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Originally published In Press as doi:10.1074/jbc.M104818200 on July 18, 2001

J. Biol. Chem., Vol. 276, Issue 41, 38166-38172, October 12, 2001
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Alternative Splicing Determines the Function of CYP4F3 by Switching Substrate Specificity*

Peter ChristmasDagger §, Jeffrey P. Jones, Christopher J. Patten||, Dan A. Rock, Yimin Zheng**, Shing-Ming ChengDagger , Brittany M. WeberDagger , Nadia CarlessoDagger Dagger , David T. ScaddenDagger Dagger , Allan E. Rettie**, and Roy J. SobermanDagger

From the Dagger  Center for Immunology and Inflammatory Diseases and the Dagger Dagger  AIDS Research Center and Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, the  Department of Chemistry, Washington State University, Pullman, Washington 99164, the ** Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195, and || Gentest Corporation, Woburn, Massachusetts 01801

Diversity of cytochrome P450 function is determined by the expression of multiple genes, many of which have a high degree of identity. We report that the use of alternate exons, each coding for 48 amino acids, generates isoforms of human CYP4F3 that differ in substrate specificity, tissue distribution, and biological function. Both isoforms contain a total of 520 amino acids. CYP4F3A, which incorporates exon 4, inactivates LTB4 by omega -hydroxylation (Km = 0.68 µM) but has low activity for arachidonic acid (Km = 185 µM); it is the only CYP4F isoform expressed in myeloid cells in peripheral blood and bone marrow. CYP4F3B incorporates exon 3 and is selectively expressed in liver and kidney; it is also the predominant CYP4F isoform in trachea and tissues of the gastrointestinal tract. CYP4F3B has a 30-fold higher Km for LTB4 compared with CYP4F3A, but it utilizes arachidonic acid as a substrate for omega -hydroxylation (Km = 22 µM) and generates 20-HETE, an activator of protein kinase C and Ca2+/calmodulin-dependent kinase II. Homology modeling demonstrates that the alternative exon has a position in the molecule which could enable it to contribute to substrate interactions. The results establish that tissue-specific alternative splicing of pre-mRNA can be used as a mechanism for changing substrate specificity and increasing the functional diversity of cytochrome P450 genes.

* This work was supported by National Institutes of Health Grants 1K01DK59991-01 (to P. C.), 5R01GM-61823 (to R. J. S.), NIEHS ES09122 (to J. P. J.), 5R01GM9054-09 (to A. E. R.), 5R01DK52234 (to D. T. S.), and 5R01HL55718 (to D. T. S.), the Richard Saltonstall Charitable Foundation (to D. T. S.), and a grant by the Jewish Communal Fund (to R. J. S.).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.

§ To whom correspondence should be addressed: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital East, 149 The Navy Yard, 13th St., Charlestown, MA 02129. Tel.: 617-724-4336; Fax: 617-726-5651; E-mail: christma@helix.mgh.harvard.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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