Branched-chain a-keto acid dehydrogenase complex

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)... 

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... 

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). 

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... 

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). 

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... 

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. ... 

In Al Martini s heart failure, which is caused by a dietary deficiency of the vitamin thiamine, pyruvate dehydrogenase, a-ketoglutarate dehydrogenase, and the branched chain a-keto acid dehydrogenase complexes are less functional than normal. Because heart muscle, skeletal muscle, and nervous tissue have a high rate of ATP production from the NADH produced by the oxidation of pyruvate to acetyl CoA and of acetyl CoA to COj in the TCA cycle, these tissues present with the most obvious signs of thiamine deficiency. 

In brain, four major enzyme systems utilize thiamine in the form of thiamine diphosphate (TDP) as a major cofactor, i.e. a-ketoglutarate dehydrogenase complex (KGDHC), pyruvate dehydrogenase complex, branched-chain a-keto acid dehydrogenase complex (BCKDHQ and transketolase. 

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