| Activation of aldo-keto reductase family member 1B14 (AKR1B14) by bile acids: Activation mechanism and bile acid-binding site. | |
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MedLine Citation:
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PMID: 21586312 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Aldo-keto reductase (AKR) 1B14, a rat ortholog of mouse androgen-dependent vas deferens protein (AKR1B7), is involved in the synthesis of prostaglandin F(2α) and detoxification of 4-oxononenal formed by lipid peroxidation. The NADPH-linked reductase activity of AKR1B14 was activated by various bile acids. Although the activation was increased by decreasing pH from 9.0 to 6.0, the concentrations giving maximum stimulation (2- to 18-fold) were 0.2-6.0 μM for bile acids at pH 7.4. Kinetic analyses of the activation by glycochenodeoxycholic acid in the forward and reverse reactions, together with fluorescence changes and protection against 4-oxononenal-induced inactivation by bile acid, indicate that the bile acid binds to the enzyme and its coenzyme binary complex as a non-essential activator. The bile acid binding to AKR1B14 mainly accelerates the NADP(+) dissociation, the rate-limited step of the enzyme reaction. AKR1B7 was also activated by bile acids, but the activation was low and independent of pH. The mutagenesis of His269 and Leu267 of AKR1B14 into the corresponding residues (Arg and Pro, respectively) of AKR1B7 resulted in low and pH-independent activation by bile acids. The results, together with the docking of the bile acid in the recently determined crystal structure of AKR1B14, identify the bile acid-binding site of which His269 plays a key role in significant activation through its electrostatic interaction with the carboxyl group of bile acid, facilitating the release of NADP(+). |
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Authors:
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Satoshi Endo; Toshiyuki Matsunaga; Anna Fujita; Tsukasa Kuragano; Midori Soda; Krithika Sundaram; Urmi Dhagat; Kazuo Tajima; Ossama El-Kabbani; Akira Hara |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-10 |
Journal Detail:
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Title: Biochimie Volume: - ISSN: 1638-6183 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-18 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 1264604 Medline TA: Biochimie Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011. Published by Elsevier Masson SAS. |
Affiliation:
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Laboratory of Biochemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu 501-1196, Japan. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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