The intermediary role of a 19-oxoandrogen in the biosynthesis of oestrogen

Akhtar, Muhammad; Skinner, S.J.M.

doi:10.1042/bj1090318

Cited by 72 publications

(29 citation statements)

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“…The oxidation of the primary hydroxy group in the compound (II) to an aldehyde group in compound (IV) is dependent on the involvement of NADPH and molecular oxygen (Akhtar & Skinner, 1968). To explain this observation it was proposed that a gem-diol, of the type shown in structure (III) of Scheme 1, may be involved in an intermediary role in this process.…”

Section: Vol 201mentioning

confidence: 99%

“…The multistep conversion of 4-androstene-3,17-dione (I) into 3-hydroxy-1,3,5 (10)-oestratriene-17-one (V) catalysed by the aromatase complex of human placenta (Ryan, 1959) has been the subject of extensive studies in this laboratory (Akhtar & Skinner, 1968;Skinner & Akhtar, 1969;Akhtar et al, 1981). The results from our experiments, when taken in conjunction with those of Meyer (1955), Wilcox & Engle (1965) and Braselton et al, (1973), Abbreviations used: TMS, trimethylsilyl: g.l.c.-m.s., gas liquid chromatography-mass spectrometry.…”

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confidence: 99%

“…The stoichiometry of this process was subsequently determined by Thompson & Siiteri (1974) who showed that the aromatization reaction, (I) to (V), indeed utilized 3 mol each of NADPH and 02' thus providing further support for the pathway of Scheme 1. According to Scheme 1, the first hydroxylation occurs at C-19 to produce 1 9-hydroxy-4-androstene-3,17-dione (II) (Meyer, 1955); this, in the second oxidation step, is converted to the corresponding 1 9-aldehyde (IV), presumably through the intermediacy of the gem-diol (III) (Akhtar & Skinner, 1968). The mechanistic details and absolute stereochemistry of the second oxidation reaction, (II) to (IV), have been elucidated by a number of independent approaches (Arigoni et al, 1975;Osawa et al, 1975;Caspi et al, 1978).…”

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Mechanistic studies on C-19 demethylation in oestrogen biosynthesis

Akhtar

Calder

Corina

et al. 1982

Biochemical Journal

279

220

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Mechanistic aspects of the biosynthesis of oestrogen have been studied with a microsomal preparation from full-term human placenta. The overall transformation, termed the aromatization process, involves three steps using O2 and NADPH, in which the C-19 methyl group of an androgen is oxidised to formic acid with concomitant production of the aromatic ring of oestrogen: [Formula: see text] To study the mechanism of this process in terms of the involvement of the oxygen atoms, a number of labelled precursors were synthesized. Notable amongst these were 19-hydroxy-4-androstene-3,17-dione (II) and 19-oxo-4-androstene-3,17-dione (IV) in which the C-19 was labelled with2H in addition to18O. In order to follow the fate of the labelled atoms at C-19 of (II) and (IV) during the aromatization, the formic acid released from C-19 was benzylated and analysed by mass spectrometry. Experimental procedures were devised to minimize the exchange of oxygen atoms in substrates and product with oxygens of the medium. In the conversion of the 19-[18O] compounds of types (II) and (IV) into 3-hydroxy-1,3,5-(10)-oestratriene-17-one (V, oestrone), it was found that the formic acid from C-19 retained the original substrate oxygen. When the equivalent16O substrates were aromatized under18O2, the formic acid from both substrates contained one atom of18O. It is argued that in the conversion of the 19-hydroxy compound (II) into the 19-oxo compound (IV), the C-19 oxygen of the former remains intact and that one atom of oxygen from O2 is incorporated into formic acid during the conversion of the 19-oxo compound (IV) into oestrogen. This conclusion was further substantiated by demonstrating that in the aromatization of 4-androstene-3,17-dione (I), both the oxygen atoms in the formic acid originated from molecular oxygen. 10β-Hydroxy-4-oestrene-3,17-dione formate, a possible intermediate in the aromatization, was synthesized and shown not to be converted into oestrogen. In the light of the cumulative evidence available to date, stereochemical aspects of the conversion of the 19-hydroxy compound (II) into the 19-oxo compound (IV), and mechanistic features of the C-10–C-19 bond cleavage step during the conversion of the 19-oxo compound (IV) into oestrogen are discussed.

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Section: Vol 201mentioning

confidence: 99%

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Mechanistic studies on C-19 demethylation in oestrogen biosynthesis

Akhtar

Calder

Corina

et al. 1982

Biochemical Journal

279

220

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“…Finally, the third step consists of a lyase reaction, in which the C 10 -C 19 bond of the androgens is cleaved, resulting in the aromatization of the phenolic A ring of the androgens, and expelling formic acid and a water molecule. The literature on this mechanism is very extensive since it has been studied by means of both experimental [12][13][14][15][23][24][25][26][27][28][29][30][31] and theoretical techniques. [32][33][34][35][36][37][38][39] However, the third oxidation step is still under discussion, in which has not yet reached a consensus.…”

Section: Introductionmentioning

confidence: 99%

“…11 This conversion consists of the aromatization of the A ring of the androgens, which occurs through a process of three consecutive oxidations of the angular C 19 methyl group of the androgens. [12][13][14][15][16] In this catalytic process, each oxidation step consumes one mol of NADPH, one mol of molecular oxygen and requires of the presence of the cytochrome P450 reductase (CPR) as a source of electrons. 10,[17][18][19][20][21][22] The overall process of aromatization of androgens via the enzyme aromatase has been depicted in Scheme 1.…”

Section: Introductionmentioning

confidence: 99%

Theoretical Study of the Mechanism of Exemestane Hydroxylation Catalyzed by Human Aromatase Enzyme

Viciano

Martí

2016

J. Phys. Chem. B

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Human aromatase (CYP19A1) aromatizes the androgens to form estrogens via a three-step oxidative process.The estrogens are necessary in humans, mainly in women, because of the role they play in the sexual and reproductive development. However, these also are involved in the development and growth of hormonedependent breast cancer. Therefore, inhibition of the enzyme aromatase, by means of drugs known as aromatase inhibitors, is the frontline therapy for these types of cancers. Exemestane is a suicidal third-generation inhibitor of aromatase, currently used in the breast cancer treatment. In this study, the hydroxylation of exemestane catalyzed by aromatase has been studied by means of hybrid QM/MM methods. The Free Energy Perturbation calculations provided a free energy of activation for the hydrogen abstraction step (rate-limiting step) of 17 kcal/mol. The results reveal that the hydroxylation of exemestane is not the inhibition stage suggesting a possible competitive mechanism between the inhibitor and the natural substrate androstenedione in the first catalytic subcycle of the enzyme. Furthermore, the analysis of the interaction energy for the substrate and the cofactor in the active site, shows that the role of the enzymatic environment during this reaction consists of a transition state stabilization by means of electrostatic effects.3

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Male Sex Hormones, Analogs, and Antagonists

Brueggemeier

2010

Burger's Medicinal Chemistry and Drug Discovery

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The steroid testosterone is the major circulating sex hormone of the male and serves as the prototype for the androgens, the anabolic agents, and androgen antagonists. The endogenous androgens are biosynthesized from cholesterol in various tissues in the body; the majority of the circulating androgens are made in the testes under the stimulation of the gonadotropin luteinizing hormone ( LH ). The reduction of testosterone to dihydrotestosterone is necessary for the androgenic actions of testosterone in many androgen target tissues such as the prostate; the oxidation of testosterone by the enzyme aromatase produces estrogens. The androgenic actions of testosterone and dihydrotestosterone are due to their binding to the androgen receptor, followed by nuclear localization, dimerization of the receptor complex, and binding to a specific DNA sequence. This binding of the homodimer to the androgen response element leads to gene expression, stimulation or repression of the synthesis of new mRNA, and subsequent protein biosynthesis. The synthetic androgens and anabolics were prepared to impart oral activity to the androgen molecule, to separate the androgenic effects of testosterone from its anabolic effects, and to improve upon its biological activities. Novel nonsteroidal androgens, termed selective androgen receptor modulators, were developed to impart agonist activity in selective tissues. Drug preparations are used for the treatment of various androgen‐deficient diseases, for the therapy of diseases characterized by muscle wasting and protein catabolism, for postoperative adjuvant therapy, and for the treatment of certain hormone‐dependent cancers. The two major categories of androgen antagonists are the antiandrogens, which block interactions of androgens with the androgen receptor, and the inhibitors of androgen biosynthesis and metabolism. Such compounds have therapeutic potential in the treatment of acne, virilization in women, hyperplasia and neoplasia of the prostate, and baldness and male contraception.

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The intermediary role of a 19-oxoandrogen in the biosynthesis of oestrogen

Abstract: Previous work in a number of Laboratories has established that the biological conversion of androstenedione (I) into oestrone (V) occurs through the involvement of a 19-hydroxy compound (II)

Cited by 72 publications

References 6 publications

Mechanistic studies on C-19 demethylation in oestrogen biosynthesis

Mechanistic studies on C-19 demethylation in oestrogen biosynthesis

Theoretical Study of the Mechanism of Exemestane Hydroxylation Catalyzed by Human Aromatase Enzyme

Male Sex Hormones, Analogs, and Antagonists

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