{"id":164,"date":"2019-04-10T11:24:28","date_gmt":"2019-04-10T11:24:28","guid":{"rendered":"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/?post_type=chapter&#038;p=164"},"modified":"2019-04-10T12:06:55","modified_gmt":"2019-04-10T12:06:55","slug":"citric-acid-cycle","status":"publish","type":"chapter","link":"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/chapter\/citric-acid-cycle\/","title":{"rendered":"Citric acid cycle"},"content":{"raw":"<div><span style=\"float: right\"><a href=\"https:\/\/youtu.be\/OInVLabpd1M\" target=\"_blank\" rel=\"noopener\"><img src=\"http:\/\/epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/2018\/11\/download.png\" alt=\"epgp books\" width=\"75px\" height=\"75px;\" \/><\/a>\r\n<\/span><\/div>\r\n<strong>\u00a0 \u00a0<\/strong>\r\n\r\n&nbsp;\r\n\r\n&nbsp;\r\n\r\n&nbsp;\r\n\r\n&nbsp;\r\n\r\n<strong>Objectives<\/strong>\r\n<ol>\r\n \t<li>History and introduction of citric acid cycle<\/li>\r\n \t<li>Conversion of pyruvate to activated acetate by pyruvate dehydrogenase<\/li>\r\n \t<li>Explain Reactions of citric acid cycle<\/li>\r\n \t<li>Amphibolic nature of Citric acid cycle<\/li>\r\n<\/ol>\r\n<strong>\u00a0 \u00a0<\/strong>\r\n\r\n&nbsp;\r\n\r\n<strong>OVERVIEW<\/strong>\r\n\r\n<strong>\u00a0<\/strong>\r\n<p style=\"text-align: justify\">Citric acid cycle is also called <strong>Tricarboxylic acid (TCA) cycle<\/strong> or <strong>Krebs cycle<\/strong> is a sequence of biochemical reactions that occurs in all aerobic organisms for energy generation.<\/p>\r\n<p style=\"text-align: justify\"><strong>\u00a0<\/strong><\/p>\r\n<p style=\"text-align: justify\">Energy is generation is carried out by the oxidation of acetate, which is derived from carbohydrates, lipids and proteins converted into Co2 and chemical energy stored in the<\/p>\r\n<p style=\"text-align: justify\"><strong>\u00a0<\/strong><\/p>\r\n<p style=\"text-align: justify\">form of adenosine triphosphate (ATP). Furthermore the TCA cycle supplies precursors for synthesis of several amino acids and reducing agent such as NADH, which involves in various other biochemical reactions. TCA cycle is one of the initially established mechanism of cellular metabolism suggested by the central importance in various biochemical pathways.<\/p>\r\n&nbsp;\r\n<p style=\"text-align: justify\">The name of this biochemical pathway is derived from tricarboxylic acid (e.g. citric acid) . Citric acid is first utilized and then regenerated by this sequential reactions to complete the cycle. The major function of these two closely associated pathways is the oxidative breakdown of nutrients into production of usable energy in the form of ATP.<\/p>\r\n&nbsp;\r\n<p style=\"text-align: justify\">In eukaryotic cells, the Krebs cycle occurs in the mitochondrial matrix. In prokaryotic cells the TCA reaction occurs in the cytosol through the proton gradient for energy generation.<\/p>\r\n&nbsp;\r\n\r\nIn 1935 Albert Szent-Gyorgyi showed that\r\n\r\n&nbsp;\r\n\r\nSuccinate \u2192\u00a0Fumarate \u2192\u00a0Malate \u2192 Oxaloacetate\r\n\r\n&nbsp;\r\n\r\nCarl Martius and Franz Knoop showed\r\n\r\n&nbsp;\r\n<div>\r\n\r\n\u00a0 \u00a0Citrate \u00a0cis-aconitate \u2192\u00a0 Isocitrate \u2192 \u03b1 ketoglutarate \u2192\u00a0 Succinate \u2192\u00a0\u00a0<span style=\"font-size: 1em;text-align: initial\">Fumarate \u2192\u00a0Malate \u2192\u00a0Oxaloacetate<\/span>\r\n\r\n<\/div>\r\n- Overall reaction of the citric acid cycle is:\r\n\r\n&nbsp;\r\n\r\n<img class=\"aligncenter size-full wp-image-165\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-70.png\" alt=\"\" width=\"491\" height=\"105\" \/>\r\n\r\n<img class=\"aligncenter size-full wp-image-166\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-71.png\" alt=\"\" width=\"558\" height=\"235\" \/>\r\n\r\n<img class=\"aligncenter size-full wp-image-167\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-72.png\" alt=\"\" width=\"657\" height=\"513\" \/>\r\n\r\n<img class=\"aligncenter size-full wp-image-168\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-73.png\" alt=\"\" width=\"606\" height=\"237\" \/><strong>\u00a0<\/strong>\r\n\r\n<strong>2. Conversion of pyruvate to activated acetate by pyruvate dehydrogenase<\/strong>\r\n\r\n&nbsp;\r\n<ul>\r\n \t<li>- Pyruvate converts into the acetyl-CoA before enters into the TCA.<\/li>\r\n \t<li>- The <strong>coenzyme A<\/strong> is act as a carrier for acetyl and other acyl group.<\/li>\r\n \t<li>- Acetyl-CoA is a \u201c<strong>high-energy<\/strong>\u201d compound.<\/li>\r\n<\/ul>\r\n<img class=\"aligncenter size-full wp-image-169\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-74.png\" alt=\"\" width=\"525\" height=\"533\" \/>\r\n\r\n&nbsp;\r\n\r\n<strong>A. Pyruvate dehydrogenase is a multienzyme complex<\/strong>\r\n<ul>\r\n \t<li style=\"text-align: justify\">- By the oxidative decarboxylation process Acetyl-CoA is formed from pyruvate using multienzyme complex named as a <strong style=\"text-align: initial;font-size: 1em\">pyruvate dehydrogenase<\/strong><span style=\"text-align: initial;font-size: 1em\">. Pyruvate + CoA + NAD+ \u2192 acetyl-CoA + CO2 + NADH<\/span><\/li>\r\n<\/ul>\r\n<img class=\"aligncenter size-full wp-image-170\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-75.png\" alt=\"\" width=\"469\" height=\"201\" \/>\r\n<ul>\r\n \t<li>- Pyruvate dehydrogenase a multienzyme complex consists of:<\/li>\r\n<\/ul>\r\n<ol>\r\n \t<li>Pyruvate dehydrogenase (E1)<\/li>\r\n \t<li>Dihydrolipoyl transacetylase (E2)<\/li>\r\n \t<li>Dihydrolipoyl dehydrogenase (E3)<\/li>\r\n<\/ol>\r\n<img class=\"aligncenter size-full wp-image-171\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-76.png\" alt=\"\" width=\"643\" height=\"311\" \/>\r\n\r\n&nbsp;\r\n\r\n<strong>B. Control of pyruvate dehydrogenase <\/strong><strong>Product inhibition<\/strong>\r\n<ul>\r\n \t<li style=\"text-align: justify\">- When the relative concentrations of NADH and acetyl-CoA are high, the reversible reactions catalyzed by E2 and E3 are driven backwards. Therefore formation of acetyl-<\/li>\r\n<\/ul>\r\nCoA is inhibited.\r\n\r\n&nbsp;\r\n<ul>\r\n \t<li style=\"text-align: justify\">- Thus the E2 and E3 activities are controlled by product inhibition (acetyl-CoA for E2 and NADH for E3).<\/li>\r\n<\/ul>\r\n<img class=\"aligncenter size-full wp-image-172\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-77.png\" alt=\"\" width=\"545\" height=\"247\" \/>\r\n\r\n<strong><em>Covalent modification <\/em><\/strong>(Eukaryotic complex only)\r\n\r\n&nbsp;\r\n<p style=\"text-align: justify\">E1 is regulated by phosphorylation\/dephosphorylation. When the Ser of E1 is phosphorylated, the enzyme is inactivated.<\/p>\r\n<img class=\"aligncenter size-full wp-image-173\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-78.png\" alt=\"\" width=\"637\" height=\"213\" \/>\r\n\r\nActivators of phosphatase: Mg2+, Ca2+\r\n\r\n&nbsp;\r\n\r\nActivators of kinase: Acetyl-CoA, NADH\r\n\r\n&nbsp;\r\n\r\nInhibitors of kinase: Pyruvate, ADP, Ca2+, high Mg2+, K+\r\n\r\n&nbsp;\r\n<p style=\"text-align: justify\">Remember: <strong>Insulin<\/strong> inhibits phosphorylation and activates dephosphorylation in order to reduce the (glucose) in blood at the starting point of glycolysis.<\/p>\r\n&nbsp;\r\n<ul>\r\n \t<li style=\"text-align: justify\">- Now, insulin also works to reduce the end product of glycolysis, i.e., activates dephosphorylation of E1 to convert pyruvate to acetyl-CoA.<\/li>\r\n \t<li>- Acetyl-CoA is not only the fuel of citric acid cycle, but also the precursor of fatty acids.<\/li>\r\n<\/ul>\r\n&nbsp;\r\n\r\n&nbsp;\r\n\r\n<strong>Reactions of the citric acid cycle<\/strong>\r\n<ol>\r\n \t<li><strong><em>Citrate is formed from Oxaloacetate and Acetyl Coenzyme A by citrate synthase enzyme<\/em><\/strong><\/li>\r\n<\/ol>\r\n<p style=\"text-align: justify\">The citric acid cycle initiates through the condensation of an oxaloacetate (four-carbon unit), and the acetyl group of acetyl CoA (a two-carbon unit). Oxaloacetate reacts with acetyl CoA and H2O to yield as citrate and CoA.<\/p>\r\n&nbsp;\r\n\r\n<img class=\"aligncenter size-full wp-image-174\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-79.png\" alt=\"\" width=\"555\" height=\"168\" \/>\r\n\r\n&nbsp;\r\n\r\n<strong><em>Isomerization of Citrate into Isocitrate<\/em><\/strong>\r\n\r\n&nbsp;\r\n<p style=\"text-align: justify\">In the citrate molecule the tertiary hydroxyl group is not properly situated for the oxidative decarboxylations that follow. Therefore, isomerization occurs of citrate into isocitrate to allow the six-carbon component to undergo oxidative decarboxylation. The isomerization of citrate is accomplished by a dehydration reaction following a hydration reaction. The result is a substitution of a hydrogen atom and a OH- group. Both the steps are catalyzed by the enzyme <em>aconitase<\/em> because cis<em>-aconitate<\/em> is an intermediate.<\/p>\r\n&nbsp;\r\n\r\n<img class=\"aligncenter size-full wp-image-177\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-80.png\" alt=\"\" width=\"506\" height=\"208\" \/>\r\n\r\n&nbsp;\r\n\r\n<strong><em>Fluorocitrate inhibits aconitase<\/em><\/strong>\r\n<ul>\r\n \t<li style=\"text-align: justify\">- Fluoroacetate, one of the most toxic small molecules (LD50 = 0.2 mg\/kg), is converted to (2R,3R)-fluorocitrate, which specifically inhibits aconitase since Ser-642 cannot remove the proton at C2.<\/li>\r\n<\/ul>\r\n<img class=\"aligncenter size-full wp-image-179\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-81.png\" alt=\"\" width=\"524\" height=\"239\" \/>\r\n\r\n<strong><em>C. Oxidation and decarboxylation of isocitrate to a-Ketoglutarate<\/em><\/strong>\r\n\r\n&nbsp;\r\n\r\nThe isocitrate is\u00a0 oxidized and decarboxylated by enzyme <em>isocitrate dehydrogenase.<\/em>\r\n\r\nOxalosuccinate act as an intermediate in this reaction.\r\n\r\n&nbsp;\r\n\r\n<img class=\"aligncenter size-full wp-image-180\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-82.png\" alt=\"\" width=\"601\" height=\"191\" \/>\r\n\r\nThere are two isozymes in mammalian cells.\r\n<ol>\r\n \t<li>NAD+-dependent form is in mitochondria and requires Mn2+ or Mg2+.<\/li>\r\n \t<li>NADP+-dependent form is in both cytosol and mitochondria.<\/li>\r\n<\/ol>\r\n&nbsp;\r\n\r\n<strong>\u00a0 D. The oxidative decarboxylation of \u03b1- Ketoglutarate to forms Succinyl CoA<\/strong>\r\n\r\n&nbsp;\r\n<p style=\"text-align: justify\">Catalyzes the oxidative decarboxylation of an \u03b1-keto acid, releasing CO2, forming succinyl-CoA and reducing NAD+ to NADH<\/p>\r\n<img class=\"aligncenter size-full wp-image-181\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-83.png\" alt=\"\" width=\"530\" height=\"139\" \/>\r\n<ul>\r\n \t<li style=\"text-align: justify\">- A \u03b1-Ketoglutarate dehydrogenase that consists of \u03b1-ketoglutarate dehydrogenase (E1), dihydrolipoyl transsuccinylase (E2), and dihydrolipoyl dehydrogenase (E3).<\/li>\r\n<\/ul>\r\n<ul style=\"text-align: justify\">\r\n \t<li>- The overall reaction closely resembles that are catalyzed by the pyruvate dehydrogenase multienzyme complex, i.e.,<\/li>\r\n<\/ul>\r\n<table class=\"aligncenter\" border=\"1\">\r\n<tbody>\r\n<tr>\r\n<td>1.<\/td>\r\n<td>Decarboxylation -----------------------<\/td>\r\n<td>E1<\/td>\r\n<\/tr>\r\n<tr>\r\n<td>2.<\/td>\r\n<td>Succinyl group transfer -----------<\/td>\r\n<td>E2<\/td>\r\n<\/tr>\r\n<tr>\r\n<td>3.<\/td>\r\n<td>Succinyl-CoA formation. --------<\/td>\r\n<td>E2<\/td>\r\n<\/tr>\r\n<tr>\r\n<td>4.<\/td>\r\n<td>Oxidation of E2. -------------------<\/td>\r\n<td>E3<\/td>\r\n<\/tr>\r\n<tr>\r\n<td>5.<\/td>\r\n<td>Reduction of NAD+. ---------------<\/td>\r\n<td>E3<\/td>\r\n<\/tr>\r\n<\/tbody>\r\n<\/table>\r\n&nbsp;\r\n\r\n<strong style=\"text-align: initial;font-size: 1em\">E. Succinate formed from succinyl-CoA<\/strong>\r\n<p style=\"text-align: justify\"><strong>\r\n<\/strong><span style=\"font-size: 1em\">- Hydrolysis of \u201chigh-energy\u201d compound succinyl-CoA is coupled with the production of a\u00a0<\/span>\u201chigh- energy\u201d nucleosidetriphosphate (GTP).<\/p>\r\n&nbsp;\r\n\r\n<img class=\"aligncenter size-full wp-image-182\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-84.png\" alt=\"\" width=\"512\" height=\"139\" \/>\r\n<ul>\r\n \t<li style=\"text-align: justify\">- The thioester bond energy of succinyl-CoA is conserved through the formation of a series of \u201chigh-energy\u201d phosphate (~Pi). The succinate formation is as follows:<\/li>\r\n<\/ul>\r\n<img class=\"aligncenter size-full wp-image-183\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-85.png\" alt=\"\" width=\"419\" height=\"247\" \/>\r\n<ul>\r\n \t<li>- GTP is converted into ATP by nucleoside diphosphate kinase.<\/li>\r\n<\/ul>\r\nGTP + ADP \u2194 GDP + ATP\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2206G\u00b0\u2019 = 0 kJ\/mol\r\n\r\n&nbsp;\r\n\r\n&nbsp;\r\n\r\n<strong>F. Fumarate is formed from Succinate<\/strong>\r\n<ul>\r\n \t<li>- Stereospecific dehydrogenation occurs of succinate to fumarate and produces FADH<\/li>\r\n<\/ul>\r\n<img class=\"aligncenter size-full wp-image-184\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-86.png\" alt=\"\" width=\"480\" height=\"140\" \/>\r\n<ul>\r\n \t<li style=\"text-align: justify\">- The FAD is covalently bound to the succinate dehydrogenase enzyme. Thus, FADH2 cannot be oxidized as a cofactor. FADH2 is oxidized by the electron transport chain reaction.<\/li>\r\n<\/ul>\r\n<ul style=\"text-align: justify\">\r\n \t<li>- For the reason, succinate dehydrogenase is the only membrane-bound enzyme of citric acid cycle. The others are dissolved in the mitochondrial matrix.<\/li>\r\n<\/ul>\r\n<ul>\r\n \t<li style=\"text-align: justify\">- The enzyme is sturdily inhibited by malonate (structural analog of succinate).<\/li>\r\n<\/ul>\r\n&nbsp;\r\n\r\n<strong>G. Malate formed from fumarate by hydrogenation<\/strong>\r\n<ul>\r\n \t<li>- Hydrogenation occurs of fumarate\u2019s double bond to form L-malate.<\/li>\r\n<\/ul>\r\n<img class=\"aligncenter size-full wp-image-185\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-87.png\" alt=\"\" width=\"595\" height=\"201\" \/>\r\n\r\n&nbsp;\r\n\r\n<strong>H. Oxaloacetate regenerates from Malate<\/strong><strong>\u00a0<\/strong>\r\n<ul>\r\n \t<li style=\"text-align: justify\">- Oxaloacetate regenerates by the oxidation of hydroxyl group of L-malate to ketone in a NAD+-dependent reaction,.<\/li>\r\n<\/ul>\r\n<img class=\"aligncenter size-full wp-image-186\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-88.png\" alt=\"\" width=\"412\" height=\"135\" \/>\r\n\r\n&nbsp;\r\n\r\nThis reaction is relatively high endergonic reaction (\u2206G\u02c30)\r\n\r\n&nbsp;\r\n\r\n<strong><em>I. Integration of the citric acid cycle<\/em><\/strong>\r\n<ul>\r\n \t<li>- Following chemical transformations occurs in Citric acid cycle.<\/li>\r\n<\/ul>\r\n<ol>\r\n \t<li>One acetyl group (-COCH3) \u2192 2CO2 (4-electron pair process).<\/li>\r\n<\/ol>\r\n<img class=\"aligncenter size-full wp-image-187\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-89.png\" alt=\"\" width=\"474\" height=\"74\" \/>\r\n<p class=\"no-indent\" style=\"text-align: justify\">2. Reduction of three NAD+ to three NADH (3-electron pairs process) and equivalent to 9ATP generation, i.e., 3NAD+ + 6H+ + 6e- \u2192 3NADH + 3H+<\/p>\r\n<p class=\"no-indent\" style=\"text-align: justify\">3. Reduction of one FAD to FADH2 (1-electron pairs process) and equivalent to 2ATP generation, i.e., FAD + 2H+ + 2e- \u2192 FADH2<\/p>\r\n<p class=\"no-indent\" style=\"text-align: justify\">4. Generation of one GTP (ATP).<\/p>\r\n<p class=\"no-indent\" style=\"text-align: justify\">- Four electron pairs generated by one acetyl group oxidation are carried by 3NADH and FADH2 to the oxidative phosphorylation pathway to generate 11ATP.<\/p>\r\n<p class=\"no-indent\" style=\"text-align: justify\">- Thus, citric acid cycle generates 12ATP from one acetyl group and sends 4-electron pairs (8 electrons) to electron-transport chain, where they reduce two molecules of O2 to 4H2O, i.e.,<\/p>\r\n<p class=\"no-indent\" style=\"text-align: justify\">O2 + 8H+ + 8e- \u2192 4H2O.<\/p>\r\n&nbsp;\r\n<p class=\"no-indent\" style=\"text-align: justify\"><strong>\u00a0 4. REGULATION OF THE CITRIC ACID CYCLE<\/strong><\/p>\r\n\r\n<ul>\r\n \t<li style=\"text-align: justify\">- Rate-limiting enzymes of the citric acid cycle are <strong>Citrate synthase<\/strong>, <strong>isocitrate<\/strong> <strong>dehydrogenase <\/strong>and \u03b1<strong>-ketoglutarate dehydrogenase <\/strong>because those \u2206G are negative.<\/li>\r\n<\/ul>\r\n<ul style=\"text-align: justify\">\r\n \t<li>The citric acid cycle reactions are carried out in mitochondria, but most of the metabolites of citric acid cycle are present in both mitochondria and cytosol. Therefore it is difficult to establish the rate-determining steps.<\/li>\r\n<\/ul>\r\n<ul>\r\n \t<li style=\"text-align: justify\">- However, three of the eight steps have significantly negative physiological free energy changes. The enzymes involved in those steps are likely to function distant from equilibrium under physiological conditions.<\/li>\r\n<\/ul>\r\n<p style=\"text-align: center\"><strong>Standard (<\/strong>\u2206<strong>G\u00b0\u2019) and physiological (<\/strong>\u2206<strong>G) free energy changes<\/strong><\/p>\r\n\r\n<table class=\"aligncenter\" style=\"width: 506px;height: 295px\" border=\"1\">\r\n<tbody>\r\n<tr style=\"height: 43px\">\r\n<td style=\"width: 68.0625px;height: 43px\"><strong>Reaction<\/strong><\/td>\r\n<td style=\"width: 217.063px;height: 43px\"><strong>Enzyme<\/strong><\/td>\r\n<td style=\"width: 84.0625px;height: 43px\"><strong>\u2206G\u00b0\u2019 (kJ\/mol)<\/strong><\/td>\r\n<td style=\"width: 80.0625px;height: 43px\"><strong>\u2206G (kJ\/mol)<\/strong><\/td>\r\n<\/tr>\r\n<tr style=\"height: 28px\">\r\n<td style=\"width: 68.0625px;height: 28px\">1<\/td>\r\n<td style=\"width: 217.063px;height: 28px\">Citrate synthase<\/td>\r\n<td style=\"width: 84.0625px;height: 28px\">-32.2<\/td>\r\n<td style=\"width: 80.0625px;height: 28px\">Negative<\/td>\r\n<\/tr>\r\n<tr style=\"height: 28px\">\r\n<td style=\"width: 68.0625px;height: 28px\">2<\/td>\r\n<td style=\"width: 217.063px;height: 28px\">Aconitase<\/td>\r\n<td style=\"width: 84.0625px;height: 28px\">+13.3<\/td>\r\n<td style=\"width: 80.0625px;height: 28px\">~0<\/td>\r\n<\/tr>\r\n<tr style=\"height: 28px\">\r\n<td style=\"width: 68.0625px;height: 28px\">3<\/td>\r\n<td style=\"width: 217.063px;height: 28px\">Isocitrate dehydrogenase<\/td>\r\n<td style=\"width: 84.0625px;height: 28px\">-20.9<\/td>\r\n<td style=\"width: 80.0625px;height: 28px\">Negative<\/td>\r\n<\/tr>\r\n<tr style=\"height: 28px\">\r\n<td style=\"width: 68.0625px;height: 28px\">4<\/td>\r\n<td style=\"width: 217.063px;height: 28px\">\u03b1-Ketoglutarate\u00a0\u00a0dehydrogenase<\/td>\r\n<td style=\"width: 84.0625px;height: 28px\">-33.5<\/td>\r\n<td style=\"width: 80.0625px;height: 28px\">Negative<\/td>\r\n<\/tr>\r\n<tr style=\"height: 28px\">\r\n<td style=\"width: 68.0625px;height: 28px\">5<\/td>\r\n<td style=\"width: 217.063px;height: 28px\">Succinyl-CoA synthetase<\/td>\r\n<td style=\"width: 84.0625px;height: 28px\">-2.9<\/td>\r\n<td style=\"width: 80.0625px;height: 28px\">~0<\/td>\r\n<\/tr>\r\n<tr style=\"height: 28px\">\r\n<td style=\"width: 68.0625px;height: 28px\">6<\/td>\r\n<td style=\"width: 217.063px;height: 28px\">Succinate dehydrogenase<\/td>\r\n<td style=\"width: 84.0625px;height: 28px\">0.0<\/td>\r\n<td style=\"width: 80.0625px;height: 28px\">~0<\/td>\r\n<\/tr>\r\n<tr style=\"height: 28px\">\r\n<td style=\"width: 68.0625px;height: 28px\">7<\/td>\r\n<td style=\"width: 217.063px;height: 28px\">Fumarase<\/td>\r\n<td style=\"width: 84.0625px;height: 28px\">-3.8<\/td>\r\n<td style=\"width: 80.0625px;height: 28px\">~0<\/td>\r\n<\/tr>\r\n<tr style=\"height: 28px\">\r\n<td style=\"width: 68.0625px;height: 28px\">8<\/td>\r\n<td style=\"width: 217.063px;height: 28px\">Malate dehydrogenase<\/td>\r\n<td style=\"width: 84.0625px;height: 28px\">+29.7<\/td>\r\n<td style=\"width: 80.0625px;height: 28px\">~0<\/td>\r\n<\/tr>\r\n<\/tbody>\r\n<\/table>\r\n&nbsp;\r\n\r\n&nbsp;\r\n<ul>\r\n \t<li style=\"text-align: justify\">- The citric acid cycle is mainly regulated by<\/li>\r\n<\/ul>\r\n<ol style=\"text-align: justify\">\r\n \t<li>substrate availability (rate of diffusion of substrate into mitochondria)<\/li>\r\n \t<li>Product inhibition. (NADH, ATP, citrate)<\/li>\r\n \t<li>Competitive feedback inhibition by intermediates further along the cycle.<\/li>\r\n<\/ol>\r\n<ul>\r\n \t<li style=\"text-align: justify\">- ADP and ATP are allosteric regulators of isocitrate dehydrogenase. High [ADP] activates the enzyme whereas high [ATP] inhibits the enzyme.<\/li>\r\n \t<li style=\"text-align: justify\">- Pyruvate dehydrogenase, isocitrate dehydrogenase and \u03b1-ketoglutarate dehydrogenase enzymes are activates by Ca2+<\/li>\r\n<\/ul>\r\n<img class=\"aligncenter size-full wp-image-188\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-90.png\" alt=\"\" width=\"418\" height=\"541\" \/>\r\n<h2 style=\"text-align: center\"><strong>Figure: A diagram of the citric acid cycle and the pyruvate dehydrogenase reaction, indicating their points of inhibition ( <em>red octagons<\/em>) and the pathway intermediates that function as inhibitors (<em>dashed red arrows<\/em>). ADP and Ca2+ (<em>green dots<\/em>) are activators.<\/strong><\/h2>\r\n&nbsp;\r\n\r\n<strong>5. THE AMPHIBOLIC NATURE OF THE CITRIC ACID CYCLE<\/strong>\r\n<ul>\r\n \t<li style=\"text-align: justify\">- In the muscle, the citric acid cycle works mainly degradation of acetyl-CoA to produce bioenergies (ATP).<\/li>\r\n \t<li style=\"text-align: justify\">- In the liver, the citric acid cycle is <strong>amphibolic<\/strong>.<\/li>\r\n<\/ul>\r\nNote: Amphibolic = both anabolic and catabolic processes.\r\n\r\n&nbsp;\r\n\r\n<img class=\"aligncenter size-full wp-image-189\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-91.png\" alt=\"\" width=\"516\" height=\"239\" \/>\r\n\r\n&nbsp;\r\n\r\n<strong>Intermediates of citric acid cycle are also various precursors<\/strong>\r\n\r\n&nbsp;\r\n\r\n<img class=\"aligncenter size-full wp-image-190\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-92.png\" alt=\"\" width=\"386\" height=\"473\" \/>\r\n<ul>\r\n \t<li>- Intermediates of citric acid cycle are also precursors of:<\/li>\r\n \t<li>- Glucose biosynthesis.<\/li>\r\n \t<li>- Lipid biosynthesis including fatty acid and cholesterol.<\/li>\r\n<\/ul>\r\n<p style=\"text-align: justify\">Note: Lipid biosynthesis is taken place in cytosol, but the mitochondrial acetyl -CoA (processor) cannot be transported across the inner mitochondrial membrane. Thus, acetylCoA is converted to citrate by <strong>ATP-citrate lyase<\/strong> since citrate can cross the membrane. Why citrate synthase is not used? --- Because no ATP is produced. ADP<\/p>\r\n\r\n<ul>\r\n \t<li>+ Pi + oxaloacetate + acetyl-CoA \u2194 ATP + citrate + CoA<\/li>\r\n \t<li>- Amino acid biosynthesis<\/li>\r\n<\/ul>\r\n\u03b1-ketoglutarate + NAD(P)H + NH4+ \u2194 Glu + NAD(P)+ + H2O \u03b1-ketoglutarate + Ala \u2194 Glu + pyruvate\r\n\r\n&nbsp;\r\n\r\nOxaloacetate + Ala \u2194 Asp + pyruvate\r\n\r\n&nbsp;\r\n<ul>\r\n \t<li>- Porphyrin biosynthesis<\/li>\r\n \t<li>- Succinyl-CoA Utilize as a starting material.<\/li>\r\n<\/ul>\r\n&nbsp;\r\n<p style=\"text-align: justify\">When the citric acid cycle intermediates are transported too much as precursors, the concentration of oxaloacetate is very low.\u00a0 In this case, it is necessary to replenish citric acid cycle intermediates.<\/p>\r\n&nbsp;\r\n\r\nThe main reaction is:\r\n\r\n&nbsp;\r\n\r\nPyruvate + CO2 + ATP + H2O \u2194 oxaloacetate + ADP + P<em>i<\/em>\r\n\r\n&nbsp;\r\n\r\n&nbsp;\r\n\r\n&nbsp;\r\n\r\n<strong><em>The citric acid cycle is the center of metabolism<\/em><\/strong>\r\n<ul>\r\n \t<li>- Reduced products: NADH and FADH2 are reoxidized to produce ATP.<\/li>\r\n \t<li>- The citric acid intermediates are utilized in the biosynthesis of many vital cellular constituents.<\/li>\r\n<\/ul>\r\n&nbsp;\r\n<table>\r\n<tbody>\r\n<tr>\r\n<td><strong>you can view video on Citric acid cycle<\/strong><\/td>\r\n<td><a href=\"https:\/\/youtu.be\/OInVLabpd1M\" target=\"_blank\" rel=\"noopener\"><img class=\"alignnone wp-image-120\" src=\"http:\/\/epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/2018\/11\/download.png\" alt=\"\" width=\"36\" height=\"36\" \/><\/a><\/td>\r\n<\/tr>\r\n<\/tbody>\r\n<\/table>\r\n&nbsp;\r\n\r\n&nbsp;\r\n<div class=\"textbox learning-objectives\">\r\n<h3><strong>References<\/strong><\/h3>\r\n&nbsp;\r\n<ul>\r\n \t<li style=\"text-align: justify\">Ivannikov, M. et al. (2013). \"Mitochondrial Free Ca2+ Levels and Their Effects on Energy Metabolism in Drosophila Motor Nerve Terminals\". Biophys. J. 104 (11): 2353\u20132361.<\/li>\r\n \t<li style=\"text-align: justify\">Denton RM, Randle PJ, Bridges BJ, Cooper RH, Kerbey AL, Pask HT, Severson DL, Stansbie D, Whitehouse S (1975). \"Regulation of mammalian pyruvate dehydrogenase\". Mol. Cell. Biochem. 9 (1): 27\u201353.<\/li>\r\n \t<li style=\"text-align: justify\">Koivunen P, Hirsil\u00e4 M, Remes AM, Hassinen IE, Kivirikko KI, Myllyharju J (2007). \"Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF\". J. Biol. Chem. 282 (7): 4524\u201332.<\/li>\r\n<\/ul>\r\n&nbsp;\r\n\r\n<strong>Web site<\/strong>\r\n<ul>\r\n \t<li style=\"text-align: justify\">http:\/\/www.watcut.uwaterloo.ca\/webnotes\/Metabolism\/tcaRegulation.html<\/li>\r\n \t<li style=\"text-align: justify\">http:\/\/www.brynmawr.edu\/Acads\/Chem\/chem242\/Chapter14Responses.html<\/li>\r\n \t<li style=\"text-align: justify\">https:\/\/www.rose-hulman.edu\/~brandt\/Chem330\/TCA_cycle.pdf<\/li>\r\n \t<li style=\"text-align: justify\">http:\/\/www.med.unc.edu\/neurology\/files\/documents\/child-teaching-pdf\/CITRIC%20ACID%20CYCLE.pdf<\/li>\r\n \t<li style=\"text-align: justify\">https:\/\/en.wikibooks.org\/wiki\/Structural_Biochemistry\/Krebs_Cycle_%28Citric_Acid _cycle%29<\/li>\r\n<\/ul>\r\n<strong>Books<\/strong>\r\n<ul>\r\n \t<li style=\"text-align: justify\">Biochemistry, Jeremy M. Berg, John L. Tomoczko, Lubert Stryer. 5th Edition<\/li>\r\n \t<li style=\"text-align: justify\">Lehninger\u2019s Principle of Biochemistry, David L. Nelson and Michael M. Cox, 5th Edition (2008)<\/li>\r\n \t<li style=\"text-align: justify\">Harper\u2019s Illustrated Biochemistry, Robert K. Murray, Daryl K. Granner, Peter A. Mayes, 26th Edition (2003)<\/li>\r\n \t<li style=\"text-align: justify\">Biochemistry, Voet D, Voet JG, New York: John Wiley &amp; Sons, Inc. 3rd Edition (2004)<\/li>\r\n<\/ul>\r\n&nbsp;\r\n\r\n<\/div>\r\n&nbsp;\r\n\r\n&nbsp;\r\n\r\n&nbsp;","rendered":"<div><span style=\"float: right\"><a href=\"https:\/\/youtu.be\/OInVLabpd1M\" target=\"_blank\" rel=\"noopener\"><img decoding=\"async\" src=\"http:\/\/epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/2018\/11\/download.png\" alt=\"epgp books\" width=\"75px\" height=\"75px;\" \/><\/a><br \/>\n<\/span><\/div>\n<p><strong>\u00a0 \u00a0<\/strong><\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Objectives<\/strong><\/p>\n<ol>\n<li>History and introduction of citric acid cycle<\/li>\n<li>Conversion of pyruvate to activated acetate by pyruvate dehydrogenase<\/li>\n<li>Explain Reactions of citric acid cycle<\/li>\n<li>Amphibolic nature of Citric acid cycle<\/li>\n<\/ol>\n<p><strong>\u00a0 \u00a0<\/strong><\/p>\n<p>&nbsp;<\/p>\n<p><strong>OVERVIEW<\/strong><\/p>\n<p><strong>\u00a0<\/strong><\/p>\n<p style=\"text-align: justify\">Citric acid cycle is also called <strong>Tricarboxylic acid (TCA) cycle<\/strong> or <strong>Krebs cycle<\/strong> is a sequence of biochemical reactions that occurs in all aerobic organisms for energy generation.<\/p>\n<p style=\"text-align: justify\"><strong>\u00a0<\/strong><\/p>\n<p style=\"text-align: justify\">Energy is generation is carried out by the oxidation of acetate, which is derived from carbohydrates, lipids and proteins converted into Co2 and chemical energy stored in the<\/p>\n<p style=\"text-align: justify\"><strong>\u00a0<\/strong><\/p>\n<p style=\"text-align: justify\">form of adenosine triphosphate (ATP). Furthermore the TCA cycle supplies precursors for synthesis of several amino acids and reducing agent such as NADH, which involves in various other biochemical reactions. TCA cycle is one of the initially established mechanism of cellular metabolism suggested by the central importance in various biochemical pathways.<\/p>\n<p>&nbsp;<\/p>\n<p style=\"text-align: justify\">The name of this biochemical pathway is derived from tricarboxylic acid (e.g. citric acid) . Citric acid is first utilized and then regenerated by this sequential reactions to complete the cycle. The major function of these two closely associated pathways is the oxidative breakdown of nutrients into production of usable energy in the form of ATP.<\/p>\n<p>&nbsp;<\/p>\n<p style=\"text-align: justify\">In eukaryotic cells, the Krebs cycle occurs in the mitochondrial matrix. In prokaryotic cells the TCA reaction occurs in the cytosol through the proton gradient for energy generation.<\/p>\n<p>&nbsp;<\/p>\n<p>In 1935 Albert Szent-Gyorgyi showed that<\/p>\n<p>&nbsp;<\/p>\n<p>Succinate \u2192\u00a0Fumarate \u2192\u00a0Malate \u2192 Oxaloacetate<\/p>\n<p>&nbsp;<\/p>\n<p>Carl Martius and Franz Knoop showed<\/p>\n<p>&nbsp;<\/p>\n<div>\n<p>\u00a0 \u00a0Citrate \u00a0cis-aconitate \u2192\u00a0 Isocitrate \u2192 \u03b1 ketoglutarate \u2192\u00a0 Succinate \u2192\u00a0\u00a0<span style=\"font-size: 1em;text-align: initial\">Fumarate \u2192\u00a0Malate \u2192\u00a0Oxaloacetate<\/span><\/p>\n<\/div>\n<p>&#8211; Overall reaction of the citric acid cycle is:<\/p>\n<p>&nbsp;<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-165\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-70.png\" alt=\"\" width=\"491\" height=\"105\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-70.png 491w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-70-300x64.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-70-65x14.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-70-225x48.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-70-350x75.png 350w\" sizes=\"auto, (max-width: 491px) 100vw, 491px\" \/><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-166\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-71.png\" alt=\"\" width=\"558\" height=\"235\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-71.png 558w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-71-300x126.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-71-65x27.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-71-225x95.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-71-350x147.png 350w\" sizes=\"auto, (max-width: 558px) 100vw, 558px\" \/><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-167\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-72.png\" alt=\"\" width=\"657\" height=\"513\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-72.png 657w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-72-300x234.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-72-65x51.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-72-225x176.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-72-350x273.png 350w\" sizes=\"auto, (max-width: 657px) 100vw, 657px\" \/><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-168\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-73.png\" alt=\"\" width=\"606\" height=\"237\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-73.png 606w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-73-300x117.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-73-65x25.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-73-225x88.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-73-350x137.png 350w\" sizes=\"auto, (max-width: 606px) 100vw, 606px\" \/><strong>\u00a0<\/strong><\/p>\n<p><strong>2. Conversion of pyruvate to activated acetate by pyruvate dehydrogenase<\/strong><\/p>\n<p>&nbsp;<\/p>\n<ul>\n<li>&#8211; Pyruvate converts into the acetyl-CoA before enters into the TCA.<\/li>\n<li>&#8211; The <strong>coenzyme A<\/strong> is act as a carrier for acetyl and other acyl group.<\/li>\n<li>&#8211; Acetyl-CoA is a \u201c<strong>high-energy<\/strong>\u201d compound.<\/li>\n<\/ul>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-169\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-74.png\" alt=\"\" width=\"525\" height=\"533\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-74.png 525w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-74-295x300.png 295w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-74-65x66.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-74-225x228.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-74-350x355.png 350w\" sizes=\"auto, (max-width: 525px) 100vw, 525px\" \/><\/p>\n<p>&nbsp;<\/p>\n<p><strong>A. Pyruvate dehydrogenase is a multienzyme complex<\/strong><\/p>\n<ul>\n<li style=\"text-align: justify\">&#8211; By the oxidative decarboxylation process Acetyl-CoA is formed from pyruvate using multienzyme complex named as a <strong style=\"text-align: initial;font-size: 1em\">pyruvate dehydrogenase<\/strong><span style=\"text-align: initial;font-size: 1em\">. Pyruvate + CoA + NAD+ \u2192 acetyl-CoA + CO2 + NADH<\/span><\/li>\n<\/ul>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-170\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-75.png\" alt=\"\" width=\"469\" height=\"201\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-75.png 469w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-75-300x129.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-75-65x28.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-75-225x96.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-75-350x150.png 350w\" sizes=\"auto, (max-width: 469px) 100vw, 469px\" \/><\/p>\n<ul>\n<li>&#8211; Pyruvate dehydrogenase a multienzyme complex consists of:<\/li>\n<\/ul>\n<ol>\n<li>Pyruvate dehydrogenase (E1)<\/li>\n<li>Dihydrolipoyl transacetylase (E2)<\/li>\n<li>Dihydrolipoyl dehydrogenase (E3)<\/li>\n<\/ol>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-171\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-76.png\" alt=\"\" width=\"643\" height=\"311\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-76.png 643w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-76-300x145.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-76-65x31.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-76-225x109.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-76-350x169.png 350w\" sizes=\"auto, (max-width: 643px) 100vw, 643px\" \/><\/p>\n<p>&nbsp;<\/p>\n<p><strong>B. Control of pyruvate dehydrogenase <\/strong><strong>Product inhibition<\/strong><\/p>\n<ul>\n<li style=\"text-align: justify\">&#8211; When the relative concentrations of NADH and acetyl-CoA are high, the reversible reactions catalyzed by E2 and E3 are driven backwards. Therefore formation of acetyl-<\/li>\n<\/ul>\n<p>CoA is inhibited.<\/p>\n<p>&nbsp;<\/p>\n<ul>\n<li style=\"text-align: justify\">&#8211; Thus the E2 and E3 activities are controlled by product inhibition (acetyl-CoA for E2 and NADH for E3).<\/li>\n<\/ul>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-172\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-77.png\" alt=\"\" width=\"545\" height=\"247\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-77.png 545w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-77-300x136.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-77-65x29.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-77-225x102.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-77-350x159.png 350w\" sizes=\"auto, (max-width: 545px) 100vw, 545px\" \/><\/p>\n<p><strong><em>Covalent modification <\/em><\/strong>(Eukaryotic complex only)<\/p>\n<p>&nbsp;<\/p>\n<p style=\"text-align: justify\">E1 is regulated by phosphorylation\/dephosphorylation. When the Ser of E1 is phosphorylated, the enzyme is inactivated.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-173\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-78.png\" alt=\"\" width=\"637\" height=\"213\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-78.png 637w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-78-300x100.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-78-65x22.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-78-225x75.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-78-350x117.png 350w\" sizes=\"auto, (max-width: 637px) 100vw, 637px\" \/><\/p>\n<p>Activators of phosphatase: Mg2+, Ca2+<\/p>\n<p>&nbsp;<\/p>\n<p>Activators of kinase: Acetyl-CoA, NADH<\/p>\n<p>&nbsp;<\/p>\n<p>Inhibitors of kinase: Pyruvate, ADP, Ca2+, high Mg2+, K+<\/p>\n<p>&nbsp;<\/p>\n<p style=\"text-align: justify\">Remember: <strong>Insulin<\/strong> inhibits phosphorylation and activates dephosphorylation in order to reduce the (glucose) in blood at the starting point of glycolysis.<\/p>\n<p>&nbsp;<\/p>\n<ul>\n<li style=\"text-align: justify\">&#8211; Now, insulin also works to reduce the end product of glycolysis, i.e., activates dephosphorylation of E1 to convert pyruvate to acetyl-CoA.<\/li>\n<li>&#8211; Acetyl-CoA is not only the fuel of citric acid cycle, but also the precursor of fatty acids.<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Reactions of the citric acid cycle<\/strong><\/p>\n<ol>\n<li><strong><em>Citrate is formed from Oxaloacetate and Acetyl Coenzyme A by citrate synthase enzyme<\/em><\/strong><\/li>\n<\/ol>\n<p style=\"text-align: justify\">The citric acid cycle initiates through the condensation of an oxaloacetate (four-carbon unit), and the acetyl group of acetyl CoA (a two-carbon unit). Oxaloacetate reacts with acetyl CoA and H2O to yield as citrate and CoA.<\/p>\n<p>&nbsp;<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-174\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-79.png\" alt=\"\" width=\"555\" height=\"168\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-79.png 555w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-79-300x91.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-79-65x20.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-79-225x68.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-79-350x106.png 350w\" sizes=\"auto, (max-width: 555px) 100vw, 555px\" \/><\/p>\n<p>&nbsp;<\/p>\n<p><strong><em>Isomerization of Citrate into Isocitrate<\/em><\/strong><\/p>\n<p>&nbsp;<\/p>\n<p style=\"text-align: justify\">In the citrate molecule the tertiary hydroxyl group is not properly situated for the oxidative decarboxylations that follow. Therefore, isomerization occurs of citrate into isocitrate to allow the six-carbon component to undergo oxidative decarboxylation. The isomerization of citrate is accomplished by a dehydration reaction following a hydration reaction. The result is a substitution of a hydrogen atom and a OH- group. Both the steps are catalyzed by the enzyme <em>aconitase<\/em> because cis<em>-aconitate<\/em> is an intermediate.<\/p>\n<p>&nbsp;<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-177\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-80.png\" alt=\"\" width=\"506\" height=\"208\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-80.png 506w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-80-300x123.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-80-65x27.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-80-225x92.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-80-350x144.png 350w\" sizes=\"auto, (max-width: 506px) 100vw, 506px\" \/><\/p>\n<p>&nbsp;<\/p>\n<p><strong><em>Fluorocitrate inhibits aconitase<\/em><\/strong><\/p>\n<ul>\n<li style=\"text-align: justify\">&#8211; Fluoroacetate, one of the most toxic small molecules (LD50 = 0.2 mg\/kg), is converted to (2R,3R)-fluorocitrate, which specifically inhibits aconitase since Ser-642 cannot remove the proton at C2.<\/li>\n<\/ul>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-179\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-81.png\" alt=\"\" width=\"524\" height=\"239\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-81.png 524w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-81-300x137.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-81-65x30.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-81-225x103.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-81-350x160.png 350w\" sizes=\"auto, (max-width: 524px) 100vw, 524px\" \/><\/p>\n<p><strong><em>C. Oxidation and decarboxylation of isocitrate to a-Ketoglutarate<\/em><\/strong><\/p>\n<p>&nbsp;<\/p>\n<p>The isocitrate is\u00a0 oxidized and decarboxylated by enzyme <em>isocitrate dehydrogenase.<\/em><\/p>\n<p>Oxalosuccinate act as an intermediate in this reaction.<\/p>\n<p>&nbsp;<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-180\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-82.png\" alt=\"\" width=\"601\" height=\"191\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-82.png 601w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-82-300x95.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-82-65x21.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-82-225x72.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-82-350x111.png 350w\" sizes=\"auto, (max-width: 601px) 100vw, 601px\" \/><\/p>\n<p>There are two isozymes in mammalian cells.<\/p>\n<ol>\n<li>NAD+-dependent form is in mitochondria and requires Mn2+ or Mg2+.<\/li>\n<li>NADP+-dependent form is in both cytosol and mitochondria.<\/li>\n<\/ol>\n<p>&nbsp;<\/p>\n<p><strong>\u00a0 D. The oxidative decarboxylation of \u03b1- Ketoglutarate to forms Succinyl CoA<\/strong><\/p>\n<p>&nbsp;<\/p>\n<p style=\"text-align: justify\">Catalyzes the oxidative decarboxylation of an \u03b1-keto acid, releasing CO2, forming succinyl-CoA and reducing NAD+ to NADH<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-181\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-83.png\" alt=\"\" width=\"530\" height=\"139\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-83.png 530w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-83-300x79.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-83-65x17.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-83-225x59.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-83-350x92.png 350w\" sizes=\"auto, (max-width: 530px) 100vw, 530px\" \/><\/p>\n<ul>\n<li style=\"text-align: justify\">&#8211; A \u03b1-Ketoglutarate dehydrogenase that consists of \u03b1-ketoglutarate dehydrogenase (E1), dihydrolipoyl transsuccinylase (E2), and dihydrolipoyl dehydrogenase (E3).<\/li>\n<\/ul>\n<ul style=\"text-align: justify\">\n<li>&#8211; The overall reaction closely resembles that are catalyzed by the pyruvate dehydrogenase multienzyme complex, i.e.,<\/li>\n<\/ul>\n<table class=\"aligncenter\">\n<tbody>\n<tr>\n<td>1.<\/td>\n<td>Decarboxylation &#8212;&#8212;&#8212;&#8212;&#8212;&#8212;&#8212;&#8211;<\/td>\n<td>E1<\/td>\n<\/tr>\n<tr>\n<td>2.<\/td>\n<td>Succinyl group transfer &#8212;&#8212;&#8212;&#8211;<\/td>\n<td>E2<\/td>\n<\/tr>\n<tr>\n<td>3.<\/td>\n<td>Succinyl-CoA formation. &#8212;&#8212;&#8211;<\/td>\n<td>E2<\/td>\n<\/tr>\n<tr>\n<td>4.<\/td>\n<td>Oxidation of E2. &#8212;&#8212;&#8212;&#8212;&#8212;&#8212;-<\/td>\n<td>E3<\/td>\n<\/tr>\n<tr>\n<td>5.<\/td>\n<td>Reduction of NAD+. &#8212;&#8212;&#8212;&#8212;&#8212;<\/td>\n<td>E3<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p>&nbsp;<\/p>\n<p><strong style=\"text-align: initial;font-size: 1em\">E. Succinate formed from succinyl-CoA<\/strong><\/p>\n<p style=\"text-align: justify\"><strong><br \/>\n<\/strong><span style=\"font-size: 1em\">&#8211; Hydrolysis of \u201chigh-energy\u201d compound succinyl-CoA is coupled with the production of a\u00a0<\/span>\u201chigh- energy\u201d nucleosidetriphosphate (GTP).<\/p>\n<p>&nbsp;<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-182\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-84.png\" alt=\"\" width=\"512\" height=\"139\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-84.png 512w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-84-300x81.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-84-65x18.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-84-225x61.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-84-350x95.png 350w\" sizes=\"auto, (max-width: 512px) 100vw, 512px\" \/><\/p>\n<ul>\n<li style=\"text-align: justify\">&#8211; The thioester bond energy of succinyl-CoA is conserved through the formation of a series of \u201chigh-energy\u201d phosphate (~Pi). The succinate formation is as follows:<\/li>\n<\/ul>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-183\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-85.png\" alt=\"\" width=\"419\" height=\"247\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-85.png 419w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-85-300x177.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-85-65x38.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-85-225x133.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-85-350x206.png 350w\" sizes=\"auto, (max-width: 419px) 100vw, 419px\" \/><\/p>\n<ul>\n<li>&#8211; GTP is converted into ATP by nucleoside diphosphate kinase.<\/li>\n<\/ul>\n<p>GTP + ADP \u2194 GDP + ATP\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2206G\u00b0\u2019 = 0 kJ\/mol<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p><strong>F. Fumarate is formed from Succinate<\/strong><\/p>\n<ul>\n<li>&#8211; Stereospecific dehydrogenation occurs of succinate to fumarate and produces FADH<\/li>\n<\/ul>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-184\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-86.png\" alt=\"\" width=\"480\" height=\"140\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-86.png 480w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-86-300x88.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-86-65x19.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-86-225x66.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-86-350x102.png 350w\" sizes=\"auto, (max-width: 480px) 100vw, 480px\" \/><\/p>\n<ul>\n<li style=\"text-align: justify\">&#8211; The FAD is covalently bound to the succinate dehydrogenase enzyme. Thus, FADH2 cannot be oxidized as a cofactor. FADH2 is oxidized by the electron transport chain reaction.<\/li>\n<\/ul>\n<ul style=\"text-align: justify\">\n<li>&#8211; For the reason, succinate dehydrogenase is the only membrane-bound enzyme of citric acid cycle. The others are dissolved in the mitochondrial matrix.<\/li>\n<\/ul>\n<ul>\n<li style=\"text-align: justify\">&#8211; The enzyme is sturdily inhibited by malonate (structural analog of succinate).<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<p><strong>G. Malate formed from fumarate by hydrogenation<\/strong><\/p>\n<ul>\n<li>&#8211; Hydrogenation occurs of fumarate\u2019s double bond to form L-malate.<\/li>\n<\/ul>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-185\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-87.png\" alt=\"\" width=\"595\" height=\"201\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-87.png 595w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-87-300x101.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-87-65x22.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-87-225x76.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-87-350x118.png 350w\" sizes=\"auto, (max-width: 595px) 100vw, 595px\" \/><\/p>\n<p>&nbsp;<\/p>\n<p><strong>H. Oxaloacetate regenerates from Malate<\/strong><strong>\u00a0<\/strong><\/p>\n<ul>\n<li style=\"text-align: justify\">&#8211; Oxaloacetate regenerates by the oxidation of hydroxyl group of L-malate to ketone in a NAD+-dependent reaction,.<\/li>\n<\/ul>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-186\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-88.png\" alt=\"\" width=\"412\" height=\"135\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-88.png 412w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-88-300x98.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-88-65x21.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-88-225x74.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-88-350x115.png 350w\" sizes=\"auto, (max-width: 412px) 100vw, 412px\" \/><\/p>\n<p>&nbsp;<\/p>\n<p>This reaction is relatively high endergonic reaction (\u2206G\u02c30)<\/p>\n<p>&nbsp;<\/p>\n<p><strong><em>I. Integration of the citric acid cycle<\/em><\/strong><\/p>\n<ul>\n<li>&#8211; Following chemical transformations occurs in Citric acid cycle.<\/li>\n<\/ul>\n<ol>\n<li>One acetyl group (-COCH3) \u2192 2CO2 (4-electron pair process).<\/li>\n<\/ol>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-187\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-89.png\" alt=\"\" width=\"474\" height=\"74\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-89.png 474w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-89-300x47.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-89-65x10.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-89-225x35.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-89-350x55.png 350w\" sizes=\"auto, (max-width: 474px) 100vw, 474px\" \/><\/p>\n<p class=\"no-indent\" style=\"text-align: justify\">2. Reduction of three NAD+ to three NADH (3-electron pairs process) and equivalent to 9ATP generation, i.e., 3NAD+ + 6H+ + 6e- \u2192 3NADH + 3H+<\/p>\n<p class=\"no-indent\" style=\"text-align: justify\">3. Reduction of one FAD to FADH2 (1-electron pairs process) and equivalent to 2ATP generation, i.e., FAD + 2H+ + 2e- \u2192 FADH2<\/p>\n<p class=\"no-indent\" style=\"text-align: justify\">4. Generation of one GTP (ATP).<\/p>\n<p class=\"no-indent\" style=\"text-align: justify\">&#8211; Four electron pairs generated by one acetyl group oxidation are carried by 3NADH and FADH2 to the oxidative phosphorylation pathway to generate 11ATP.<\/p>\n<p class=\"no-indent\" style=\"text-align: justify\">&#8211; Thus, citric acid cycle generates 12ATP from one acetyl group and sends 4-electron pairs (8 electrons) to electron-transport chain, where they reduce two molecules of O2 to 4H2O, i.e.,<\/p>\n<p class=\"no-indent\" style=\"text-align: justify\">O2 + 8H+ + 8e- \u2192 4H2O.<\/p>\n<p>&nbsp;<\/p>\n<p class=\"no-indent\" style=\"text-align: justify\"><strong>\u00a0 4. REGULATION OF THE CITRIC ACID CYCLE<\/strong><\/p>\n<ul>\n<li style=\"text-align: justify\">&#8211; Rate-limiting enzymes of the citric acid cycle are <strong>Citrate synthase<\/strong>, <strong>isocitrate<\/strong> <strong>dehydrogenase <\/strong>and \u03b1<strong>-ketoglutarate dehydrogenase <\/strong>because those \u2206G are negative.<\/li>\n<\/ul>\n<ul style=\"text-align: justify\">\n<li>The citric acid cycle reactions are carried out in mitochondria, but most of the metabolites of citric acid cycle are present in both mitochondria and cytosol. Therefore it is difficult to establish the rate-determining steps.<\/li>\n<\/ul>\n<ul>\n<li style=\"text-align: justify\">&#8211; However, three of the eight steps have significantly negative physiological free energy changes. The enzymes involved in those steps are likely to function distant from equilibrium under physiological conditions.<\/li>\n<\/ul>\n<p style=\"text-align: center\"><strong>Standard (<\/strong>\u2206<strong>G\u00b0\u2019) and physiological (<\/strong>\u2206<strong>G) free energy changes<\/strong><\/p>\n<table class=\"aligncenter\" style=\"width: 506px;height: 295px\">\n<tbody>\n<tr style=\"height: 43px\">\n<td style=\"width: 68.0625px;height: 43px\"><strong>Reaction<\/strong><\/td>\n<td style=\"width: 217.063px;height: 43px\"><strong>Enzyme<\/strong><\/td>\n<td style=\"width: 84.0625px;height: 43px\"><strong>\u2206G\u00b0\u2019 (kJ\/mol)<\/strong><\/td>\n<td style=\"width: 80.0625px;height: 43px\"><strong>\u2206G (kJ\/mol)<\/strong><\/td>\n<\/tr>\n<tr style=\"height: 28px\">\n<td style=\"width: 68.0625px;height: 28px\">1<\/td>\n<td style=\"width: 217.063px;height: 28px\">Citrate synthase<\/td>\n<td style=\"width: 84.0625px;height: 28px\">-32.2<\/td>\n<td style=\"width: 80.0625px;height: 28px\">Negative<\/td>\n<\/tr>\n<tr style=\"height: 28px\">\n<td style=\"width: 68.0625px;height: 28px\">2<\/td>\n<td style=\"width: 217.063px;height: 28px\">Aconitase<\/td>\n<td style=\"width: 84.0625px;height: 28px\">+13.3<\/td>\n<td style=\"width: 80.0625px;height: 28px\">~0<\/td>\n<\/tr>\n<tr style=\"height: 28px\">\n<td style=\"width: 68.0625px;height: 28px\">3<\/td>\n<td style=\"width: 217.063px;height: 28px\">Isocitrate dehydrogenase<\/td>\n<td style=\"width: 84.0625px;height: 28px\">-20.9<\/td>\n<td style=\"width: 80.0625px;height: 28px\">Negative<\/td>\n<\/tr>\n<tr style=\"height: 28px\">\n<td style=\"width: 68.0625px;height: 28px\">4<\/td>\n<td style=\"width: 217.063px;height: 28px\">\u03b1-Ketoglutarate\u00a0\u00a0dehydrogenase<\/td>\n<td style=\"width: 84.0625px;height: 28px\">-33.5<\/td>\n<td style=\"width: 80.0625px;height: 28px\">Negative<\/td>\n<\/tr>\n<tr style=\"height: 28px\">\n<td style=\"width: 68.0625px;height: 28px\">5<\/td>\n<td style=\"width: 217.063px;height: 28px\">Succinyl-CoA synthetase<\/td>\n<td style=\"width: 84.0625px;height: 28px\">-2.9<\/td>\n<td style=\"width: 80.0625px;height: 28px\">~0<\/td>\n<\/tr>\n<tr style=\"height: 28px\">\n<td style=\"width: 68.0625px;height: 28px\">6<\/td>\n<td style=\"width: 217.063px;height: 28px\">Succinate dehydrogenase<\/td>\n<td style=\"width: 84.0625px;height: 28px\">0.0<\/td>\n<td style=\"width: 80.0625px;height: 28px\">~0<\/td>\n<\/tr>\n<tr style=\"height: 28px\">\n<td style=\"width: 68.0625px;height: 28px\">7<\/td>\n<td style=\"width: 217.063px;height: 28px\">Fumarase<\/td>\n<td style=\"width: 84.0625px;height: 28px\">-3.8<\/td>\n<td style=\"width: 80.0625px;height: 28px\">~0<\/td>\n<\/tr>\n<tr style=\"height: 28px\">\n<td style=\"width: 68.0625px;height: 28px\">8<\/td>\n<td style=\"width: 217.063px;height: 28px\">Malate dehydrogenase<\/td>\n<td style=\"width: 84.0625px;height: 28px\">+29.7<\/td>\n<td style=\"width: 80.0625px;height: 28px\">~0<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<ul>\n<li style=\"text-align: justify\">&#8211; The citric acid cycle is mainly regulated by<\/li>\n<\/ul>\n<ol style=\"text-align: justify\">\n<li>substrate availability (rate of diffusion of substrate into mitochondria)<\/li>\n<li>Product inhibition. (NADH, ATP, citrate)<\/li>\n<li>Competitive feedback inhibition by intermediates further along the cycle.<\/li>\n<\/ol>\n<ul>\n<li style=\"text-align: justify\">&#8211; ADP and ATP are allosteric regulators of isocitrate dehydrogenase. High [ADP] activates the enzyme whereas high [ATP] inhibits the enzyme.<\/li>\n<li style=\"text-align: justify\">&#8211; Pyruvate dehydrogenase, isocitrate dehydrogenase and \u03b1-ketoglutarate dehydrogenase enzymes are activates by Ca2+<\/li>\n<\/ul>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-188\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-90.png\" alt=\"\" width=\"418\" height=\"541\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-90.png 418w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-90-232x300.png 232w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-90-65x84.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-90-225x291.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-90-350x453.png 350w\" sizes=\"auto, (max-width: 418px) 100vw, 418px\" \/><\/p>\n<h2 style=\"text-align: center\"><strong>Figure: A diagram of the citric acid cycle and the pyruvate dehydrogenase reaction, indicating their points of inhibition ( <em>red octagons<\/em>) and the pathway intermediates that function as inhibitors (<em>dashed red arrows<\/em>). ADP and Ca2+ (<em>green dots<\/em>) are activators.<\/strong><\/h2>\n<p>&nbsp;<\/p>\n<p><strong>5. THE AMPHIBOLIC NATURE OF THE CITRIC ACID CYCLE<\/strong><\/p>\n<ul>\n<li style=\"text-align: justify\">&#8211; In the muscle, the citric acid cycle works mainly degradation of acetyl-CoA to produce bioenergies (ATP).<\/li>\n<li style=\"text-align: justify\">&#8211; In the liver, the citric acid cycle is <strong>amphibolic<\/strong>.<\/li>\n<\/ul>\n<p>Note: Amphibolic = both anabolic and catabolic processes.<\/p>\n<p>&nbsp;<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-189\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-91.png\" alt=\"\" width=\"516\" height=\"239\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-91.png 516w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-91-300x139.png 300w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-91-65x30.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-91-225x104.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-91-350x162.png 350w\" sizes=\"auto, (max-width: 516px) 100vw, 516px\" \/><\/p>\n<p>&nbsp;<\/p>\n<p><strong>Intermediates of citric acid cycle are also various precursors<\/strong><\/p>\n<p>&nbsp;<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-190\" src=\"http:\/\/biocp04.epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/sites\/215\/2019\/04\/1-92.png\" alt=\"\" width=\"386\" height=\"473\" srcset=\"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-92.png 386w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-92-245x300.png 245w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-92-65x80.png 65w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-92-225x276.png 225w, https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-content\/uploads\/sites\/215\/2019\/04\/1-92-350x429.png 350w\" sizes=\"auto, (max-width: 386px) 100vw, 386px\" \/><\/p>\n<ul>\n<li>&#8211; Intermediates of citric acid cycle are also precursors of:<\/li>\n<li>&#8211; Glucose biosynthesis.<\/li>\n<li>&#8211; Lipid biosynthesis including fatty acid and cholesterol.<\/li>\n<\/ul>\n<p style=\"text-align: justify\">Note: Lipid biosynthesis is taken place in cytosol, but the mitochondrial acetyl -CoA (processor) cannot be transported across the inner mitochondrial membrane. Thus, acetylCoA is converted to citrate by <strong>ATP-citrate lyase<\/strong> since citrate can cross the membrane. Why citrate synthase is not used? &#8212; Because no ATP is produced. ADP<\/p>\n<ul>\n<li>+ Pi + oxaloacetate + acetyl-CoA \u2194 ATP + citrate + CoA<\/li>\n<li>&#8211; Amino acid biosynthesis<\/li>\n<\/ul>\n<p>\u03b1-ketoglutarate + NAD(P)H + NH4+ \u2194 Glu + NAD(P)+ + H2O \u03b1-ketoglutarate + Ala \u2194 Glu + pyruvate<\/p>\n<p>&nbsp;<\/p>\n<p>Oxaloacetate + Ala \u2194 Asp + pyruvate<\/p>\n<p>&nbsp;<\/p>\n<ul>\n<li>&#8211; Porphyrin biosynthesis<\/li>\n<li>&#8211; Succinyl-CoA Utilize as a starting material.<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<p style=\"text-align: justify\">When the citric acid cycle intermediates are transported too much as precursors, the concentration of oxaloacetate is very low.\u00a0 In this case, it is necessary to replenish citric acid cycle intermediates.<\/p>\n<p>&nbsp;<\/p>\n<p>The main reaction is:<\/p>\n<p>&nbsp;<\/p>\n<p>Pyruvate + CO2 + ATP + H2O \u2194 oxaloacetate + ADP + P<em>i<\/em><\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p><strong><em>The citric acid cycle is the center of metabolism<\/em><\/strong><\/p>\n<ul>\n<li>&#8211; Reduced products: NADH and FADH2 are reoxidized to produce ATP.<\/li>\n<li>&#8211; The citric acid intermediates are utilized in the biosynthesis of many vital cellular constituents.<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<table>\n<tbody>\n<tr>\n<td><strong>you can view video on Citric acid cycle<\/strong><\/td>\n<td><a href=\"https:\/\/youtu.be\/OInVLabpd1M\" target=\"_blank\" rel=\"noopener\"><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-120\" src=\"http:\/\/epgpbooks.inflibnet.ac.in\/wp-content\/uploads\/2018\/11\/download.png\" alt=\"\" width=\"36\" height=\"36\" \/><\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<div class=\"textbox learning-objectives\">\n<h3><strong>References<\/strong><\/h3>\n<p>&nbsp;<\/p>\n<ul>\n<li style=\"text-align: justify\">Ivannikov, M. et al. (2013). &#8220;Mitochondrial Free Ca2+ Levels and Their Effects on Energy Metabolism in Drosophila Motor Nerve Terminals&#8221;. Biophys. J. 104 (11): 2353\u20132361.<\/li>\n<li style=\"text-align: justify\">Denton RM, Randle PJ, Bridges BJ, Cooper RH, Kerbey AL, Pask HT, Severson DL, Stansbie D, Whitehouse S (1975). &#8220;Regulation of mammalian pyruvate dehydrogenase&#8221;. Mol. Cell. Biochem. 9 (1): 27\u201353.<\/li>\n<li style=\"text-align: justify\">Koivunen P, Hirsil\u00e4 M, Remes AM, Hassinen IE, Kivirikko KI, Myllyharju J (2007). &#8220;Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF&#8221;. J. Biol. Chem. 282 (7): 4524\u201332.<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<p><strong>Web site<\/strong><\/p>\n<ul>\n<li style=\"text-align: justify\">http:\/\/www.watcut.uwaterloo.ca\/webnotes\/Metabolism\/tcaRegulation.html<\/li>\n<li style=\"text-align: justify\">http:\/\/www.brynmawr.edu\/Acads\/Chem\/chem242\/Chapter14Responses.html<\/li>\n<li style=\"text-align: justify\">https:\/\/www.rose-hulman.edu\/~brandt\/Chem330\/TCA_cycle.pdf<\/li>\n<li style=\"text-align: justify\">http:\/\/www.med.unc.edu\/neurology\/files\/documents\/child-teaching-pdf\/CITRIC%20ACID%20CYCLE.pdf<\/li>\n<li style=\"text-align: justify\">https:\/\/en.wikibooks.org\/wiki\/Structural_Biochemistry\/Krebs_Cycle_%28Citric_Acid _cycle%29<\/li>\n<\/ul>\n<p><strong>Books<\/strong><\/p>\n<ul>\n<li style=\"text-align: justify\">Biochemistry, Jeremy M. Berg, John L. Tomoczko, Lubert Stryer. 5th Edition<\/li>\n<li style=\"text-align: justify\">Lehninger\u2019s Principle of Biochemistry, David L. Nelson and Michael M. Cox, 5th Edition (2008)<\/li>\n<li style=\"text-align: justify\">Harper\u2019s Illustrated Biochemistry, Robert K. Murray, Daryl K. Granner, Peter A. Mayes, 26th Edition (2003)<\/li>\n<li style=\"text-align: justify\">Biochemistry, Voet D, Voet JG, New York: John Wiley &amp; Sons, Inc. 3rd Edition (2004)<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<\/div>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n","protected":false},"author":3,"menu_order":11,"template":"","meta":{"pb_show_title":"on","pb_short_title":"","pb_subtitle":"","pb_authors":["dr-ramesh-kothari"],"pb_section_license":""},"chapter-type":[],"contributor":[58],"license":[],"class_list":["post-164","chapter","type-chapter","status-publish","hentry","contributor-dr-ramesh-kothari"],"part":3,"_links":{"self":[{"href":"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-json\/pressbooks\/v2\/chapters\/164","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-json\/pressbooks\/v2\/chapters"}],"about":[{"href":"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-json\/wp\/v2\/types\/chapter"}],"author":[{"embeddable":true,"href":"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-json\/wp\/v2\/users\/3"}],"version-history":[{"count":6,"href":"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-json\/pressbooks\/v2\/chapters\/164\/revisions"}],"predecessor-version":[{"id":193,"href":"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-json\/pressbooks\/v2\/chapters\/164\/revisions\/193"}],"part":[{"href":"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-json\/pressbooks\/v2\/parts\/3"}],"metadata":[{"href":"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-json\/pressbooks\/v2\/chapters\/164\/metadata\/"}],"wp:attachment":[{"href":"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-json\/wp\/v2\/media?parent=164"}],"wp:term":[{"taxonomy":"chapter-type","embeddable":true,"href":"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-json\/pressbooks\/v2\/chapter-type?post=164"},{"taxonomy":"contributor","embeddable":true,"href":"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-json\/wp\/v2\/contributor?post=164"},{"taxonomy":"license","embeddable":true,"href":"https:\/\/ebooks.inflibnet.ac.in\/biocp04\/wp-json\/wp\/v2\/license?post=164"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}