Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 398, Issue 4, Pages 497-506Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2010.03.034
Keywords
mevalonate; ketone bodies; HMG-CoA; condensation; mitochondrial HMGCS deficiency
Categories
Funding
- Canadian Institutes for Health Research [1097737]
- Canadian Foundation for Innovation
- GlaxoSmithKline
- Karolinska Institutet
- Knut and Alice Wallenberg Foundation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation
- Novartis Research Foundation
- Swedish Agency
- Swedish Foundation for Strategic Research
- Wellcome Trust
- Genome Canada through the Ontario Genomics Institute
- Merck and Co., Inc
Ask authors/readers for more resources
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. (C) 2010 Elsevier Ltd. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available