Epimerase activity of the human 11beta-hydroxysteroid dehydrogenase type 1 on 7-hydroxylated C19-steroids.
Cytochrome P4507B1 7alpha-hydroxylates dehydroepiandrosterone (DHEA), epiandrosterone (EpiA) and 5alpha-androstane-3beta,17beta-diol (Adiol). 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts 7alpha- and 7beta-forms. Whether the interconversion proceeds through oxido-reductive steps or epimerase activity was investigated. Experiments using [(3)H]-labelled 7beta-hydroxy-DHEA, 7beta-hydroxy-EpiA and 7beta-hydroxy-Adiol showed the (3)H-label to accumulate in the 7-oxo-DHEA trap but not in 7-oxo-EpiA or 7-oxo-Adiol traps. Computed models of 7-oxygenated steroids docked in the active site of 11beta-HSD1 either in a flipped or turned form relative to cortisone and cortisol. 7-Oxo-steroid reduction in 7alpha- or 7beta-hydroxylated derivatives resulted from either turned or flipped forms. 11beta-HSD1 incubation in H(2)(18)O medium with each 7-hydroxysteroid did not incorporate (18)O in 7-hydroxylated derivatives of EpiA and Adiol independently of the cofactor used. Thus oxido-reductive steps apply for the interconversion of 7alpha- and 7beta-hydroxy-DHEA through 7-oxo-DHEA. Epimerization may proceed on the 7-hydroxylated derivatives of EpiA and Adiol through a mechanism involving the cofactor and Ser(170). The physiopathological importance of this epimerization process is related to 7beta-hydroxy-EpiA production and its effects in triggering the resolution of inflammation.
Hennebert
Olivier
O
Chaire de Génie Biologique, EA-3199, Biotechnologie, Conservatoire National des Arts et Métiers, 2 rue Conté, 75003 Paris, France.
Montes
Matthieu
M
Favre-Reguillon
Alain
A
Chermette
Henry
H
Ferroud
Clotilde
C
Morfin
Robert
R
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015113:Androstane-3,17-diol / Q000737:chemistry / Q000378:metabolism; D000738:Androsterone / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D000072474:Cytochrome P450 Family 7; D003687:Dehydroepiandrosterone / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D013256:Steroids / Q000737:chemistry / Q000378:metabolism
D013256:Steroids; D015113:Androstane-3,17-diol; D003687:Dehydroepiandrosterone; D000738:Androsterone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C499571:CYP7B1 protein, human