The pyruvate dehydrogenase complex (PDHC) oxidatively decarboxylates pyruvate, resulting in the production of acetyl coenzyme A (CoA) and carbon dioxide. This process requires the involvement of five coenzymes: thiamine pyrophosphate, lipoic acid, flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide (NAD+), and CoA. Covalent modification of E1 (pyruvate decarboxylase) by PDH kinase and PDH phosphatase regulates the activity of PDHC. E1 is inhibited by phosphorylation, which is facilitated by PDH kinase and ATP, acetyl CoA, and NADH allosterically activate this kinase while pyruvate inhibits it. The phosphatase, on the other hand, is activated by calcium (Ca2+). A deficiency in E1 is the primary cause of congenital lactic acidosis, which particularly affects the brain and is inherited in an X-linked dominant manner. Arsenic poisoning leads to the inactivation of PDHC by binding to lipoic acid. In the tricarboxylic acid (TCA) cycle, citrate is formed by the synthesis of oxaloacetate (OAA) and acetyl CoA through the action of citrate synthase. The activity of citrate synthase is inhibited by its product. Aconitase (aconitate hydratase) is responsible for the isomerization of citrate to isocitrate. Isocitrate is then oxidatively decarboxylated by isocitrate dehydrogenase, resulting in the formation of α-ketoglutarate, along with the production of carbon dioxide (CO2) and NADH. ATP and NADH inhibit the activity of isocitrate dehydrogenase, while adenosine diphosphate (ADP) and calcium (Ca2+) activate it. α-Ketoglutarate is further oxidatively decarboxylated to succinyl CoA by the α-ketoglutarate dehydrogenase complex, producing carbon dioxide (CO2) and NADH. This complex shares the same coenzymes as the PDHC and is activated by calcium (Ca2+) and inhibited by NADH and succinyl CoA, but it is not covalently regulated. The cleavage of succinyl CoA by succinate thiokinase (also known as succinyl CoA synthetase) generates succinate and guanosine triphosphate (GTP) via substrate-level phosphorylation. This step involves the transfer of the terminal phosphate of GTP to adenosine diphosphate (ADP) by nucleoside diphosphate kinase, resulting in the production of another ATP. Succinate is converted to fumarate by succinate dehydrogenase, generating flavin adenine dinucleotide (FADH2). Fumarate is then hydrated to malate by fumarase (fumarate hydratase), and malate is subsequently oxidized to oxaloacetate (OAA) by malate dehydrogenase, producing NADH. One round of the TCA cycle generates three NADH molecules and one FADH2 molecule. In addition, the oxidation of NADH and FADH2 by the electron transport chain (ETC) leads to the production of 14 ATP. Furthermore, the terminal phosphate of the GTP produced during substrate-level phosphorylation in the TCA cycle can be transferred to ADP by nucleoside diphosphate kinase, resulting in the production of another ATP. Therefore, the complete mitochondrial oxidation of pyruvate to carbon dioxide (CO2) yields a total of 15 ATP.
Pyruvate is oxidatively decarboxylated by the pyruvate dehydrogenase complex (PDHC), producing acetyl coenzyme A (CoA), which is the major fuel for the tricarboxylic acid (TCA) cycle (Fig. 9.9). The multienzyme PDHC requires five coenzymes: thiamine pyrophosphate, lipoic acid, flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide (NAD+), and CoA. The PDHC is regulated by covalent modification of E1 (pyruvate decarboxylase) by PDH kinase and PDH phosphatase: Phosphorylation inhibits E1. PDH kinase is allosterically activated by ATP, acetyl CoA, and NADH and inhibited by pyruvate. The phosphatase is activated by calcium (Ca2+). E1 deficiency is the most common biochemical cause of congenital lactic acidosis. The brain is particularly affected in this X-linked dominant disorder. Arsenic poisoning causes inactivation of the PDHC by binding to lipoic acid. In the TCA cycle, citrate is synthesized from oxaloacetate (OAA) and acetyl CoA by citrate synthase, which is inhibited by product. Citrate is isomerized to isocitrate by aconitase (aconitate hydratase). Isocitrate is oxidatively decarboxylated by isocitrate dehydrogenase to α-ketoglutarate, producing carbon dioxide (CO2) and NADH. The enzyme is inhibited by ATP and NADH and activated by adenosine diphosphate (ADP) and Ca2+ . α-Ketoglutarate is oxidatively decarboxylated to succinyl CoA by the α-ketoglutarate dehydrogenase complex, producing CO2 and NADH. The enzyme is very similar to the PDHC and uses the same coenzymes. The α-ketoglutarate dehydrogenase complex is activated by Ca2+ and inhibited by NADH and succinyl CoA but is not covalently regulated. Succinyl CoA is cleaved by succinate thiokinase (also called succinyl CoA synthetase), producing succinate and guanosine triphosphate (GTP). This is an example of substrate-level phosphorylation. Succinate is oxidized to fumarate by succinate dehydrogenase, producing FADH2. Fumarate is hydrated to malate by fumarase (fumarate hydratase), and malate is oxidized to OAA by malate dehydrogenase, producing NADH. Three NADH and one FADH2 are produced by one round of the TCA cycle. The generation of acetyl CoA by the oxidation of pyruvate via the PDHC also produces an NADH. Oxidation of the NADH and FADH2 by the ETC yields 14 ATP. The terminal phosphate of the GTP produced by substrate-level phosphorylation in the TCA cycle can be transferred to ADP by nucleoside diphosphate kinase, yielding another ATP. Therefore, a total of 15 ATP are produced from the complete mitochondrial oxidation of pyruvate to CO2.
NAD(H) = nicotinamide adenine dinucleotide; FAD(H2) = flavin adenine dinucleotide; GDP and GTP = guanosine di-and triphosphates; ADP = adenosine diphosphate; Pi = inorganic phosphate.
Choose the ONE best answer.
.1. The conversion of pyruvate to acetyl coenzyme A and carbon dioxide:
A. involves the participation of lipoic acid.
B. is activated when pyruvate decarboxylase of the pyruvate dehydrogenase complex (PDHC) is phosphorylated by PDH kinase in the presence of ATP.
C. is reversible.