STERIC CONSIDERATIONS IN THE ENZYMATIC COURSE OF THE HYDROXYLATION OF STEROIDS<sup>*</sup>

Hayano, Mika; Gut, Marcel; Dorfman, Ralph I.; Sebek, Oldrich K.; Peterson, D. H.

doi:10.1021/ja01542a080

Cited by 96 publications

(20 citation statements)

References 7 publications

(1 reference statement)

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“…The analogous chemical insertion of carbene into a C-H or C-D bond proceeds with an observed isotope effect of 1.8 (38). This mechanism is consistent with the low observed isotope effects, and the retention of configuration observed in such processes (39,40).…”

Section: Resultssupporting

confidence: 80%

Enzymic aromatization of deuterium labelled testosterone and androst-4-ene-3,17-dione

Holland¹,

Taylor²

1981

Can. J. Chem.

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The preparation and aromatization by human placental microsomes of androst-4-ene-3-ones labelled with deuterium at C-4, C-6α, C-6β, C-16, and C-19 is described. Deuterium nmr spectra are reported for these compounds and for a sample of a 1,2-dideuterated androst-4-ene-3-one; the latter is formed nonstereospecifically by reduction of the C-1(2) double bond of a Δ1,4-diene-3-one. Aromatization by placental microsomes occurs with retention of deuterium at C-4 and C-6, but with some loss from C-16. The aromatization of 19-d1 and 19,19,19-d3 steroids in the presence of 16,16-d2 steroids has been carried out to determine the deuterium isotope effect for the oxidative removal of C-19. The values obtained (kH/kD for 19-d1 = 2.3, kH/kD for 19,19, 19-d3 = 3.2) are a combination of primary and secondary effects, but suggest that oxidation at C-19 is a rate-limiting reaction of the biosynthetic sequence.The fungus Pellicularia filamentosa NRRL 2727, reported to hydroxylate androst-4-ene-3,17-dione at C-19, gave only the products of hydroxylation at C-11α, C-11β, and C-14.

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Section: Resultssupporting

confidence: 80%

Enzymic aromatization of deuterium labelled testosterone and androst-4-ene-3,17-dione

Holland¹,

Taylor²

1981

Can. J. Chem.

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“…Thus, Corey, Gregoriou & Peterson (98) subjected S,B-pregnane-3,20-dione9a,lla,12a-H 2 and S,B-pregnane-3,20-dione-11,B-H 2 to the l1a-hydroxylating action of Rhizopus nigricans and showed that the lla-deuterium atom was lost during the reaction, whereas the l1,B-deuterium atom remained undis turbed. Hayano et al (99,100) independently established the stereospecific ity of lla-hydroxylation by R. nigricans, using S,B-pregnane-3,20-dione lla,12a-H 3 and progesterone-lla, 1 2a-HB. These workers further examined the stereospecificity of l1,B-hydroxylation by perfusion of bovine adrenal glands with progesterone-l1a, 1 2a-H8, and they investigated also the 12a hydroxylation of the same substrate by cultures of Calonectria decora.…”

Section: Hydroxylation Reactionsmentioning

confidence: 99%

Enzymatic Mechanisms in Steroid Biochemistry

Talalay¹

1965

Annu. Rev. Biochem.

105

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This selective review of the present status of steroid biochemistry is con fined largely to consideration of the enzymatic basis of the transformations of steroids. This subject was comprehensively reviewed in 1957 (1). The in tervening years have witnessed considerable progress toward a better under standing of the manner of formation of the truly formidable number and variety of steroids from animal, plant, and microbial sources.Although this review is oriented toward discussion of the effects of en zymes on steroids, there is intense interest in the effects of steroids on enzyme systems and the possible relation of these phenomena to the molecular basis of steroid hormone action. Progress in the understanding of the details of the biosynthesis of both proteins and nucleic acids has made it possible to show that the regulatory influences of a number of hormones may find a common . basis in the control of the synthesis of various specific prot�ins. This control appears to be exerted at least in part on the process of the transcription of genetic information which directs protein synthesis. Many new studies have appeared in this area since the review by Tomkins & Maxwell (2), and excellent comprehensive discussions of this subject have been provided by Williams-Ashman (3, 4, 5), and by the book Actions of Hormones on Molecular Processes, edited by Litwack & Kritchevsky (6). These studies have not yet revealed the precise manner in which steroids modulate protein synthesis.However, it is now abundantly clear that steroid hormones may affect directly the activities of a number of relatively well-defined enzymatic pro cesses in two quite distinct ways: (a) certain steroids can participate in a catalytic manner in hydrogen transport reactions-the chemistry and pos sible physiological significance of these reactions has been reviewed in detail (7,8,9) ; (b) steroids may affect the activities of a number of enzymes in an "allosteric" way (2,5,7,9) , in accordance with the very imaginative pro posal of Monod, Changeux & Jacob (10).It has not been possible to cover all aspects of the enzymology of steroid transformations. Especially to be regretted are omissions of the discussion of contributions to sterol biosynthesis and the discovery of inhibitors which ap pear specifically to interrupt certain stages in the formation of cholesterol 1 The survey of literature pertaining to this review was completed in Decembe r 1964. 2 Studies from the author's laboratory were supported in part by grants from the National Institutes of Health of the United States Public Health Service. 347 Annu. Rev. Biochem. 1965.34:347-380. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/05/15. For personal use only. Quick links to online content Further ANNUAL REVIEWS

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“…The proposal that microbial hydroxylation at saturated carbon proceeds by direct electrophilic insertion of oxygen into a C-H bond followed from the discovery of a relationship between microbial hydroxylation of steroids at C, and microbial epoxidation of steroids unsaturated at C,, demonstrating the electrophilic nature of microbial hydroxylation (3,4) and the observation that microbial hydroxylation at saturated carbon proceeds with retention of configuration (5)(6)(7).…”

mentioning

confidence: 99%

The Mechanism of The Microbial Hydroxylation of Steroids. Part 1. The C-21 Hydroxylation of Progesterone by Aspergillusniger ATCC 9142

Holland¹,

Auret²

1975

Can. J. Chem.

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. Can. J. Chem. 53,845 (1975). The mechanism of the C-21 hydroxylation of progesterone (la) by Aspergillus niger ATCC 9142 to give 11deoxycorticosterone (lb) has been studied by the use of progesterone derivatives and of C-21 deuterium labelled progesterones. The requirement of the C-21 hydroxylase system for a C-20 carbonyl group is demonstrated and the possiblity of the involvement of this group, in the C-20,21 enol form, in the C-21 hydroxylation reaction has been discussed. However, on the basis of the observed deuterium isotope effect (KHIKD = 1.25), a mechanism for the microbial C-21 hydroxylation reaction is proposed in which the rate-determining step is the direct insertion of oxygen into a C-21 carbon-hydrogen bond and not one involving enolization of the C-20 carbonyl.In addition, C-1 l a and C-15P hydroxylation of both 20a-and 20P-hydroxypregn-4-ene-3-one (2a and 2b) by A. niger has been observed.HERBERT L. HOLLAND et BARBARA J. AURET. Can. J. Chem. 53,845(1975).On a etudit le mtcanisme de l'hydroxylation (en position C-21) de la progesttrone ( l a ) par I'Aspergill~rs niger ATCC 9142 conduisant B la dtoxy-11 corticosttrone (lb); cette Ctude a t t t effectute i I'aide de dtrivts de la progesterone et de progesttrone marqute au deuterium en position C-21. On a dtmontre la ntcessitt d'un groupe carbonyle en C-20 pour rendre efficace le systkme d'hydroxylase en C-21; on discute aussi de la possibilitt de I'implication du groupement carbonyle en position 20 sous forme d'tnol C-20,21 lors d e la riaction d'hydroxylation en C-21. Toutefois, sur la base de I'observation d'un effet isotopique ( K H / K~ = 1.25), on propose un micanisme pour la rkaction d'hydroxylation microbiologique en C-21 dans lequel I'itape dtterminante est I'insertion directe de I'oxygene dans le lien carbone-hydrogene en C-21 et on suggtre que cette reaction n'implique pas une tnolisation du groupement carbonyle en position C-20.De plus I'Aspergillus niger provoque I'hydroxylation en C-1 l a et en C-15P des hydroxy-2Oaet -20P pregene-4 one-3 (2a et 2b).[ Traduit par lejournal] In spite of the wide application of microbial steroid hydroxylation in both industry and research (1) and a thorough investigation of related biochemical processes (2), comparatively little is known about the chemistry of this reaction.The proposal that microbial hydroxylation at saturated carbon proceeds by direct electrophilic insertion of oxygen into a C-H bond followed from the discovery of a relationship between microbial hydroxylation of steroids at C, and microbial epoxidation of steroids unsaturated at C,, demonstrating the electrophilic nature of microbial hydroxylation (3, 4) and the observation that microbial hydroxylation at saturated carbon proceeds with retention of configuration (5-7).The question of enzymic substrate activation has received little consideration. For hydroxylation at saturated carbon, chemical analogy suggests that activation is unnecessary : oxidation of steroids at saturated carbon has been achieved under electrophilic conditio...

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STERIC CONSIDERATIONS IN THE ENZYMATIC COURSE OF THE HYDROXYLATION OF STEROIDS^*

Cited by 96 publications

References 7 publications

Enzymic aromatization of deuterium labelled testosterone and androst-4-ene-3,17-dione

Enzymic aromatization of deuterium labelled testosterone and androst-4-ene-3,17-dione

Enzymatic Mechanisms in Steroid Biochemistry

The Mechanism of The Microbial Hydroxylation of Steroids. Part 1. The C-21 Hydroxylation of Progesterone by Aspergillusniger ATCC 9142

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STERIC CONSIDERATIONS IN THE ENZYMATIC COURSE OF THE HYDROXYLATION OF STEROIDS*

Cited by 96 publications

References 7 publications

Enzymic aromatization of deuterium labelled testosterone and androst-4-ene-3,17-dione

Enzymic aromatization of deuterium labelled testosterone and androst-4-ene-3,17-dione

Enzymatic Mechanisms in Steroid Biochemistry

The Mechanism of The Microbial Hydroxylation of Steroids. Part 1. The C-21 Hydroxylation of Progesterone by Aspergillusniger ATCC 9142

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STERIC CONSIDERATIONS IN THE ENZYMATIC COURSE OF THE HYDROXYLATION OF STEROIDS^*