The pyruvate dehydrogenase complex: from molecular organization to clinical issues

The mammalian pyruvate dehydrogenase complex (PDHc) plays a key role in the irreversible decarboxylation of pyruvate derived from glucose and amino acids to form acetyl-CoA in the mitochondria. This enzyme complex contains multiple copies of three catalytic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and dihydrolipoamide dehydrogenase (E3), two regulatory components (El-kinase, phospho-E1 phosphatase) and one non-catalytic protein X. The enzyme complex is under short-and long-term regulation by nutritional, metabolic, developmental and hormonal factors. Both E1-kinase and phospho-E1 phosphatase determine the activation (phosphorylation) state of the PDHc, and in many circumstances changes in the activation state correlate with the activity of El-kinase. Cer tain dietary or hormonal manipulations result in changes in total PDHc activity with an increase in components proteins, with the major regulatory step in this process being positioned at the translational and/or postranslational level. PDHc deficiency is one of the major genetic disorders of oxidative metabolism causing elevation of lactate in blood and/or CSF. The consequences primarily affect the developing central nervous system, but range vastly in severity. The most com,mon defects are associated with mutations of the E1 alpha gene located on chromosome X. To date, some 52 mutations within the reading frame of E1 alpha have been reported in around 76 individuals, with less than 10% recurring in the same family. Defects of other components; are less com mon; to dale, mutations have been characterized for E3 component and protein X. Characterization of a large variety of missense mutations of E1 alpha, consideration of their consequences and description of new mutations on protein X provide opportunities for better understanding the relationship of structure and function of these proteins and their respective role in the complex.