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Mutagenesis of 3α-Hydroxysteroid Dehydrogenase Reveals a “Push−Pull” Mechanism for Proton Transfer in Aldo−Keto Reductases

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Departments of Pharmacology and Biochemistry & Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
Cite this: Biochemistry 1998, 37, 10, 3538–3548
Publication Date (Web):February 20, 1998
https://doi.org/10.1021/bi9723055
Copyright © 1998 American Chemical Society

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    Abstract

    Rat liver 3α-hydroxysteroid dehydrogenase (3α-HSD, E.C. 1.1.1.213, AKR1C9) is a member of the aldo−keto reductase (AKR) superfamily which inactivates circulating steroid hormones. We have proposed a catalytic mechanism in which Tyr 55 acts as a general acid with its pK value being lowered by a hydrogen bond with Lys 84 which is salt-linked to Asp 50. To test this mechanism, residues at the active site were mutated and the mutant enzymes (Y55F, Y55S, K84M, K84R, D50N, D50E, and H117A) were purified to homogeneity from an Escherichia coli expression system. Spectrophotometric assays showed that mutations of Tyr 55 and Lys 84 gave enzymes that were apparently inactive for steroid oxidation and reduction. All mutants appeared inactive for steroid reduction. The catalytic efficiencies for steroid oxidation were reduced 4−10-fold for the Asp 50 mutants and 300-fold for the H117A mutant. Fluorescence titration with NADPH demonstrated that each mutant bound cofactor unimpeded. Equilibrium dialysis indicated that the competitive inhibitor testosterone formed E·NADH·testosterone complexes only with the Y55F, Y55S, and D50N mutants with Kd values 10-fold greater than those for wild-type. Therefore the loss of steroid oxidoreductase activity observed for the Tyr 55 mutants cannot be attributed simply to an inability to bind steroid. Using a highly sensitive radiometric assay in which the conversion of [14C]-5α-dihydrotestosterone (DHT) to [14C]-3α-androstanediol (3α-Diol) was measured, the rate enhancement (kcat/knoncat) for the reaction was estimated to be 2.6 × 109. Using this assay, all mutants formed steroid product with decreases in an overall rate enhancement of 101−104. It was found that Tyr 55 made the single largest contribution to rate enhancement. This is the first instance where point mutations in the conserved catalytic tetrad of an AKR yielded enzymes which were still catalytically active. This enabled the construction of pH vs kcat profiles for the reduction of [14C]-5α-DHT catalyzed by the tetrad mutants. These profiles revealed that the titratable group assigned to the general acid (pK = 6.50 ± 0.42) was eliminated in the Y55F and H117A mutants. The pH-independent value of kcat was decreased in the H117A and Y55F mutants, by 2 and 4 log units, respectively. pH vs kcat(app) profiles for the oxidation of [3H]-3α-Diol showed that the same titratable group (pK = 7.50 ± 0.30) was eliminated in both the Y55F and K84M mutants but was retained in the H117A mutant. Since only the Y55F mutant eliminated the titratable group in both the reduction and oxidation directions it is assigned as the catalytic general acid/base. The differential effects of His 117 and Lys 84 on the ionization of Tyr 55 are explained by a “push−pull” mechanism in which His 117 facilitates proton donation and Lys 84 facilitates proton removal by Tyr 55.

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     This work was supported by NIH Grant DK47015 (to T.M.P.). A preliminary account of this study was presented at the International Symposium on DHEA Transformation into Androgens and Estrogens in Target Tissues:  Intracrinology, Quebec City, Canada, Sept 13−15, 1995, and the 2nd International Symposium on Molecular Steroidogenesis, Monterey, CA, June 7−11, 1996.

     Department of Pharmacology.

    §

     Current address:  Department of Pathology, Brigham & Women's Hospital, 20 Shattuck St., Boston, MA 02115.

     Department of Biochemistry & Biophysics.

    *

     To whom correspondence should be addressed:  Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104-6084. Telephone:  (215) 898-9445. Fax:  (215) 573-2236. E-mail:  [email protected].

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