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  • Substituents at the C position An oxygen containing substitu

    2020-07-30

    Substituents at the C11 position — An oxygen-containing substituent at the C11 position also affects the catalytic activity of Δ1-KSTDs. The Δ1-KSTDs from the Gram-positive bacteria R. equi [29], N. simplex ATCC 6946 and IFO 12069 [48,49,52], and R. rhodochrous IFO 3338 [27] were able to 1(2)-dehydrogenate 11α-hydroxy-, 11β-hydroxy-, or 11-keto-3-ketosteroids, e.g. 11α-hydroxyprogesterone (45), 11β-hydroxy-4-ansdrostene-3,17-dione (36), adrenosterone (37), Thalidomide (48), cortisone (53) or corticosterone (46). Likewise, Δ1-KSTD1 and Δ1-KSTD2 from R. erythropolis SQ1 were active on cortisol [28]. On the other hand, Δ1-KSTDs from the Gram-negative bacteria C. testosteroni ATCC 11996 [50] and S. denitrificans Chol-1ST [47] were inactive on both 11β-hydroxy- and 11-keto-3-ketosteroids, although the Δ1-KSTD from C. testosteroni ATCC 11996 could 1(2)-dehydrogenate 11α-hydroxytestosterone (25) [50]. In general, 3-ketosteroids oxygenated at C11 are less easily converted by Δ1-KSTDs than their non-oxygenated analogs [27,29,50]. Yet, the Δ1-KSTD from R. equi catalyzed the 1(2)-dehydrogenation of 11α-hydroxy-progesterone (45) at a similar rate as progesterone (43) [29] and cortisone (53) was a good substrate for the Δ1-KSTD from R. rhodochrous IFO 3338 [27]. Thus, an oxygen-containing substituent at the C11 position of 3-ketosteroids may adversely affect conversion by Δ1-KSTDs. Particularly, 11β-hydroxy and 11-keto groups have a negative effect on the activity of the Δ1-KSTDs from Gram-negative bacteria [48]. Substituents at the C17 position — Δ1-KSTDs accept 3-ketosteroid substrates with varying substituents at the C17 position. In the crystal structure of Δ1-KSTD1•ADD, the C17 atom of ADD (9) is exposed to solvent. In agreement with this observation, most characterized Δ1-KSTDs reacted well on 3-ketosteroids with their C17 carbon atom substituted with hydroxyl (e.g. testosterone; 24), ketone (e.g. AD; 8), acyl (e.g. progesterone; 43), or hydroxyacyl groups (e.g. cortexolone; 47) [27,28,29,47,48,49,50,52,53]. Δ1-KSTDs from R. equi [91], N. simplex ATCC 6946 [52], and S. denitrificans Chol-1ST [47] were even able to 1(2)-dehydrogenate 4-cholesten-3-one (2), and a Δ1-KSTD from Clostridium paraputrificum was active on 3-oxo-5β-cholan-24-oic acid (57) [92]. Furthermore, a study on M. tuberculosis H37Rv [56] implied that its Δ1-KSTD is active on a steroid with a C17 side chain degradation intermediate. Effects of such substituents on the reactivity of Δ1-KSTDs toward 3-ketosteroids are variable. For instance, testosterone was the best tested substrate for the Δ1-KSTDs from R. equi [29] and N. simplex IFO 12069 [48], but was a somewhat worse substrate for the enzymes from C. testosteroni ATCC 11996 [50] and S. denitrificans Chol-1ST [47]. Furthermore, the activity of the Δ1-KSTD from C. testosteroni ATCC 11996 [50] and the Δ1-KSTD2 from R. erythropolis SQ1 [28] on progesterone was, respectively, about 60 and 185% of their activity on AD. Thus, Δ1-KSTDs can generally accept 3-ketosteroid substrates with diverse substituents at the C17 position, but with varied, not yet understood, effects on their activity.