details of this reaction scheme 221 00:10:38,270 --> 00:10:40,490 later, but keep in mind now that this 222 00:10:40,490 --> 00:10:44,510 is a biotin-requiring reaction, just as the one we just looked 223 00:10:44,510 --> 00:10:47,630 at with pyruvate carboxylase. 224 00:10:47,630 --> 00:10:50,660 Let's look now a panel C. My last example 225 00:10:50,660 --> 00:10:53,260 of carboxylase chemistry will be propionyl 226 00:10:53,260 --> 00:10:55,370 Coenzyme A carboxylase. 227 00:10:55,370 --> 00:10:58,370 I mentioned earlier that the breakdown of odd chain number 228 00:10:58,370 --> 00:11:00,980 fatty acids results in the formation 229 00:11:00,980 --> 00:11:05,270 of a 3-carbon linear fatty acid called propionyl CoA. 230 00:11:05,270 --> 00:11:07,130 I also said that nature doesn't want 231 00:11:07,130 --> 00:11:09,060 to waste any of the carbons. 232 00:11:09,060 --> 00:11:13,160 What she is going to do is add a carbon dioxide or a CO2 233 00:11:13,160 --> 00:11:16,520 to the central carbon of the propionyl group. 234 00:11:16,520 --> 00:11:20,360 As well as fatty acids with odd numbers of carbons, 235 00:11:20,360 --> 00:11:22,290 certain amino acids-- 236 00:11:22,290 --> 00:11:26,180 such as isoleucine, methionine, valine, and threonine, 237 00:11:26,180 --> 00:11:27,260 for example-- 238 00:11:27,260 --> 00:11:30,500 also break down to form propionyl CoA. 239 00:11:30,500 --> 00:11:32,390 So what I'm going to do now is describe 240 00:11:32,390 --> 00:11:34,310 a fairly general method of metabolism 241 00:11:34,310 --> 00:11:36,890 that involves restructuring of the carbon chain 242 00:11:36,890 --> 00:11:39,530 subsequent to the carboxylase reaction. 243 00:11:39,530 --> 00:11:41,280 In this overall reaction, a carboxylase 244 00:11:41,280 --> 00:11:43,730 is going to carboxylate the middle carbon 245 00:11:43,730 --> 00:11:45,260 of the propionyl group. 246 00:11:45,260 --> 00:11:47,930 Then, following the carboxylase reaction, 247 00:11:47,930 --> 00:11:50,300 there's going to be a skeletal rearrangement 248 00:11:50,300 --> 00:11:55,160 to form succinyl CoA, which will then enter the TCA cycle. 249 00:11:55,160 --> 00:11:58,340 As shown in the reaction scheme, propionyl Coenzyme A 250 00:11:58,340 --> 00:12:02,810 carboxylase carboxylates propionyl CoA to form a very 251 00:12:02,810 --> 00:12:08,480 specific stereoisomer, (S)-methylmalonyl Coenzyme A. 252 00:12:08,480 --> 00:12:11,030 Please note the position of the carbonyl group 253 00:12:11,030 --> 00:12:13,010 that's highlighted in blue. 254 00:12:13,010 --> 00:12:15,290 This carboxylate in blue is attached 255 00:12:15,290 --> 00:12:19,070 to a methylene carbon that has an inverted triangle on top 256 00:12:19,070 --> 00:12:19,770 of it. 257 00:12:19,770 --> 00:12:23,000 Epimerization about the carbon with the triangle 258 00:12:23,000 --> 00:12:26,930 results in the blue carboxylate pointed down 259 00:12:26,930 --> 00:12:29,200 the way I've drawn it. 260 00:12:29,200 --> 00:12:33,460 The resulting epimer is (R)-methylmalonyl Coenzyme A. 261 00:12:33,460 --> 00:12:36,580 In the (R)-methylmalonyl Coenzyme A molecule, 262 00:12:36,580 --> 00:12:41,110 I put a little lasso around the hydrogen atom at the methylene 263 00:12:41,110 --> 00:12:42,760 moiety of the molecule. 264 00:12:42,760 --> 00:12:45,250 I've also lassoed an electron in some 265 00:12:45,250 --> 00:12:48,780 of the atoms of the Coenzyme A moiety. 266 00:12:48,780 --> 00:12:52,810 A vitamin B12-dependent enzyme called methylmalonyl Coenzyme 267 00:12:52,810 --> 00:12:57,580 A mutase, which contains an adenosylcobalamin functional 268 00:12:57,580 --> 00:13:00,850 group, will now act on this molecule. 269 00:13:00,850 --> 00:13:03,340 In this enzyme, a cobalt residue is 270 00:13:03,340 --> 00:13:07,030 going to enable the formation of an adenosyl radical. 271 00:13:07,030 --> 00:13:09,610 Look at the book for the detailed mechanism. 272 00:13:09,610 --> 00:13:13,600 But for now, it's sufficient to say that this adenosyl radical 273 00:13:13,600 --> 00:13:17,110 is going to facilitate the homolytic scission of the bond 274 00:13:17,110 --> 00:13:20,570 between the carbon and hydrogen of the (R)-methylmalonyl 275 00:13:20,570 --> 00:13:24,160 Coenzyme A. That is, you're going to get a free radical 276 00:13:24,160 --> 00:13:28,150 formed at the carbon that has the small blue o written over 277 00:13:28,150 --> 00:13:29,140 it. 278 00:13:29,140 --> 00:13:32,260 That molecule will lose its hydrogen atom. 279 00:13:32,260 --> 00:13:35,020 That hydrogen atom will migrate to the carbon that 280 00:13:35,020 --> 00:13:37,680 has the small blue triangle. 281 00:13:37,680 --> 00:13:40,320 Coordinately, the carbon with the small box 282 00:13:40,320 --> 00:13:42,730 that's part of the Coenzyme A carbonyl group 283 00:13:42,730 --> 00:13:45,310 will migrate to the position originally occupied 284 00:13:45,310 --> 00:13:47,380 by the hydrogen atom on the carbon 285 00:13:47,380 --> 00:13:49,180 with the small o over it. 286 00:13:49,180 --> 00:13:53,230 The skeletal re-arrangement is shown here in panel C, 287 00:13:53,230 --> 00:13:55,240 and it results in a linearization 288 00:13:55,240 --> 00:13:58,690 of the original methylmalonyl Coenzyme A. 289 00:13:58,690 --> 00:14:00,790 If we redraw it as in the box, you'll 290 00:14:00,790 --> 00:14:05,230 see that you form succinyl Coenzyme A. Succinyl Coenzyme 291 00:14:05,230 --> 00:14:08,500 A will then feed directly into the TCA cycle. 292 00:14:08,500 --> 00:14:10,300 This is an anaplerotic reaction. 293 00:14:10,300 --> 00:14:13,180 That is, it will increase the volume of carbon that's 294 00:14:13,180 --> 00:14:17,300 rotating in the TCA cycle. 295 00:14:17,300 --> 00:14:20,540 Overall, in the way of a review, the three-carbon compound 296 00:14:20,540 --> 00:14:24,410 propionyl Coenzyme A, by way of the carboxylase reaction, 297 00:14:24,410 --> 00:14:27,445 is converted to a four-carbon branched molecule called 298 00:14:27,445 --> 00:14:31,850 (S)-methylmalonyl Coenzyme A. It's epimerization forms 299 00:14:31,850 --> 00:14:34,760 the (R)-methylmalonyl Coenzyme A, 300 00:14:34,760 --> 00:14:37,220 which is the substrate for a third enzyme, 301 00:14:37,220 --> 00:14:42,390 methylmalonyl Coenzyme A mutase, a vitamin B12 enzyme. 302 00:14:42,390 --> 00:14:45,920 This enzyme catalyzes a free radical-mediated rearrangement 303 00:14:45,920 --> 00:14:47,150 of the side change. 304 00:14:47,150 --> 00:14:49,070 Specifically, one hydrogen and one 305 00:14:49,070 --> 00:14:53,090 Coenzyme A functionality switch positions. 306 00:14:53,090 --> 00:14:55,640 This rearrangement linearizes the molecule 307 00:14:55,640 --> 00:14:58,940 forming, ultimately, succinyl Coenzyme A, which 308 00:14:58,940 --> 00:15:01,960 then flows into the TCA cycle.