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Papers In Press, published online ahead of print July 18, 2001
J. Biol. Chem, 10.1074/jbc.M104818200
Submitted on May 25, 2001
Revised on July 16, 2001
Accepted on July 18, 2001

Alternative splicing determines the function of CYP4F3 by switching substrate specificity

Peter Christmas, Jeffrey P. Jones, Christopher J. Patten, Dan Rock, Yimin Zheng, Shing-Ming Cheng, Brittany M. Weber, Nadia Carlesso, David T. Scadden, Allan E. Rettie, and Roy J. Soberman

Rheumatology, Allergy, and Immunology, Massachusetts General Hospital-East, Charlestown, MA 02129

Corresponding Author: christma{at}helix.mgh.harvard.edu

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 mM) but has low activity for arachidonic acid (Km = 185 mM); 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 to CYP4F3A, but it utilizes arachidonic acid as a substrate for w-hydroxylation (Km = 22 mM) 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 contibute 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.


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