The 2-oxo acid dehydrogenase complexes: recent advances.

Abstract

The 2-oxo acid dehydrogenase complexes represent the classic examples of multienzyme complexes, a knowledge of whose structure and function has wide implications for our understanding of macromolecular assembly and organization and of protein structure and function. Each complex consists of multiple copies of three enzymes, termed El, E2 and E3. El is a 2-oxo acid dehydrogenase which has thiamin pyrophosphate as an essential co-factor. E2 is a dihydrolipoamide acyltransferase, with a covalently attached lipoic acid cofactor, and E3 is an FAD-containing dihydrolipoamide dehydrogenase. The components catalyse consecutive steps in the overall reaction, as outlined in Fig. 1. These complexes have molecular masses of several million [mammalian pyruvate dehydrogenase complex (PDC) is slightly larger than a ribosome] and are truly self-assembling [1,2]. These macromolecules are not however merely of interest from a structural viewpoint. Each of the 2-oxo acid dehydrogenase complexes occupies key positions in intermediary metabolism and the activity of each mammalian complex, located within mitochondria, is under stringent control by hormones and dietary factors. PDC oxidatively decarboxylates pyruvate to acetyl-CoA, an irreversible step in the utilization of carbohydrate, whilst 2-oxoglutarate dehydrogenase complex (OGDC) is a potentially regulatory enzyme of the tricarboxylic acid cycle. Branched-chain 2-oxo acid dehydrogenase complex (BCOADC) catalyses an irreversible step in the catabolism of several essential amino acids, including the branched-chain amino acids [2]. PDC and OGDC have narrow substrate specificities, with OGDC being essentially specific for 2-oxoglutarate, whereas PDC will oxidize 2-oxobutyrate, in addition to pyruvate, at a significant rate [3]. In contrast, BCOADC has a relatively broad specificity, oxidizing 4-methylthio-2-oxobutyrate and 2-oxobutyrate at comparable rates and with similar Km values as for the three branched-chain 2-oxo acid substrates, namely 3-methyl-2-oxobutyrate, 4-methyl-2oxopentanoate and 3-methyl-2-oxopentanoate [3-5]. BCOADC will also oxidize pyruvate, but the Km value is