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Crystal structures of human HMG-CoA synthase isoforms provide insights into inherited ketogenesis disorders and inhibitor design.
J Mol Biol. 2010 May 14; 398(4):497-506.JM

Abstract

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.

Authors+Show Affiliations

Structural Genomics Consortium, University of Oxford, Oxford OX3 7DU, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20346956

Citation

Shafqat, Naeem, et al. "Crystal Structures of Human HMG-CoA Synthase Isoforms Provide Insights Into Inherited Ketogenesis Disorders and Inhibitor Design." Journal of Molecular Biology, vol. 398, no. 4, 2010, pp. 497-506.
Shafqat N, Turnbull A, Zschocke J, et al. Crystal structures of human HMG-CoA synthase isoforms provide insights into inherited ketogenesis disorders and inhibitor design. J Mol Biol. 2010;398(4):497-506.
Shafqat, N., Turnbull, A., Zschocke, J., Oppermann, U., & Yue, W. W. (2010). Crystal structures of human HMG-CoA synthase isoforms provide insights into inherited ketogenesis disorders and inhibitor design. Journal of Molecular Biology, 398(4), 497-506. https://doi.org/10.1016/j.jmb.2010.03.034
Shafqat N, et al. Crystal Structures of Human HMG-CoA Synthase Isoforms Provide Insights Into Inherited Ketogenesis Disorders and Inhibitor Design. J Mol Biol. 2010 May 14;398(4):497-506. PubMed PMID: 20346956.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Crystal structures of human HMG-CoA synthase isoforms provide insights into inherited ketogenesis disorders and inhibitor design. AU - Shafqat,Naeem, AU - Turnbull,Andrew, AU - Zschocke,Johannes, AU - Oppermann,Udo, AU - Yue,Wyatt W, Y1 - 2010/03/25/ PY - 2010/01/25/received PY - 2010/03/16/revised PY - 2010/03/18/accepted PY - 2010/3/30/entrez PY - 2010/3/30/pubmed PY - 2010/5/5/medline SP - 497 EP - 506 JF - Journal of molecular biology JO - J Mol Biol VL - 398 IS - 4 N2 - 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. SN - 1089-8638 UR - https://www.unboundmedicine.com/medline/citation/20346956/Crystal_structures_of_human_HMG_CoA_synthase_isoforms_provide_insights_into_inherited_ketogenesis_disorders_and_inhibitor_design_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-2836(10)00296-2 DB - PRIME DP - Unbound Medicine ER -