Partial reduction of steroid hormones and related substances

Norymberski, J. K.; Woods, G. Forrest

doi:10.1039/jr9550003426

Cited by 110 publications

(39 citation statements)

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“…That Glu 120 appears in AKR1D1 represents a unique exception for AKRs having an (␣/␤) 8 Crystal Structure of ⌬ sponding histidine residue in this complex (27). Interestingly, the hydrogen-bonded water molecule between Tyr 58 and Glu 120 occupies a position close to that of an acetate oxygen atom observed in the AKR1C2⅐NADP ϩ ⅐testosterone complex (27), and a corresponding water molecule is also observed in the crystal structure of AKR1C9 (32).…”

Section: Discussionmentioning

confidence: 86%

“…As a member of the AKR superfamily, it is not surprising that the (␣/␤) 8 -barrel fold and the NADP ϩ cofactor-binding site of AKR1D1 are highly conserved with those other members of the superfamily. However, the structures of AKR1D1⅐substrate complexes reported herein illuminate new features of steroid substrate recognition, the catalytic mechanism, and the positions of natural mutations associated with bile acid deficiency.…”

Section: Discussionmentioning

confidence: 99%

“…In the absence of enzyme catalysis, this reaction is extremely difficult to perform with chemical reductants. Treatment with borohydride favors formation of the 3␤-allylic alcohol, and under harsher conditions, the 3␤,5␣-tetrahydrosteroid is formed (8,9). It is possible to generate a 5␤-cholestane from the corresponding ⌬ 4 -3-ketosteroid only if a large directing group is placed at C-4 or C-7 to direct the face of hydride addition or catalytic hydrogenation (10,11).…”

mentioning

confidence: 99%

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Crystal Structure of Human Liver Δ4-3-Ketosteroid 5β-Reductase (AKR1D1) and Implications for Substrate Binding and Catalysis

Costanzo

Drury

Penning

et al. 2008

Journal of Biological Chemistry

120

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AKR1D1 (steroid 5␤-reductase) reduces all ⌬ 4-3-ketosteroids to form 5␤-dihydrosteroids, a first step in the clearance of steroid hormones and an essential step in the synthesis of all bile acids. The reduction of the carbon-carbon double bond in an ␣,␤-unsaturated ketone by 5␤-reductase is a unique reaction in steroid enzymology because hydride transfer from NADPH to the ␤-face of a ⌬ 4 -3-ketosteroid yields a cis-A/B-ring configuration with an ϳ90°b end in steroid structure. Here, we report the first x-ray crystal structure of a mammalian steroid hormone carbon-carbon double bond reductase, human ⌬ 120. The Y58F and E120A mutants are devoid of activity, supporting a role for this dyad in the catalytic mechanism. Intriguingly, testosterone binds nonproductively, thereby rationalizing the substrate inhibition observed with this particular steroid. The locations of disease-linked mutations thought to be responsible for bile acid deficiency are also revealed.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Crystal Structure of Human Liver Δ4-3-Ketosteroid 5β-Reductase (AKR1D1) and Implications for Substrate Binding and Catalysis

Costanzo

Drury

Penning

et al. 2008

Journal of Biological Chemistry

120

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“…It requires a strong reductant and stereo-controlled hydride addition to achieve the A/B cis ring junction. Common chemical reductants like borohydride will reduce ⌬ 4 -3-ketosteroids to yield the 3␤-allylic alcohol, and when forced, the double bond is reduced to the 5␣-configuration, but the 5␤-configuration is rarely obtained (16,17). Thus, Glu 120 has been proposed to play a unique role in steroid 5␤-reduction.…”

Section: Two Subfamilies Of Nad(p)(h)-dependent Steroid Transforming mentioning

confidence: 99%

Conversion of Human Steroid 5β-Reductase (AKR1D1) into 3β-Hydroxysteroid Dehydrogenase by Single Point Mutation E120H

Chen

Drury

Christianson

et al. 2012

Journal of Biological Chemistry

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Background:The aldo-keto reductase (AKR) subfamily AKR1D comprises steroid 5␤-reductases, whereas the AKR1C subfamily comprises hydroxysteroid dehydrogenases. Results: A single E120H mutation in AKR1D1 converts human steroid 5␤-reductase into a 3␤-hydroxysteroid dehydrogenase. Conclusion: Glu 120 controls the positional specificity of hydride transfer and facilitates double bond reduction. Significance: This is an example of a perfect change-of-function that can be achieved by a single point mutation.

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“…This metabolite was found to have the same Rf value on TLC plates with various solvent systems as 17a-ethynyl-3ß-hydroxy-4-estrene-17j3-acetate (E-9). The latter compound was obtained by hydrogenation of 17a-ethynyl-170-acetoxy-4-estrene-3-one (E-4) with NaBH4 according to a procedure reported by Norymberski and Woods (1955). The IR Fig.…”

Section: Oc-ethynyl-17ß-acetoxy-4-estrene-3-one (E-4)mentioning

confidence: 99%

Kinetic Study of the Enzymatic Inactivation of Progestogens by Rat Liver Microsomes

Abraham¹,

Taubert²

1975

Horm Res

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The kinetics of enzymatic hydrogenation of synthetic progestogens by female rat liver microsomes with NADPH as hydrogen donor were investigated by means of an optical test. Steroids with high progestational activity (Clauberg test) showed a low hydrogenation rate (V_max). There also seemed to be a certain correlation between molecular structure and V_max. The metabolites from incubation with the progestogens were isolated from the micro-preparations, and identified by infrared spectroscopy. It was found that the hydrogenation of the olefinic and carbonylic groups involved the uptake of hydrogen from NADPH.

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Partial reduction of steroid hormones and related substances

Cited by 110 publications

References 0 publications

Crystal Structure of Human Liver Δ4-3-Ketosteroid 5β-Reductase (AKR1D1) and Implications for Substrate Binding and Catalysis

Crystal Structure of Human Liver Δ4-3-Ketosteroid 5β-Reductase (AKR1D1) and Implications for Substrate Binding and Catalysis

Conversion of Human Steroid 5β-Reductase (AKR1D1) into 3β-Hydroxysteroid Dehydrogenase by Single Point Mutation E120H

Kinetic Study of the Enzymatic Inactivation of Progestogens by Rat Liver Microsomes

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