Crystal structure of 2-oxoisovalerate and dehydrogenase and the architecture of 2-oxo acid dehydrogenase multienzyme complexes

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Abstract
The family of giant multienzyme complexes metabolizing pyruvate, 2-oxoglutarate, branched-chain 2-oxo acids or acetoin contains several of the largest and most sophisticated protein assemblies known, with molecular masses between 4 and 10 million Da. The principal enzyme components, E1, E2 and E3, are present in numerous copies and utilize multiple cofactors to catalyze a directed sequence of reactions via substrate channeling. The crystal structure of a heterotetrameric (α2β2) E1, 2-oxoisovalerate dehydrogenase from Pseudomonas putida, reveals a tightly packed arrangement of the four subunits with the β2-dimer held between the jaws of a 'vise' formed by the α2-dimer. A long hydrophobic channel, suitable to accommodate the E2 lipoyl-lysine arm, leads to the active site, which contains the cofactor thiamin diphosphate (ThDP) and an inhibitor-derived covalent modification of a histidine side chain. The E1 structure, together with previous structural information on E2 and E3, completes the picture of the shared architectural features of these enormous macromolecular assemblies.

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