PMID: 9173902Apr 1, 1997Paper

Identification of amino acid residues responsible for differences in substrate specificity and inhibitor sensitivity between two human liver dihydrodiol dehydrogenase isoenzymes by site-directed mutagenesis

The Biochemical Journal
K MatsuuraA Hara

Abstract

Human liver dihydrodiol dehydrogenase isoenzymes (DD1 and DD2), in which only seven amino acid residues are substituted, differ remarkably in specificity for steroidal substrates and inhibitor sensitivity: DD1 shows 20alpha-hydroxysteroid dehydrogenase activity and sensitivity to 1,10-phenanthroline, whereas DD2 oxidizes 3alpha-hydroxysteroids and is highly inhibited by bile acids. In the present study we performed site-directed mutagenesis of the seven residues (Thr-38, Arg-47, Leu-54, Cys-87, Val-151, Arg-170 and Gln-172) of DD1 to the corresponding residues (Val, His, Val, Ser, Met, His and Leu respectively) of DD2. Of the seven mutations, only the replacement of Leu-54 with Val produced an enzyme that had almost the same properties as DD2. No significant changes were observed in the other mutant enzymes. An additional site-directed mutagenesis of Tyr-55 of DD1 to Phe yielded an inactive protein, suggesting the catalytically important role of this residue. Thus a residue at a position before the catalytic Tyr residue might play a key role in determining the orientation of the substrates and inhibitors.

Citations

Mar 21, 2006·Drug Metabolism and Pharmacokinetics·Toshiyuki MatsunagaAkira Hara
Dec 17, 2014·The Journal of Steroid Biochemistry and Molecular Biology·Trevor M PenningYi Jin
Jun 1, 2007·Archives of Biochemistry and Biophysics·Trevor M Penning, Jason E Drury
Aug 24, 2018·Endocrine Reviews·Trevor M PenningRichard J Auchus
Aug 20, 2011·The Biochemical Journal·F Xavier RuizXavier Parés
Sep 3, 2013·Biological & Pharmaceutical Bulletin·Satoshi EndoToshiyuki Matsunaga
Aug 3, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Diane RamsdenMatthew A Cerny
Oct 11, 2017·Journal of Biochemistry·Akira HaraOssama El-Kabbani
Mar 5, 2009·The Journal of Pharmacology and Experimental Therapeutics·Ryan H TakahashiK Wayne Riggs

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