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Originally published In Press as doi:10.1074/jbc.M212356200 on January 31, 2003

J. Biol. Chem., Vol. 278, Issue 15, 13159-13165, April 11, 2003
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Structure of Human Carnitine Acetyltransferase
MOLECULAR BASIS FOR FATTY ACYL TRANSFER*

Donghai WuDagger , Lakshmanan Govindasamy§, Wei LianDagger , Yunrong GuDagger , Thomas KukarDagger , Mavis Agbandje-McKenna§, and Robert McKenna§

From the Dagger  Department of Medicinal Chemistry, College of Pharmacy and § Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida 32610

Carnitine acyltransferases are a family of ubiquitous enzymes that play a pivotal role in cellular energy metabolism. We report here the x-ray structure of human carnitine acetyltransferase to a 1.6-Å resolution. This structure reveals a monomeric protein of two equally sized alpha /beta domains. Each domain is shown to have a partially similar fold to other known but oligomeric enzymes that are also involved in group-transfer reactions. The unique monomeric arrangement of the two domains constitutes a central narrow active site tunnel, indicating a likely universal feature for all members of the carnitine acyltransferase family. Superimposition of the substrate complex of a related protein, dihydrolipoyl trans-acetylase, reveals that both substrates localize to the active site tunnel of human carnitine acetyltransferase, suggesting the location of the ligand binding sites for carnitine and coenzyme A. Most significantly, this structure provides critical insights into the molecular basis for fatty acyl chain transfer and a possible common mechanism among a wide range of acyltransferases utilizing a catalytic dyad.


* This work was supported in part by the University of Florida, College of Medicine start-up funds (to R. M.) and National Institutes of Health Grant R01 GM58197 (to D. H. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and the structure factors (code 1NM8) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, College of Medicine, P. O. Box 100245, University of Florida, Gainesville, Florida 32610. Tel.: 352-392-5696; Fax: 352-392-3422; E-mail: rmckenna@.ufl.edu.


Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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