title: Aldo-keto reductases in which the conserved catalytic histidine is substituted.
abstract: Aldo-keto reductases (AKRs) are a major superfamily of monomeric NADPH-dependent carbonyl oxidoreductases. They are characterized by an (alpha/beta)(8)-barrel structure, which at its base contains a conserved catalytic tetrad of Tyr, Lys, His and Asp. Two AKR subfamilies contain other residues substituted for the catalytic His and perform different functions. First, the steroid 5beta-reductase (AKR1D1), which reduces CC double bonds instead of carbonyl groups, has a Glu substituted for His. Second, the Kvbeta subunits (AKR6A3, AKR6A5 and AKR6A9) which modulate opening of the voltage-gated potassium channel (Kv1) by oxidizing NADPH, have an Asn substituted for the His. Previously, we noted that conserved catalytic residues in AKRs perform similar functions in the short-chain dehydrogenases (SDRs). With the availability of crystal structures of AKR1D1 and two SDRs that catalyze double-bond reduction reactions, Digitalis steroid 5beta-reductase and 2,4-dienoyl-CoA reductase, we have compared their active sites to outline the features that govern whether 1,2-, 1,4- or 1,6-hydride transfer occurs.
authors.affiliation: Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, PA 19104-6323, United States. luigidi@sas.upenn.edu
authors.forename: Luigi
authors.initials: L
authors.lastname: Di Costanzo
authors.forename: Trevor M
authors.initials: TM
authors.lastname: Penning
authors.forename: David W
authors.initials: DW
authors.lastname: Christianson
mesh_terms: D000429:Alcohol Oxidoreductases / Q000737:chemistry / Q000378:metabolism; D000449:Aldehyde Reductase; D000074408:Aldo-Keto Reductases; D055162:Biocatalysis; D020134:Catalytic Domain; D017124:Conserved Sequence; D006639:Histidine / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D008958:Models, Molecular; D051637:Shaker Superfamily of Potassium Channels / Q000737:chemistry
chemical_list: D051637:Shaker Superfamily of Potassium Channels; D006639:Histidine; D000429:Alcohol Oxidoreductases; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase