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Originally published In Press as doi:10.1074/jbc.M102076200 on April 9, 2001

J. Biol. Chem., Vol. 276, Issue 25, 22278-22286, June 22, 2001
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Characterization of a Novel Type of Human Microsomal 3alpha -Hydroxysteroid Dehydrogenase
UNIQUE TISSUE DISTRIBUTION AND CATALYTIC PROPERTIES*

Sergei V. Chetyrkin, Olga V. Belyaeva, Wendy H. GoughDagger , and Natalia Y. Kedishvili§

From the Division of Molecular Biology and Biochemistry, School of Biological Sciences, University of Missouri-Kansas City, Kansas City, Missouri 64110

We report characterization of a novel member of the short chain dehydrogenase/reductase superfamily. The 1513-base pair cDNA encodes a 319-amino acid protein. The corresponding gene spans over 26 kilobase pairs on chromosome 2 and contains five exons. The recombinant protein produced using the baculovirus system is localized in the microsomal fraction of Sf9 cells and is an integral membrane protein with cytosolic orientation of its catalytic domain. The enzyme exhibits an oxidoreductase activity toward hydroxysteroids with NAD+ and NADH as the preferred cofactors. The enzyme is most efficient as a 3alpha -hydroxysteroid dehydrogenase, converting 3alpha -tetrahydroprogesterone (allopregnanolone) to dihydroprogesterone and 3alpha -androstanediol to dihydrotestosterone with similar catalytic efficiency (Vmax values of 13-14 nmol/min/mg microsomal protein and Km values of 5-7 µM). Despite ~44-47% sequence identity with retinol/3alpha -hydroxysterol dehydrogenases, the enzyme is not active toward retinols. The corresponding message is abundant in human trachea and is present at lower levels in the spinal cord, bone marrow, brain, heart, colon, testis, placenta, lung, and lymph node. Thus, the new short chain dehydrogenase represents a novel type of microsomal NAD+-dependent 3alpha -hydroxysteroid dehydrogenase with unique catalytic properties and tissue distribution.

* This work was supported by the National Institute on Alcohol Abuse and Alcoholism Grants AA00221 and AA12153 (to N. Y. K.).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 nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF343729.

Dagger Present address: Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN 46285.

§ To whom correspondence should be addressed: Division of Molecular Biology and Biochemistry, School of Biological Sciences, University of Missouri-Kansas City, 5007 Rockhill Rd., 103 BSB, Kansas City, MO 64110. Tel.: 816-235-2658; Fax: 816-235-5595; E-mail kedishvilin@umkc.edu.

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