5β-Reduced steroids and human Δ4-3-ketosteroid 5β-reductase (AKR1D1)

• 5β-Reduced steroids are metabolites of Δ4-3-ketosteroids.
• 5β-Reduced androstanes, pregnanes, and cholanes perform biological functions.
• All mammalian bile-acids are 5β-cholanes.
• Aldo–keto reductase (AKR) 1D1 is the only human 5β-reductase.
• Structure–function studies on AKR1D1 provide a basis for bile-acid deficiency.

5β-Reduced steroids are non-planar steroids that have a 90° bend in their structure to create an A/B cis-ring junction. This novel property is required for bile-acids to act as emulsifiers, but in addition 5β-reduced steroids have remarkable physiology and may act as potent tocolytic agents, endogenous cardiac glycosides, neurosteroids, and can act as ligands for orphan and membrane bound receptors. In humans there is only a single 5β-reductase gene AKR1D1, which encodes Δ4-3-ketosteroid-5β-reductase (AKR1D1). This enzyme is a member of the aldo–keto reductase superfamily, but possesses an altered catalytic tetrad, in which Glu120 replaces the conserved His residue. This predominant liver enzyme generates all 5β-dihydrosteroids in the C19–C27 steroid series. Mutations exist in the AKR1D1 gene, which result in loss of protein stability and are causative in bile-acid deficiency.

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