7.11 - Coenzyme A Biosynthesis and Enzymology

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Coenzyme A (CoA) is a ubiquitous and essential cofactor that is involved in a large proportion of all central metabolic reactions. In most of these reactions, the cofactor acts as an acyl carrier, and either activates the acyl group for group transfer or electrophilic attack, or increases the acidity of the protons adjacent to the carbonyl to facilitate the formation of a nucleophilic enolate. This chapter describes the discovery of CoA and the early studies on its biosynthesis and enzymology, and the current status of our knowledge of its universal five-step biosynthetic pathway from pantothenic acid (vitamin B5) – including an overview of the variations in the pathway across sequenced genomes, and of the data on the essentiality of the genes encoding the CoA biosynthetic enzymes. This chapter also discusses CoA enzymology, with a special focus on enzymes that consume, degrade, and recycle CoA, on enzymes that biosynthesize CoA thioesters, and on enzymes that subsequently use these thioesters for group transfer reactions. The enzymology of proteins that act in the Claisen condensation of CoA thioesters (and the retro-Claisen cleavage reactions), is also described. Finally, an overview of the use of CoA analogues in biotechnological applications and in the design and development of drugs and enzyme inhibitors is provided.

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Erick Strauss was born and bred in Pretoria, South Africa, where he obtained his Bachelors in Science in Chemistry in 1997. He subsequently moved to the United States to pursue his graduate studies at Cornell University, where he worked on the biosynthesis of coenzyme A with Professor Tadhg Begley. He received a Ph.D. in chemistry and chemical biology in 2003. He returned to South Africa in the same year to accept an offer from Stellenbosch University to establish his own research group, with a focus on chemical biology, in the Department of Chemistry and Polymer Science. In 2008 he moved to the Department of Biochemistry, Stellenbosch University, where currently he is an associate professor. Erick is a recipient of the President’s Award from the South African National Research Foundation, and the Rector’s Award for Excellence in Teaching from Stellenbosch University. He continues to pursue his research interests in the mechanistic aspects of CoA biosynthesis, as well as the applications of CoA analogues and precursors in inhibitor and drug design –with special emphasis on compounds that could be applied to the treatment of the so-called ‘neglected diseases,’ such as tuberculosis, malaria, and human sleeping sickness.

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