Transformation of some 3α-substituted steroids by Aspergillus tamarii KITA reveals stereochemical restriction of steroid binding orientation in the minor hydroxylation pathway |
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| Authors: | A Christy Hunter Hedda Khuenl-Brady Patrice Barrett Howard T Dodd Cinzia Dedi |
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| Institution: | 1. Department of Physics, Tampere University of Technology, P.O. Box 692, FI-33101 Tampere, Finland;2. Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, 30-387 Kraków, Poland;1. Area de Química Orgánica, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, INTEQUI-CONICET, San Luis 5700, Argentina;2. Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, INFIQC-CONICET, Córdoba 5000, Argentina;1. Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China;2. School of Pharmaceutical Science and Technology, State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China;3. University of Chinese Academy of Sciences, Beijing 100049, China;1. Manchester Pharmacy School, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, United Kingdom;2. University of Brighton, School of Pharmacy and Biomolecular Sciences, Huxley Building, Lewes Road, Brighton BN2 4GJ, United Kingdom;1. College of Pharmacy, Liaoning Medical University, Jinzhou, China;2. College of Pharmacy, Pharmacokinetic and Drug Transport Key Laboratory, Dalian Medical University, Dalian, China |
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| 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. |
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