Activation of aldo-keto reductase family member 1B14 (AKR1B14) by bile acids: Activation mechanism and bile acid-binding site

Satoshi Endo, Toshiyuki Matsunaga, Anna Fujita, Tsukasa Kuragano, Midori Soda, Krithika Sundaram, Urmi Dhagat, Kazuo Tajima, Ossama El-Kabbani, Akira Hara

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

Abstract

Aldo-keto reductase (AKR) 1B14, a rat ortholog of mouse androgen-dependent vas deferens protein (AKR1B7), is involved in the synthesis of prostaglandin F(2 alpha) 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 mu M 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(+). (C) 2011 Elsevier Masson SAS. All rights reserved.
Original languageEnglish
Pages (from-to)1476 - 1486
Number of pages11
JournalBiochimie
Volume93
Issue number9
DOIs
Publication statusPublished - 2011

Cite this

Endo, Satoshi ; Matsunaga, Toshiyuki ; Fujita, Anna ; Kuragano, Tsukasa ; Soda, Midori ; Sundaram, Krithika ; Dhagat, Urmi ; Tajima, Kazuo ; El-Kabbani, Ossama ; Hara, Akira. / Activation of aldo-keto reductase family member 1B14 (AKR1B14) by bile acids: Activation mechanism and bile acid-binding site. In: Biochimie. 2011 ; Vol. 93, No. 9. pp. 1476 - 1486.
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title = "Activation of aldo-keto reductase family member 1B14 (AKR1B14) by bile acids: Activation mechanism and bile acid-binding site",
abstract = "Aldo-keto reductase (AKR) 1B14, a rat ortholog of mouse androgen-dependent vas deferens protein (AKR1B7), is involved in the synthesis of prostaglandin F(2 alpha) 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 mu M 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(+). (C) 2011 Elsevier Masson SAS. All rights reserved.",
author = "Satoshi Endo and Toshiyuki Matsunaga and Anna Fujita and Tsukasa Kuragano and Midori Soda and Krithika Sundaram and Urmi Dhagat and Kazuo Tajima and Ossama El-Kabbani and Akira Hara",
year = "2011",
doi = "10.1016/j.biochi.2011.04.022",
language = "English",
volume = "93",
pages = "1476 -- 1486",
journal = "Biochimie",
issn = "0300-9084",
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Endo, S, Matsunaga, T, Fujita, A, Kuragano, T, Soda, M, Sundaram, K, Dhagat, U, Tajima, K, El-Kabbani, O & Hara, A 2011, 'Activation of aldo-keto reductase family member 1B14 (AKR1B14) by bile acids: Activation mechanism and bile acid-binding site', Biochimie, vol. 93, no. 9, pp. 1476 - 1486. https://doi.org/10.1016/j.biochi.2011.04.022

Activation of aldo-keto reductase family member 1B14 (AKR1B14) by bile acids: Activation mechanism and bile acid-binding site. / Endo, Satoshi; Matsunaga, Toshiyuki; Fujita, Anna; Kuragano, Tsukasa; Soda, Midori; Sundaram, Krithika; Dhagat, Urmi; Tajima, Kazuo; El-Kabbani, Ossama; Hara, Akira.

In: Biochimie, Vol. 93, No. 9, 2011, p. 1476 - 1486.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Activation of aldo-keto reductase family member 1B14 (AKR1B14) by bile acids: Activation mechanism and bile acid-binding site

AU - Endo, Satoshi

AU - Matsunaga, Toshiyuki

AU - Fujita, Anna

AU - Kuragano, Tsukasa

AU - Soda, Midori

AU - Sundaram, Krithika

AU - Dhagat, Urmi

AU - Tajima, Kazuo

AU - El-Kabbani, Ossama

AU - Hara, Akira

PY - 2011

Y1 - 2011

N2 - Aldo-keto reductase (AKR) 1B14, a rat ortholog of mouse androgen-dependent vas deferens protein (AKR1B7), is involved in the synthesis of prostaglandin F(2 alpha) 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 mu M 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(+). (C) 2011 Elsevier Masson SAS. All rights reserved.

AB - Aldo-keto reductase (AKR) 1B14, a rat ortholog of mouse androgen-dependent vas deferens protein (AKR1B7), is involved in the synthesis of prostaglandin F(2 alpha) 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 mu M 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(+). (C) 2011 Elsevier Masson SAS. All rights reserved.

UR - http://www.sciencedirect.com.ezproxy.lib.monash.edu.au/science/article/pii/S0300908411001416

U2 - 10.1016/j.biochi.2011.04.022

DO - 10.1016/j.biochi.2011.04.022

M3 - Article

VL - 93

SP - 1476

EP - 1486

JO - Biochimie

JF - Biochimie

SN - 0300-9084

IS - 9

ER -