Abstract
Hydroxysteroid dehydrogenases (HSDHs) are from two superfamilies of short-chain dehydrogenase (SDR) and aldo–keto reductase (AKR). The HSDHs were summarized and classified according to their structural and functional differences. A typical pair of enzymes, 7α–hydroxysteroid dehydrogenase (7α–HSDH) and 7β–hydroxysteroid dehydrogenase (7β–HSDH), have been reported before. Molecular docking of 7-keto–lithocholic acid(7–KLA) to the binary of 7β–HSDH and nicotinamide adenine dinucleotide phosphate (NADP+) was realized via YASARA, and a possible binding model of 7β–HSDH and 7–KLA was obtained. The α side of 7–KLA towards NADP+ in 7β–HSDH, while the β side of 7–KLA towards nicotinamide adenine dinucleotide (NAD+) in 7α–HSDH, made the orientations of C7–OH different in products. The interaction between Ser193 and pyrophosphate of NAD(P)+ [Ser193–OG⋯3.11Å⋯O1N–PN] caused the upturning of PN–phosphate group, which formed a barrier with the side chain of His95 to make 7–KLA only able to bind to 7β–HSDH with α side towards nicotinamide of NADP+. A possible interaction of Tyr253 and C24 of 7–KLA may contribute to the formation of substrate binding orientation in 7β–HSDH. The results of sequence alignment showed the conservation of His95, Ser193, and Tyr253 in 7β–HSDHs, exhibiting a significant difference to 7α–HSDHs. The molecular docking of other two enzymes, 17β–HSDH from the SDR superfamily and 3(17)α–HSDH from the AKR superfamily, has furtherly verified that the stereospecificity of HSDHs was related to the substrate binding orientation.
Highlights
Hydroxysteroid dehydrogenases (HSDHs) are a type of nicotinamide adenine dinucleotide NAD(H)/NADP(H)-dependent oxidoreductase that can catalyze the reduction of carbonyl to hydroxy of steroid-skeleton structures such as steroid hormones and bile acids, in addition to a reversible reaction
The structure binding model is analogous when in a tetramer crystal of 7α–hydroxysteroid dehydrogenase (7α–HSDH) from Clostridium absonum, even though with a coenzyme of NADP+ and a substrate of taurochenodeoxycholic acid (TCDCA); even the Ser of Tyr–Lys–Ser was changed by Thr [94]
The different NAD(P)(H)-binding models of these two types of HSDHs were analyzed, with the pro-S side of nicotinamide group towards catalytic residues in short-chain dehydrogenase (SDR) superfamily while pro-R side of nicotinamide group towards catalytic residues in aldo–keto reductase (AKR) superfamily. It impacts the catalytic mechanisms of SDR–HSDHs and AKR–HSDHs
Summary
Hydroxysteroid dehydrogenases (HSDHs) are a type of nicotinamide adenine dinucleotide (phosphate) NAD(H)/NADP(H)-dependent oxidoreductase that can catalyze the reduction of carbonyl to hydroxy of steroid-skeleton structures such as steroid hormones and bile acids, in addition to a reversible reaction. Most of them belong to the SDR superfamily, such as 7α–HSDH (EC 1.1.1.159), 7β–HSDH (EC 1.1.1.201), and 11β–HSDH (EC 1.1.1.146), which have been identified in Escherichia coli, Collinsella aerofaciens, and Homo sapiens, respectively [3,4,5], usually with a length of 250–350 amino acids [6]. They all have a core composed of seven parallel β-sheets and several α-helices wraps around the core (Figure 1), which form two typical domains named Rossmann fold (each composed of two βαβ units) for coenzyme binding [6,7]. 3α–HSDHs from Comamonas testosteron [10] and Pseudomonas sp. [11] belong to the SDR superfamily, while from Rattus norvegicus [12] and Homo sapiens [13] belong to the AKR superfamily (Figure 2)
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