MECHANISMS OF ME-TRANSFER AND ACETYL-COA SYNTHESIS

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Methanogenic bacteria form an important part of the human intestinal flora where their presence and/or absence has been shown to have a distinct epidemiology. Hence the understanding of the metabolic pathways of methanogenes has unexpected relevance to human health. The objective of this proposal is to elucidate the structures of multi- subunit complexes that participate in fundamental methyl transfer reactions in methanogens. The larger of these complexes, the acetyl-CoA decarbonylase synthase (ACDS), mediates the C-C bond cleavage of acetate. This complex is compartmentalized into three discrete components, each of which catalyzes one of three reactions: reversible acetyl-CoA transferase activity, CO:CO2 oxidoreductase activity, and methyltransferase activity. The long-term goal is to determine the structures of each of these components in order to gain insight into their catalytic mechanisms. Once all of these structures are obtained, they will be utilized to assemble a complete picture of the ACDS complex that can serve as a framework for understanding the mechanisms of substrate transfer between the different components. The second target is directed at the structural determination of proteins involved in methylotrophic growth from methylamines. Here too the major focus is not only in elucidating the structures of a methyl transferase and its cognate corrinoid protein, but also to understand how a methyl group is transferred to and from a corrinoid factor. As these corrinoid centers are ubiquitous in biology, such insights will be of general relevance to many biological systems.