ABSTRACT

Reactions Catalyzed by Mitochondrial Enzymes That Require Lipoic Acid .............................................................................................. 102

a-Ketoglutarate Dehydrogenase Complex................................................... 103 Pyruvate Dehydrogenase Complex.............................................................. 103 Branched-Chain a-Keto Acid Dehydrogenase Complex ............................ 104 A Hypothetical a-Ketoadipate Dehydrogenase Complex ........................... 105 Glycine Cleavage System ............................................................................ 106

Regulation of Mitochondrial Enzymes That Require Lipoic Acid ................. 107 a-Ketoglutarate Dehydrogenase Complex................................................... 107 Pyruvate Dehydrogenase Complex.............................................................. 108 Branched-Chain a-Keto Acid Dehydrogenase Complex ............................ 115 A Hypothetical a-Ketoadipate Dehydrogenase Complex ........................... 119

Glycine Cleavage System ............................................................................ 119 Physiological Roles of Mitochondrial Enzymes That Require Lipoic Acid ... 120 a-Ketoglutarate Dehydrogenase Complex................................................... 120 Pyruvate Dehydrogenase Complex.............................................................. 121 Branched-Chain a-Keto Acid Dehydrogenase Complex ............................ 130 Glycine Cleavage System ............................................................................ 134

Acknowledgments............................................................................................ 135 References ........................................................................................................ 135

Four enzyme complexes requiring lipoic acid are located in the mitochondrial matrix space of higher eurkaryotes. Three of them are a-keto acid dehydrogenase complexes that catalyze the same overall general reaction-the oxidative decarboxylation of an a-keto acid with the formation of CO2, NADH, and an acyl-CoA:

CO2RC

O

+ NAD+ CoASH+ + RC

O

NADHCO2− + SCoA

The fourth is a related enzyme system for the cleavage of glycine with the formation of CO2, NH

þ 4 , NADH, and N

5, N10-CH2-tetrahydrofolate (THF)

The a-keto acid dehydrogenase complexes are composed of multiple copies of three enzymes that catalyze a total of five reactions (Figure 5.1). The enzymes are

FIGURE 5.1 Reactions catalyzed by components of the a-keto acid dehydrogenase complexes. TPP, thiamine pyrophosphate; FAD, flavin adenine dinucleotide.