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3-Hydroxy-3-methylglutaryl coenzyme A (CoA) synthase (HMGCS) catalyzes the condensation of acetyl-CoA and acetoacetyl-CoA into 3-hydroxy-3-methylglutaryl CoA. It is ubiquitous across the phylogenetic tree and is broadly classified into three classes. The prokaryotic isoform is essential in Gram-positive bacteria for isoprenoid synthesis via the mevalonate pathway. The eukaryotic cytosolic isoform also participates in the mevalonate pathway but its end product is cholesterol. Mammals also contain a mitochondrial isoform; its deficiency results in an inherited disorder of ketone body formation. Here, we report high-resolution crystal structures of the human cytosolic (hHMGCS1) and mitochondrial (hHMGCS2) isoforms in binary product complexes. Our data represent the first structures solved for human HMGCS and the mitochondrial isoform, allowing for the first time structural comparison among the three isoforms. This serves as a starting point for the development of isoform-specific inhibitors that have potential cholesterol-reducing and antibiotic applications. In addition, missense mutations that cause mitochondrial HMGCS deficiency have been mapped onto the hHMGCS2 structure to rationalize the structural basis for the disease pathology.

Original publication

DOI

10.1016/j.jmb.2010.03.034

Type

Journal article

Journal

Journal of molecular biology

Publication Date

05/2010

Volume

398

Pages

497 - 506

Addresses

Structural Genomics Consortium, University of Oxford, Oxford OX3 7DU, UK.

Keywords

Humans, Ketones, Hydroxymethylglutaryl-CoA Synthase, Protein Isoforms, Crystallography, X-Ray, Protein Structure, Quaternary, Dimerization, Mutation, Missense, Models, Molecular