Transformation of a series of saturated isomeric steroidal diols by Aspergillus tamarii KITA reveals a precise stereochemical requirement for entrance into the lactonization pathway.
Four isomers of 5α-androstan-3,17-diol have been transformed by the filamentous fungus Aspergillus tamarii, an organism which has the ability to convert progesterone to testololactone in high yield through an endogenous four step enzymatic pathway. The only diol handled within the lactonization pathway was 5α-androstan-3α,17β-diol which, uniquely underwent oxidation of the 17β-alcohol to the 17-ketone prior to its Baeyer-Villiger oxidation and the subsequent production of 3α-hydroxy-17a-oxa-D-homo-5α-androstan-17-one. This demonstrated highly specific stereochemical requirements of the 17β-hydroxysteroid dehydrogenase for oxidation of this specific steroidal diol to occur. In contrast, the other three diols were transformed within the hydroxylation pathway resulting in functionalization at C-11β. Only 5α-androstan-3β,17α-diol could bind to the hydroxylase in multiple binding modes undergoing monohydroxylation in 6β and 7β positions. Evidence from this study has indicated that hydroxylation of saturated steroidal lactones may occur following binding of ring-D in its open form in which an α-alcohol is generated with close spatial parity to the C-17α hydroxyl position. All metabolites were isolated by column chromatography and were identified by (1)H, (13)C NMR and DEPT analysis and further characterized using infra-red, elemental analysis and accurate mass measurement.
Hunter
A Christy
AC
Molecular Targeting and Polymer Toxicology Group, School of Pharmacy, The Huxley Biosciences Building, University of Brighton, East Sussex BN2 4GJ, UK. c.hunter@bton.ac.uk
Collins
Catherine
C
Dodd
Howard T
HT
Dedi
Cinzia
C
Koussoroplis
Salomé-Juliette
SJ
D015113:Androstane-3,17-diol / Q000378:metabolism*; D001230:Aspergillus / Q000378:metabolism*; D006900:Hydroxylation; D007536:Isomerism; D015394:Molecular Structure; D010084:Oxidation-Reduction
D015113:Androstane-3,17-diol