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J. Biol. Chem., Vol. 280, Issue 13, 12422-12429, April 1, 2005

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Cloning, Expression, and Characterization of the Human Mitochondrial -Ketoacyl Synthase

COMPLEMENTATION OF THE YEAST CEM1 KNOCK-OUT STRAIN^*

Lei Zhang, Anil K. Joshi, Jörg Hofmann¶, Eckhart Schweizer¶, and Stuart Smith||

From the Children's Hospital Oakland Research Institute, Oakland, California 94609 and ^¶Lehrstuhl für Biochemie, Universität Erlangen, Staudtstrasse 5, D-91058, Erlangen, Germany

A human -ketoacyl synthase implicated in a mitochondrial pathway for fatty acid synthesis has been identified, cloned, expressed, and characterized. Sequence analysis indicates that the protein is more closely related to freestanding counterparts found in prokaryotes and chloroplasts than it is to the -ketoacyl synthase domain of the human cytosolic fatty acid synthase. The full-length nuclear-encoded 459-residue protein includes an N-terminal sequence element of 38 residues that functions as a mitochondrial targeting sequence. The enzyme can elongate acyl-chains containing 2–14 carbon atoms with malonyl moieties attached in thioester linkage to the human mitochondrial acyl carrier protein and is able to restore growth to the respiratory-deficient yeast mutant cem1 that lacks the endogenous mitochondrial -ketoacyl synthase and exhibits lowered lipoic acid levels. To date, four components of a putative type II mitochondrial fatty acid synthase pathway have been identified in humans: acyl carrier protein, malonyl transferase, -ketoacyl synthase, and enoyl reductase. The substrate specificity and complementation data for the -ketoacyl synthase suggest that, as in plants and fungi, in humans this pathway may play an important role in the generation of octanoyl-acyl carrier protein, the lipoic acid precursor, as well as longer chain fatty acids that are required for optimal mitochondrial function.

Received for publication, December 6, 2004 , and in revised form, January 18, 2005.

^* This work was supported by Grants GM 69717 and DK 16073 (to S. S.) from the National Institutes of Health and Deutsche Forschungsgemeinschaft (to E. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Postdoctoral Fellow of the American Heart Association.

^|| To whom correspondence should be addressed: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609. Tel.: 510-450-7675; Fax: 510-450-7910; E-mail: ssmith{at}chori.org.

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