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J. Biol. Chem., Vol. 266, Issue 14, 8820-8825, May, 1991
JE Pawlowski, M Huizinga and TM Penning
Rat liver 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD, EC 1.1.1.50)
is an NAD(P)(+)-dependent oxidoreductase which will terminate androgen
action by converting 5 alpha-dihydrotestosterone to 3 alpha-
androstanediol. It is identical to dihydrodiol dehydrogenase and it can
function as a 9-, 11-, and 15-hydroxyprostaglandin dehydrogenase. Its
reactions are potently inhibited by the nonsteroidal anti-inflammatory
drugs (NSAIDs). A cDNA (2.1 kilobases) for 3 alpha-HSD was cloned from a
rat liver cDNA expression library in lambda gt11. Portions of the cDNA
insert which contained an internal EcoRI site were subcloned into pGEM3,
and dideoxysequencing revealed that the cDNA contains an open reading frame
of 966 nucleotides which encode a protein of 322 amino acids with a monomer
Mr of 37,029. The identity of this clone was confirmed by locating two
tryptic peptides and two endoproteinase Lys-C peptides from purified 3
alpha-HSD within the nucleotide sequence. The amino acid sequence of rat
liver 3 alpha-HSD bears no significant homology with 3 beta-, 17 beta- or
11 beta-hydroxysteroid dehydrogenases but has striking homology with bovine
lung prostaglandin F synthase (69% homology at the amino acid level and 74%
homology at the nucleotide level) which is a member of the aldehyde/aldose
reductase family. This sequence homology supports previous correlates which
suggest that in rat 3 alpha-HSD may represent an important target for
NSAIDs. The nucleotide sequence also contains three peptides that have been
identified by affinity labeling with either 3 alpha-
bromoacetoxyandrosterone (substrate analog) or 11 alpha-
bromoacetoxyprogesterone (glucocorticoid analog) to comprise the active
site (see accompanying article (Penning, T. M., Abrams, W. R., and
Pawlowski, J. E. (1991) J. Biol. Chem. 266, 8826-8834]. The sequence data
presented suggests that 3 alpha-HSD, prostaglandin F synthase, and
aldehyde/aldose reductases are members of a common gene family.
Cloning and sequencing of the cDNA for rat liver 3 alpha- hydroxysteroid/dihydrodiol dehydrogenase
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104-6084.
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