title: Aldo-keto Reductase 1B15 (AKR1B15): a mitochondrial human aldo-keto reductase with activity toward steroids and 3-keto-acyl-CoA conjugates.
abstract: Aldo-keto reductases (AKRs) comprise a superfamily of proteins involved in the reduction and oxidation of biogenic and xenobiotic carbonyls. In humans, at least 15 AKR superfamily members have been identified so far. One of these is a newly identified gene locus, AKR1B15, which clusters on chromosome 7 with the other human AKR1B subfamily members (i.e. AKR1B1 and AKR1B10). We show that alternative splicing of the AKR1B15 gene transcript gives rise to two protein isoforms with different N termini: AKR1B15.1 is a 316-amino acid protein with 91% amino acid identity to AKR1B10; AKR1B15.2 has a prolonged N terminus and consists of 344 amino acid residues. The two gene products differ in their expression level, subcellular localization, and activity. In contrast with other AKR enzymes, which are mostly cytosolic, AKR1B15.1 co-localizes with the mitochondria. Kinetic studies show that AKR1B15.1 is predominantly a reductive enzyme that catalyzes the reduction of androgens and estrogens with high positional selectivity (17β-hydroxysteroid dehydrogenase activity) as well as 3-keto-acyl-CoA conjugates and exhibits strong cofactor selectivity toward NADP(H). In accordance with its substrate spectrum, the enzyme is expressed at the highest levels in steroid-sensitive tissues, namely placenta, testis, and adipose tissue. Placental and adipose expression could be reproduced in the BeWo and SGBS cell lines, respectively. In contrast, AKR1B15.2 localizes to the cytosol and displays no enzymatic activity with the substrates tested. Collectively, these results demonstrate the existence of a novel catalytically active AKR, which is associated with mitochondria and expressed mainly in steroid-sensitive tissues.
authors.affiliation: From the Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Institute of Experimental Genetics, Genome Analysis Center, 85764 Neuherberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Weber
authors.affiliation: the Diabetes and Obesity Center, School of Medicine, University of Louisville, Louisville, Kentucky 40202.
authors.forename: Joshua K
authors.initials: JK
authors.lastname: Salabei
authors.affiliation: From the Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Institute of Experimental Genetics, Genome Analysis Center, 85764 Neuherberg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Möller
authors.affiliation: the Institute of Molecular Immunology, German Research Center for Environmental Health, Helmholtz Zentrum Muenchen, 81377 Muenchen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.affiliation: the Diabetes and Obesity Center, School of Medicine, University of Louisville, Louisville, Kentucky 40202.
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.affiliation: From the Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Institute of Experimental Genetics, Genome Analysis Center, 85764 Neuherberg, Germany, the Lehrstuhl für Experimentelle Genetik, Technische Universitaet Muenchen, 85356 Freising-Weihenstephan, Germany, and the German Center for Diabetes Research, 85764 Neuherberg, Germany Adamski@helmholtz-muenchen.de.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.affiliation: the Diabetes and Obesity Center, School of Medicine, University of Louisville, Louisville, Kentucky 40202, olegbarski@gmail.com.
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Barski
mesh_terms: D000214:Acyl Coenzyme A / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007700:Kinetics; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D010084:Oxidation-Reduction; D050837:Oxidoreductases Acting on Aldehyde or Oxo Group Donors / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013256:Steroids / Q000378:metabolism*
chemical_list: D000214:Acyl Coenzyme A; D020033:Protein Isoforms; D013256:Steroids; C560504:AKR1B15 protein, human; D050837:Oxidoreductases Acting on Aldehyde or Oxo Group Donors
keywords: 3-Keto-acyl-CoA; Aldo-Keto Reductase; Alternative Splicing; Enzyme Kinetics; Gene Expression; Mitochondria; Oxidation-Reduction (Redox); Reductase; Steroid