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

Endo, Shunsuke; Matsunaga, Toshiyuki; Fujita, Anna; Kuragano, Tsukasa; Soda, Midori; Sundaram, K. Soma; Dhagat, Urmi; Tajima, Kazuo; El‐Kabbani, Ossama; Hara, Akira

doi:10.1016/j.biochi.2011.04.022

Cited by 6 publications

(7 citation statements)

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“…However, the two enzymes differ in their K m value for the coenzyme NADP(H). The value for AKR1B14 is lower than that for AKR1B7, which is similar to that for AKR1B1 (Kubiseski & Flynn, 1995;Endo, Matsunaga, Fujita et al, 2010;Endo et al, 2011).…”

Section: Introductionsupporting

confidence: 72%

Structure of the His269Arg mutant of the rat aldose reductase-like protein AKR1B14 complexed with NADPH

et al. 2012

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Rat aldose reductase-like protein (AKR1B14) is an orthologue of mouse vas deferens protein (AKR1B7) and plays roles in the detoxification of reactive aldehydes and synthesis of prostaglandin F 2. Here, the 1.87 Å resolution crystal structure of the His269Arg mutant of AKR1B14 complexed with NADPH is described and shows that the negatively charged 2 0-phosphate group of the coenzyme forms an ionic interaction with the positively charged guanidinium group of Arg269 that is also observed in the human aldose reductase (AKR1B1) structure. Previous experiments on the site-directed mutagenesis of His269 to Arg, Phe and Met revealed fourfold, sevenfold and 127-fold increases in the K m for NADPH, respectively, which are in agreement with the present molecularmodelling and X-ray crystallographic studies. This is the first tertiary structure of a mutant form of this AKR1B7 orthologue to be reported in order to investigate the structure-function relationship of the nonconserved His269 and its role in coenzyme binding.

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Section: Introductionsupporting

confidence: 72%

Structure of the His269Arg mutant of the rat aldose reductase-like protein AKR1B14 complexed with NADPH

et al. 2012

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“…Recently three independent studies proposed that Akr1b7 or its rat ortholog Akr1b14 could be involved in bile acid metabolism and/or signaling (Endo et al, 2011; Ge et al, 2011; Schmidt et al, 2011). …”

Section: Akr1b and Glucido-lipidic Homeostasismentioning

confidence: 99%

“…An in vitro enzymatic study using recombinant Akr1b14 (rat) and Akr1b7 (mouse) proteins showed that conjugated and unconjugated bile acids (chenodeoxycholic acid (CDCA)/glyco-CDCA and hyodeoxycolic acid (HDCA)/glyco-HDCA) specifically, quickly, and significantly activated the NADPH-linked reductase activity of Akr1b14 and to a lesser extent Akr1b7 activity (Endo et al, 2011). More accurately, higher specific activation of Akr1b14 was mediated by an interaction of bile acids with the His269 facilitating the release of NADP + .…”

Section: Akr1b and Glucido-lipidic Homeostasismentioning

confidence: 99%

“…Those of r-Akr1b10 share this tissue expression pattern but are also found in brain, heart, and lungs (Endo et al, 2010b). Akr1b13 expression has been observed at mRNA level in almost all organs, except brain and liver but the protein remains undetectable in small intestine and colon (Endo et al, 2011). …”

Section: Introductionmentioning

confidence: 99%

“…Several studies allowed identification of Akr1b4 , Akr1b13 , and Akr1b14 as the orthologs of mouse Akr1b3 , Akr1b8 , and Akr1b7 , respectively (Barski et al, 2008; Endo et al, 2011). This phylogenetic analysis between rat and mouse AR has some limits: Akr1b14 and Akr1b7 do not exactly display the same expression pattern.…”

Section: Introductionmentioning

confidence: 99%

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Aldo-Keto Reductases 1B in Endocrinology and Metabolism

Pastel¹,

Pointud²,

Volat³

et al. 2012

Front. Pharmacol.

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The aldose reductase (AR; human AKR1B1/mouse Akr1b3) has been the focus of many research because of its role in diabetic complications. The starting point of these alterations is the massive entry of glucose in polyol pathway where it is converted into sorbitol by this enzyme. However, the issue of AR function in non-diabetic condition remains unresolved. AR-like enzymes (AKR1B10, Akr1b7, and Akr1b8) are highly related isoforms often co-expressed with bona fide AR, making functional analysis of one or the other isoform a challenging task. AKR1B/Akr1b members share at least 65% protein identity and the general ability to reduce many redundant substrates such as aldehydes provided from lipid peroxidation, steroids and their by-products, and xenobiotics in vitro. Based on these properties, AKR1B/Akr1b are generally considered as detoxifying enzymes. Considering that divergences should be more informative than similarities to help understanding their physiological functions, we chose to review specific hallmarks of each human/mouse isoforms by focusing on tissue distribution and specific mechanisms of gene regulation. Indeed, although the AR shows ubiquitous expression, AR-like proteins exhibit tissue-specific patterns of expression. We focused on three organs where certain isoforms are enriched, the adrenal gland, enterohepatic, and adipose tissues and tried to connect recent enzymatic and regulation data with endocrine and metabolic functions of these organs. We presented recent mouse models showing unsuspected physiological functions in the regulation of glucido-lipidic metabolism and adipose tissue homeostasis. Beyond the widely accepted idea that AKR1B/Akr1b are detoxification enzymes, these recent reports provide growing evidences that they are able to modify or generate signal molecules. This conceptually shifts this class of enzymes from unenviable status of scavenger to upper class of messengers.

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Toxicogenomic assessment of liver responses following subchronic exposure to furan in Fischer F344 rats

et al. 2015

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Furan is a widely used industrial chemical and a contaminant in heated foods. Chronic furan exposure causes cholangiocarcinoma and hepatocellular tumors in rats at doses of 2 mg/kg bw/day or greater, with gender differences in frequency and severity. The hepatic transcriptional alterations induced by low doses of furan (doses below those previously tested for induction of liver tumors) and the potential mechanisms underlying gender differences are largely unexplored. We used DNA microarrays to examine the global hepatic mRNA and microRNA transcriptional profiles of male and female rats exposed to 0, 0.03, 0.12, 0.5 or 2 mg/kg bw/day furan over 90 days. Marked gender differences in gene expression responses to furan were observed, with many more altered genes in exposed males than females, confirming the increased sensitivity of males even at the low doses. Pathway analysis supported that key events in furan-induced liver tumors in males include gene expression changes related to oxidative stress, apoptosis and inflammatory response, while pathway changes in females were consistent with primarily adaptive responses. Pathway benchmark doses (BMDs) were estimated and compared to relevant apical endpoints. Transcriptional pathway BMDs could only be examined in males. These median BMDs ranged from 0.08 to 1.43 mg/kg bw/day and approximated those derived from traditional histopathology. MiR-34a (a P53 target) was the only microRNA significantly increased at the 2 mg/kg bw/day, providing evidence to support the importance of apoptosis and cell proliferation in furan hepatotoxicity. Overall, this study demonstrates the use of transcriptional profiling to discern mode of action and mechanisms involved in gender differences.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-015-1561-2) contains supplementary material, which is available to authorized users.

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

Cited by 6 publications

References 44 publications

Structure of the His269Arg mutant of the rat aldose reductase-like protein AKR1B14 complexed with NADPH

Structure of the His269Arg mutant of the rat aldose reductase-like protein AKR1B14 complexed with NADPH

Aldo-Keto Reductases 1B in Endocrinology and Metabolism

Toxicogenomic assessment of liver responses following subchronic exposure to furan in Fischer F344 rats

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