Structural Requirements in 20-Oxo-steroids for Interaction with the Binding Site of 20β-Hydroxysteroid Dehydrogenase

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In order to investigate the functional role of the region around the C and D rings in the interaction of steroids with the binding site of 20β-hydroxysteroid dehydrogenase, kinetic measurements were made for 34 kinds of steroids which differed in the nature of substituents, and in the shape and electronic character of the region around the C and D rings. Introduction of an oxo group at C-11 increased the apparent V_<max>, apparent K_m and II (K_m/V_<max>) values 2- to 9-, 13- to 195-, and 2- to 30-fold, respectively. Introduction of a hydroxyl group at the C-11β-position markedly increased the apparent K_m (58- to 119-fold) and II (164- to 256-fold) values, but decreased the apparent V_<max> value to one-half to one-third. An 11α-hydroxyl group caused an increase in the apparent K_m value similar to that caused by an 11β-hydroxyl group, but the degree of decrease in the apparent V_<max> value was rather lower. Esterification of the 11α-hydroxyl group led to a decrease in the apparent K_m value (0.3-fold) without any significant change in the V_<max> value. It is suggested that a binding interaction may occur between the region around C-11 of the steroid and the enzyme-coenzyme complex ; the interaction is probably hydrophobic in nature. A substituent at C-16 had an inhibitory effect on the hydrogen transfer stage since it resulted in loss of the substrate activity or a marked decrease in the V_<max> value (to about 1%) and an increase in the K_m value (23-fold). Introduction of a C-16/C-17 double bond, which caused a change in the configurational relationship between the 17β-side chain and the D ring, markedly decreased the apparent V_<max> value (to one-thirtieth) and increased the apparent K_m value (43-fold). Introduction of a hydroxyl group at C-18 had a marked effect on the kinetic constants, though the extent of the effect depended on the substituent at C-21. The steric and polar properties of the substituent at C-18 seem to be important factors in the interaction of the steroid with the binding site of the enzyme, and indirectly in that with the catalytic site. The features of the interaction between 20β-hydroxysteroid dehydrogenase and 20-oxo-steroids, as deduced from the results of the present and previous studies, are discussed.
公益社団法人日本薬学会の論文
1981-02-25

Structural Requirements in 20-Oxo-steroids for Interaction with the Binding Site of 20β-Hydroxysteroid Dehydrogenase

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