Keto acid dehydrogenase complexes

The most important enzyme complexes involved in the oxidative decarboxylation of x-keto acids are pyruvate and -ketoglutarate dehydrogenases, which catalyze the following reaction  

TPP thiamine pyrophosphate LipS2 and Lip(SH)2 lipoyl moiety and its reduced form CoASH coenzyme A 

Three enzyme activities forming a relatively stable complex participate in the overall reaction (Fig. 22) -ketoacid dehydrogenase, dihydrolipoamide acyl-transferase and the flavoprotein dihydrolipoamide reductase. Thiamine pyrophosphate (D 10.4.5), lipoic acid (Table 16) and coenzyme A (D 11) are involved. Acids shortened by one C-atom and activated by binding to CoA are the final products. The activated bond is formed during the dehydrogenation of intermediate I by formation of the acylated lipoic acid (intermediate II). The last steps are transfer of the acyl moiety to coenzyme A and regeneration of the lipoic acid. 

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Branched-chain 2-keto acid dehydrogenase complex (bkd) f... 

Komuniecki, R. (1996) In Roche, T., Patel, M. and Harris, R.A. (eds) a-Keto Acid Dehydrogenase Complexes. Birkhauser Verlag AG, Basel, pp. 96-99. 

BRANCHED-CHAIN a-KETO ACID DEHYDROGENASE COMPLEX... 

Thiamin-dependent enzymes, ACETOLACTATE SYNTHASE BENZOYLFORMATE DECARBOXYLASE BRANCHED-CHAIN a-KETO ACID DEHYDROGENASE COMPLEX... 

Reed, L.J. Damuni, Z. Merryfield, M.L. Regulation of mammalian pyruvate and branched-chain a-keto acid dehydrogenase complexes by phosphorylation-dephosphorylation. Curr. Top. Cell. ReguL, 27, 41-49 (1985)... 

Espinal, J. Beggs, M. Randle, P.J. Assay of branched-chain a-keto acid dehydrogenase kinase in mitochondrial extracts and purified branched-chain a-keto acid dehydrogenase complexes. Methods Enzymol., 166, 166-175 (1988)... 

W. H. Holms (Control of Flux through the Citric Acid Cycle and the Glyoxylate Bypass in Escherichia coli), and R. N. Perham et al. (a-Keto Acid Dehydrogenase Complexes). 

Maple syrup urine disease (branched-chain ketoaciduria) <0.4 Isoleucine, leucine, and valine degradation Branched-chain a-keto acid dehydrogenase complex Vomiting convulsions mental retardation early death... 

FIGURE 18-28 Catabolic pathways for the three branched-chain amino acids valine, isoleucine, and leucine. The three pathways, which occur in extrahepatic tissues, share the first two enzymes, as shown here. The branched-chain -keto acid dehydrogenase complex... 

Experiments with rats have shown that the branched-chain a-keto acid dehydrogenase complex is regulated by covalent modification in response to the content of branched-chain amino acids in the diet. With little or no excess dietary intake of branched-chain amino acids, the enzyme complex is phosphorylated and thereby inactivated by a protein kinase. Addition of excess branched-chain amino acids to the diet results in dephosphoiylation and consequent activation of the enzyme. Recall that the pyruvate dehydrogenase complex is subject to similar regulation by phosphorylation and dephosphorylation (p. 621). 

Roche, T. E., and Patel, M. E., eds. (1990) Alpha-Keto Acid Dehydrogenase Complexes Organization, Regulation, and Biomedical Ramifications, Vol. 573, New York Academy of Sciences, New York... 

Lipoic acid mediates electron transfer and acyl-group transfer in a-keto acid dehydrogenase complexes. 

Branched-C hain a-Keto Acid Dehydrogenase Complex... 

CWC Hu, KS Lau, TA Griffin, JL Chuang, CW Fisher, RP Cox, DT Chuang. Isolation and sequencing of a cDNA encoding the decarboxylase (El)-a precursor of bovine branched-chain a-keto acid dehydrogenase complex expression of El-a mRNA and subunit in maple-syrup-urine-disease and 3T3-L1 cells. J Biol Chem... 

Tsai CS, Burgett MW, Reed LJ. a-Keto Acid dehydrogenase complexes. XX. A kinetic study of the pyruvate dehydrogenase complex from bovine kidney. J. Biol. Chem. 1973 248 8348-8352. 

Degradation of all three branched-chain amino acids begins with a transamination followed by an oxidative decarboxylation catalyzed by the branched-chain a-keto acid dehydrogenase complex. This enzyme, like a-ketoglutarate dehydrogenase, requires thiamine pyrophosphate, lipoic acid, coenzyme A, FAD, and NAD+ (Figure 7-11). 

The Ej and components are specific for each of the pyruvate dehydrogenase, oc-ketoglutarate dehydrogenase, and branched-chain oc-keto acid dehydrogenase complexes. However, the Ej component is identical for... 

In maple syrup urine disease, also called branched chain ketoaciduria, the a-keto acids derived from leucine, isoleucine, and valine accumulate in large quantities in blood. Their presence in urine imparts a characteristic odor that gives the malady its name. All three a-keto acids accumulate because of a deficient branched chain a-keto acid dehydrogenase complex. (This enzymatic activity is responsible for the conversion of the a-keto acids to their acyl-CoA derivatives.) If left untreated, affected individuals experience vomiting, convulsions, severe brain damage, and mental retardation. They often die before 1 year of age. As with phenylketonuria, treatment consists of rigid dietary control. 

Branched-chain a-keto acid dehydrogenase complex A lipoamide-containing multienzyme complex that... 

A. de Kok W. J. H. van Berkel, Lipoamide Dehydrogenase. n Alpha-Keto Acid Dehydrogenase Complexes M. S. Patel,... 

There is a relatively rare genetic disease in which the three branched-chain a-keto acids (as well as their precursor amino acids, especially leucine) accumulate in the blood and spill over into the urine. This condition, called maple syrup urine disease because of the characteristic odor imparted to the urine by the a-keto acids, results from a defective branched-chain a-keto acid dehydrogenase complex. Untreated, the disease results in abnormal development of the brain, mental retardation, and death in early infancy. Treatment entails rigid control of the diet, limiting the intake of valine, isoleucine, and leucine to the minimum required to permit normal growth. ... 

The a-ketoglutarate dehydrogenase complex is one of a three-member family of similar a-keto acid dehydrogenase complexes. The other members of this family are the pyruvate dehydrogenase complex, and the branched chain amino acid a-keto acid dehydrogenase complex. Each of these complexes is specific for a different a-keto acid structure. In the seqnence of reactions catalyzed by the complexes, the a-ketoacid is decarboxylated (i.e., releases the carboxyl gronp as CO2) (Fig.20.8). The keto gronp is oxidized to the level of a carboxylic acid, and then combined with CoASH to form an acyl CoA thioester (e.g., succinyl CoA). 

The E° for FAD accepting electrons is -0.20 (see Table 19.4). The E° for NAD+ accepting electrons is -0.32. Thus, transfer of electrons from FAD(2H) to NAD is energetically unfavorable. How do the a-keto acid dehydrogenase complexes allow this electron transfer to occur ... 

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