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 ac ids to form acetyl-CoA in the mitochondria. This enzyme complex contains mu ltiple copies of three catalytic components: pyruvate dehydrogenase (E1), d ihydrolipoamide 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 re gulation by nutritional, metabolic, developmental and hormonal factors. Bot h E1-kinase and phospho-E1 phosphatase determine the activation (phosphoryl ation) state of the PDHc, and in many circumstances changes in the activati on state correlate with the activity of El-kinase. Cer tain dietary or horm onal manipulations result in changes in total PDHc activity with an increas e in components proteins, with the major regulatory step in this process be ing positioned at the translational and/or postranslational level. PDHc def iciency is one of the major genetic disorders of oxidative metabolism causi ng elevation of lactate in blood and/or CSF. The consequences primarily aff ect the developing central nervous system, but range vastly in severity. Th e most com,mon defects are associated with mutations of the E1 alpha gene l ocated 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 m on; 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 pro tein X provide opportunities for better understanding the relationship of s tructure and function of these proteins and their respective role in the co mplex.