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64-85-7Relevant articles and documents
1,4-Dioxene(2,3-Dihydro-1,4-dioxine) in Organic Synthesis. Part 91. Preparation of Biologically Active Side-Chains From 17-Oxosteroids
Fetizon, Marcel,Goulaouic, Pierre,Hanna, Issam
, p. 1107 - 1110 (1990)
Steroidal (17α-2,3-dihydro-1,4-dioxin-6-yl)-17β-ols of type (2), readily available from 17-oxo steroids and 2,3-dihydro-1,4-dioxine, are easely converted into 21-hydroxy-20-oxo steroids with or without a double bond at the 16(17) position as well as to the dihydroxyacetone side-chain.
CYP154C5 Regioselectivity in Steroid Hydroxylation Explored by Substrate Modifications and Protein Engineering**
Bracco, Paula,Wijma, Hein J.,Nicolai, Bastian,Buitrago, Jhon Alexander Rodriguez,Klünemann, Thomas,Vila, Agustina,Schrepfer, Patrick,Blankenfeldt, Wulf,Janssen, Dick B.,Schallmey, Anett
, p. 1099 - 1110 (2020/12/03)
CYP154C5 from Nocardia farcinica is a P450 monooxygenase able to hydroxylate a range of steroids with high regio- and stereoselectivity at the 16α-position. Using protein engineering and substrate modifications based on the crystal structure of CYP154C5, an altered regioselectivity of the enzyme in steroid hydroxylation had been achieved. Thus, conversion of progesterone by mutant CYP154C5 F92A resulted in formation of the corresponding 21-hydroxylated product 11-deoxycorticosterone in addition to 16α-hydroxylation. Using MD simulation, this altered regioselectivity appeared to result from an alternative binding mode of the steroid in the active site of mutant F92A. MD simulation further suggested that the entrance of water to the active site caused higher uncoupling in this mutant. Moreover, exclusive 15α-hydroxylation was observed for wild-type CYP154C5 in the conversion of 5α-androstan-3-one, lacking an oxy-functional group at C17. Overall, our data give valuable insight into the structure–function relationship of this cytochrome P450 monooxygenase for steroid hydroxylation.
Biotransformation of progesterone by the ascomycete Aspergillus niger N402
Savinova,Solyev,Vasina,Tyazhelova,Fedorova,Savinova
, p. 26 - 31 (2018/02/06)
The ability of the ascomyceteAspergillus niger N402 to transform exogenous progesterone was investigated. We found that this strain has steroid-hydroxylating activity and can introduce a hydroxyl group into the progesterone molecule mainly at positions C11(α) and C21 with predominant formation of 21-hydroxyprogesterone (deoxycortone). In addition, formation of 6β,11α-dihydroxyprogesterone was also observed. Studying the effects of the growth medium composition and temperature on progesterone conversion by A. niger N402 showed that the most intense accumulation of 21-hydroxyprogesterone occurred in minimal synthetic medium at 28°C. Increasing the cultivation temperature to 37°C resulted in almost complete inhibition of the hydroxylase activity in the minimal medium. In the complete medium, a similar increase in temperature inhibited 11α-hydroxylase activity and completely suppressed 6β-hydroxylase activity, but it produced no effect on 21-hydroxylating activity.
Functional analysis of human cytochrome P450 21A2 variants involved in congenital adrenal hyperplasia
Wang, Chunxue,Pallan, Pradeep S.,Zhang, Wei,Lei, Li,Yoshimoto, Francis K.,Waterman, Michael R.,Egli, Martin,Guengerich, F. Peter
, p. 10767 - 10778 (2017/07/07)
Cytochrome P450 (P450, CYP) 21A2 is the major steroid 21-hydroxylase, converting progesterone to 11-deoxycorticosterone and 17-hydroxyprogesterone (17-OH-progesterone) to 11-deoxycortisol. More than 100 CYP21A2 variants give rise to congenital adrenal hyperplasia (CAH). We previously reported a structure ofWT human P450 21A2 with bound progesterone and now present a structure bound to the other substrate (17-OH-progesterone).We found that the 17-OH-progesterone- and progesterone-bound complex structures are highly similar, with only some minor differences in surface loop regions. Twelve P450 21A2 variants associated with either saltwasting or nonclassical forms of CAH were expressed, purified, and analyzed. The catalytic activities of these 12 variants ranged from 0.00009% to 30% of WT P450 21A2 and the extent of heme incorporation from 10% to 95% of the WT. Substrate dissociation constants (Ks) for four variants were 37–13,000-fold higher than for WT P450 21A2. Cytochrome b5, which augments several P450 activities, inhibited P450 21A2 activity. Similar to the WT enzyme, high noncompetitive intermolecular kinetic deuterium isotope effects (> 5.5) were observed for all six P450 21A2 variants examined for 21-hydroxylation of 21-d3- progesterone, indicating that C–H bond breaking is a ratelimiting step over a 104 -fold range of catalytic efficiency. Using UV-visible and CD spectroscopy, we found that P450 21A2 thermal stability assessed in bacterial cells and with purified enzymes differed among salt-wasting- and nonclassical-associated variants, but these differences did not correlate with catalytic activity. Our in-depth investigation of CAH-associated P450 21A2 variants reveals critical insigh into the effects of disease-causing mutations on this important enzyme.