Le complexe pyruvate déshydrogénase : de l'organisation moléculaire à la pathologie.

Abstract

Le déficit en pyruvate déshydrogénase (PDH), décrit pour la première fois en 1970, est une maladie héréditaire du métabolisme intermédiaire affectant principalement le système nerveux. Plus d’une centaine d’observations en ont déjà été rapportées, mettant en évidence l’extrême hétérogénéité clinique et moléculaire de ce déficit. Cette hétérogénéité est liée à deux caractéristiques de la PDH : (1) sa structure caractérisée par l’assemblage de six sous-unités dont l’une est codée par un gène situé sur le chromosome X ; (2) son rôle dans le métabolisme du glucose et sa régulation, en particulier au niveau cérébral. La découverte d’un grand nombre de mutations différentes a conduit à mieux comprendre les mécanismes moléculaires complexes responsables de la diversité des tableaux cliniques observés dans les déficits en PDH.

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 (E1-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 E1-kinase. Certain 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 common defects are associated with mutations of the E1alpha gene located on chromosome X. To date, some 52 mutations within the reading frame of E1alpha have been reported in around 76 individuals, with less than 10% recurring in the same family. Defects of other components are less common; to date, mutations have been characterized for E3 component and protein X. Characterization of a large variety of missense mutations of E1alpha, 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. [References: 40]