Transformation of some 3α-substituted steroids by Aspergillus tamarii KITA reveals stereochemical restriction of steroid binding orientation in the minor hydroxylation pathway

Hunter, A Christy, Khuenl-Brady, Hedda, Barrett, Patrice , Dodd, Howard T and Dedi, Cinzia (2010) Transformation of some 3α-substituted steroids by Aspergillus tamarii KITA reveals stereochemical restriction of steroid binding orientation in the minor hydroxylation pathway. The Journal of steroid biochemistry and molecular biology, 118 (3). pp. 171-176. ISSN 0960-0760

Full content URL: https://doi.org/10.1016/j.jsbmb.2009.12.003

Full text not available from this repository.

Item Type:Article
Item Status:Live Archive

Abstract

Aspergillus tamarii contains an endogenous lactonization pathway which can transform progesterone to testololactone in high yield through a sequential four step enzymatic pathway. In this pathway testosterone is formed which primarily undergoes oxidation of the C-17β-alcohol to a C-17 ketone but, can also enter a minor hydroxylation pathway where 11β-hydroxytestosterone is produced. It was recently demonstrated that this hydroxylase could monohydroxylate 3β-hydroxy substituted saturated steroidal lactones in all four possible binding orientations (normal, reverse, inverted normal, inverted reverse) on rings B and C of the steroid nucleus. It was therefore of interest to determine the fate of a series of 3α-substituted steroidal analogues to determine stereochemical effect on transformation. Hydroxylation on the central rings was found to be restricted to the 11β-position (normal binding), indicating that the 3α-stereochemistry removes freedom of binding orientation within the hydroxylase. The only other hydroxylation observed was at the 1β-position. Interestingly the presence of this functional group did not prevent lactonization of the C-17 ketone. In contrast the presence of the 11β-hydroxyl completely inhibited Baeyer–Villiger oxidation, a result which again demonstrates that single functional groups can exert significant control over metabolic handling of steroids in this organism. This may also explain why lactonization of 11β-hydroxytestosterone does not occur. Lactonization of the C-17 ketone was not significantly affected by the 3α-alcohol with significant yields achieved (53%). Interestingly a time course experiment demonstrated that the presence of the 3α-acetate inhibited the Baeyer–Villiger monooxygenase with its activity being observed 24 h later than non-acetate containing analogues. Apart from oxidative transformations observed a minor reductive pathway was revealed with the C-17 ketone being reduced to a C-17β-alcohol for the first time in this organism.

Divisions:College of Science > School of Pharmacy
ID Code:45542
Deposited On:29 Jun 2021 16:16

Repository Staff Only: item control page