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Journal ArticleDOI

Mechanism-Based Inhibition of Human Steroid 5α-Reductase by Finasteride: Enzyme-Catalyzed Formation of NADP−Dihydrofinasteride, a Potent Bisubstrate Analog Inhibitor

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TLDR
The intermediate NADP−dihydrofinasteride adduct can be recovered intact by denaturation of the enzyme−inhibitor complex and has been purified.
Abstract
Finasteride is employed in treatment of benign prostatic hyperplasia in man, where its target enzyme is steroid 5α-reductase. It is a novel, potent mechanism-based inhibitor of the human prostate (type 2) isozyme. Although it is accepted as an alternate substrate and is ultimately reduced to dihydrofinasteride, this proceeds through an enzyme-bound NADP−dihydrofinasteride adduct. Finasteride is processed with a second-order rate constant, ki/Ki = 1 × 106 M-1 s-1, that approaches kcat/Km for reduction of testosterone, 3 × 106 M-1 s-1, and essentially every catalytic event is lethal (partition ratio ≤ 1.07). The membrane-bound enzyme−inhibitor complex formed from [3H]finasteride appears to release [3H]dihydrofinasteride with a half-life of 1 month at 37 °C (k = (2.57 ± 0.03) × 10-7 s-1), as identified by mass spectroscopy. The intermediate NADP−dihydrofinasteride adduct can be recovered intact by denaturation of the enzyme−inhibitor complex and has been purified. Free in solution, it likewise decomposes to ...

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Journal ArticleDOI

Drug–target residence time and its implications for lead optimization

TL;DR: The potential advantages of long residence time in terms of duration of pharmacological effect and target selectivity are described, as quantified by the dissociative half-life of the drug–target binary complex.
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Human Cytochrome P450 Enzymes

TL;DR: Human P450s 1A1,6 1A2,7 2A6,8 2C8,9 2C9,9,10 2D67,11,12 and lanosterol 14α-demethylase18 were isolated in this general manner.
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Drugs, their targets and the nature and number of drug targets

TL;DR: This work considers the nature of drug targets, and by classifying known drug substances on the basis of the discussed principles it provides an estimation of the total number of current drug targets.
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The drug-target residence time model: a 10-year retrospective

TL;DR: This model is revisited and key applications of it over the past 10 years are highlighted and it is shown that the lifetime (or residence time) of the binary drug–target complex, and not the binding affinity per se, dictates much of the in vivo pharmacological activity.
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Residence time of receptor-ligand complexes and its effect on biological function.

TL;DR: The impact of residence time on the optimization of potential ligands as drugs for human medicine is described and its significance to biological function is described.
References
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Journal ArticleDOI

FtsZ ring structure associated with division in Escherichia coli.

TL;DR: The results suggest that FtsZ self-assembles into a ring structure at the future division site and may function as a cytoskeletal element and the formation of this ring may be the point at which division is regulated.
Journal ArticleDOI

Steroid 5α-Reductase Deficiency in Man: An Inherited Form of Male Pseudohermaphroditism

TL;DR: In male pseudohermaphrodites born with ambiguity of the external genitalia but with marked virilization at puberty, biochemical evaluation reveals a marked decrease in plasma dihydrotestosterone secondary to a decrease in steroid 5α-reductase activity.
Journal ArticleDOI

Steroid 5 alpha-reductase: two genes/two enzymes.

TL;DR: The structure of the determinants of apoptosis, a type of cell death, and the role that individual cells play in this process are studied.
Journal ArticleDOI

On the attribution and additivity of binding energies.

TL;DR: It can be useful to describe the Gibbs free energy changes for the binding to a protein of a molecule and of its component parts in terms of the "intrinsic binding energies" of A and B, DeltaG(A) (i) and DeltaG (i), and a "connection Gibbs energy" that is derived largely from changes in translational and rotational entropy.
Journal ArticleDOI

Deletion of steroid 5α-reductase 2 gene in male pseudohermaphroditism

TL;DR: The results verify the existence of at least two 5α-reductases in man and provide insight into a fundamental hormone-mediated event in male sexual differentiation.
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