Enzymatic characteristics of an aldo–keto reductase family protein (AKR1C15) and its localization in rat tissues

Endo, Shunsuke; Matsunaga, Toshiyuki; Horie, Kenji; Tajima, Kazuo; Bunai, Yasuo; Carbone, Vincenzo; El‐Kabbani, Ossama; Hara, Akira

doi:10.1016/j.abb.2007.05.008

Cited by 22 publications

(17 citation statements)

References 60 publications

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“…The results suggest that the observed alterations in secretion and properties of the surfactant result from the ROS generated during 9,10-PQ exposure, rather than from the quinone and its metabolites. 9,10-PQ is an excellent substrate of AKR1C15 (Endo et al 2007) and its reduction by AKR1C15 has recently been reported to promote superoxide anion generation through redox cycling ). In addition, the level of 8-hydroxydeoxyguanosine, indicative of oxidative DNA damage, in BALF is enhanced 1.5-fold upon the intratracheal injection of 9,10-PQ into rats (data not shown).…”

Section: Resultsmentioning

confidence: 97%

“…After a blocking step with 5% skim milk, the membrane was allowed to react with primary antibodies against surfactant protein (SP) A (Santa Cruz Biotechnology, Santa Cruz, Calif., USA), CuZn-SOD (Binding Site, Birmingham, UK), AKR1C2 (Deyashiki et al 1994), AKR1C3 and AKR1C15 (Endo et al 2007). The antibodies against AKR1C2 cross-reacted with AKR1C1 and were therefore named anti-AKR1C1/1C2 antibodies.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…In contrast to the presence of only four members of the AKR1C subfamily in humans, rats express at least seven members: AKR1C8, AKR1C9, AKR1C15, AKR1C16, AKR1C17, AKR1C24 and RAKh (17β-hydroxysteroid dehydrogenase). Among the rat AKR1C members, AKR1C15 is unique in showing its high affinity for various carbonyl compounds, such as 17-ketosteroids, monosaccharides, lipid-derived aldehydes, aromatic and aliphatic ketones and quinones including 9,10-PQ (Endo et al 2007). AKR1C15 is highly expressed in vascular endothelial cells and epithelial cells of rat respiratory and digestive organs.…”

Section: Introductionmentioning

confidence: 99%

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9,10-Phenanthrenequinone promotes secretion of pulmonary aldo-keto reductases with surfactant

et al. 2012

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9,10-Phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust particles, induces apoptosis via the generation of reactive oxygen species (ROS) because of 9,10-PQ redox cycling. We have found that intratracheal infusion of 9,10-PQ facilitates the secretion of surfactant into rat alveolus. In the cultured rat lung, treatment with 9,10-PQ results in an increase in a lower-density surfactant by ROS generation through redox cycling of the quinone. The surfactant contains aldo-keto reductase (AKR) 1C15, which reduces 9,10-PQ and the enzyme level in the surfactant increases on treatment with 9,10-PQ suggesting an involvement of AKR1C15 in the redox cycling of the quinone. In six human cell types (A549, MKN45, Caco2, Hela, Molt4 and U937) only type II epithelial A549 cells secrete three human AKR1C subfamily members (AKR1C1, AKR1C2 and AKR1C3) with the surfactant into the medium; this secretion is highly increased by 9,10-PQ treatment. Using in vitro enzyme inhibition analysis, we have identified AKR1C3 as the most abundantly secreted AKR1C member. The AKR1C enzymes in the medium efficiently reduce 9,10-PQ and initiate its redox cycling accompanied by ROS production. The exposure of A549 cells to 9,10-PQ provokes viability loss, which is significantly protected by the addition of the AKR1C3 inhibitor and antioxidant enzyme and by the removal of the surfactants from the culture medium. Thus, the AKR1C enzymes secreted in pulmonary surfactants probably participate in the toxic mechanism triggered by 9,10-PQ.

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Section: Resultsmentioning

confidence: 97%

Section: Western Blot Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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9,10-Phenanthrenequinone promotes secretion of pulmonary aldo-keto reductases with surfactant

et al. 2012

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“…*Kinetics was performed in 0.1 M potassium phosphate buffer, pH 6.5, at 37°C, and products were analyzed by reverse phase HPLC equilibrated with 80% (v/v) acetonitrile in water. a Crosas et al (2003), b Gallego et al (2007b), c Quinn et al (2008), d Joshi et al (2010), e Crosas et al (2001), f Endo et al (2009), g Endo et al (2010a), h Endo et al (2010b), i Endo et al (2001), j Endo et al (2007) .…”

Section: Characterization Of Akrs As Retinaldehyde Reductasesmentioning

confidence: 99%

Biological Role of Aldo–Keto Reductases in Retinoic Acid Biosynthesis and Signaling

et al. 2012

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Several aldo–keto reductase (AKR) enzymes from subfamilies 1B and 1C show retinaldehyde reductase activity, having low Km and kcat values. Only AKR1B10 and 1B12, with all-trans-retinaldehyde, and AKR1C3, with 9-cis-retinaldehyde, display high catalytic efficiency. Major structural determinants for retinaldehyde isomer specificity are located in the external loops (A and C for AKR1B10, and B for AKR1C3), as assessed by site-directed mutagenesis and molecular dynamics. Cellular models have shown that AKR1B and 1C enzymes are well suited to work in vivo as retinaldehyde reductases and to regulate retinoic acid (RA) biosynthesis at hormone pre-receptor level. An additional physiological role for the retinaldehyde reductase activity of these enzymes, consistent with their tissue localization, is their participation in β-carotene absorption. Retinaldehyde metabolism may be subjected to subcellular compartmentalization, based on enzyme localization. While retinaldehyde oxidation to RA takes place in the cytosol, reduction to retinol could take place in the cytosol by AKRs or in the membranes of endoplasmic reticulum by microsomal retinaldehyde reductases. Upregulation of some AKR1 enzymes in different cancer types may be linked to their induction by oxidative stress and to their participation in different signaling pathways related to cell proliferation. AKR1B10 and AKR1C3, through their retinaldehyde reductase activity, trigger a decrease in the RA biosynthesis flow, resulting in RA deprivation and consequently lower differentiation, with an increased cancer risk in target tissues. Rational design of selective AKR inhibitors could lead to development of novel drugs for cancer treatment as well as reduction of chemotherapeutic drug resistance.

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“…3,[5][6][7][8][9][10] In rabbits, such AKRs are six, which are AKR1C5 acting as 17β/20α-HSD, 11,12) AKR1C29 (that is identical to 3-hydroxyhexobarbital dehydrogenase and exhibits 3α/3β/17β/20α-HSD activity), 13) AKR1C30 (that is identical to naloxone reductase type 1 and acts as 17β-HSD), AKR1C31 (that acts as 3α/17β/20α-HSD), AKR1C32 (that is identical to loxoprofen reductase and acts as 3α/20α-HSD) and AKR1C33 (that is identical to naloxone reductase type 2 and mainly acts as 3α-HSD).…”

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Probing AKR1C30 and AKR1C31 with Site-Directed Mutagenesis: Identifying the Roles of Residues 54 and 56 in the Binding of Substrates and Inhibitors

Endo

Arai

Matsunaga

et al. 2014

Biological & Pharmaceutical Bulletin

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Five rabbit aldo-keto reductases (AKRs) that participate in the reduction of drug ketones and endogenous ketosteroids have recently been cloned and characterized. Among them, AKR1C30 and AKR1C31 show the highest amino acid sequence identity of 91%, but markedly differ in their substrate specificity and inhibitor sensitivity. AKR1C30 reduces two drugs (ketotifen and naloxone) and 17-keto-5β-androstanes, whereas AKR1C31 does not reduce the two drugs, but is active towards loxoprofen and various 3/17/20-ketosteroids. In addition, AKR1C30 is selectively inhibited by carbenoxolone, valproic acid and phenobarbital. Residues A54 and R56 are located adjacent to the catalytic residue Y55 of AKR1C30. To clarify the determinants for the substrate specificity and inhibitor sensitivity of AKR1C30, we performed the mutagenesis of A54 and R56 to the corresponding residues (L and Q) of AKR1C31. The A54L mutation produced an enzyme that had almost the same substrate specificity as AKR1C31 and decreased the sensitivity to the inhibitors except for carbenoxolone. The R56Q mutation decreased the affinity for only carbenoxolone among the substrates and inhibitors. Thus, the difference in the properties between the two enzymes can be attributed to their residue difference at positions 54 and 56.Key words aldo-keto reductase; carbenoxolone; drug ketone reductase; hydroxysteroid dehydrogenase; sitedirected mutagenesis Carbonyl reduction into the alcohol metabolites is an important Phase-I metabolism of carbonyl-containing drugs. 1,2)To detoxify and excrete the chemically divergent carbonyl compounds, nicotinamide adenine dinucleotide phosphate reduced form (NADPH)-dependent reductases with broad substrate specificity for carbonyl compounds exist in multiple forms in the body. The enzymes with known primary structures are grouped into two distinct protein families: the shortchain dehydrogenase/reductase 1,3) and aldo-keto reductase (AKR) 2-4) superfamilies. Major human enzymes responsible for the reduction of drug ketones in the AKR superfamily are four cytosolic hydroxysteroid dehydrogenase (HSD) isoforms, 2,3) which belong to the AKR1C subfamily and named AKR1C1, AKR1C2, AKR1C3 and AKR1C4.In laboratory animal rats or mice, five NADPH-dependent AKRs similar to the human HSD isoforms were identified and suggested to reduce xenobiotic carbonyl compounds. 3,[5][6][7][8][9][10] In rabbits, such AKRs are six, which are AKR1C5 acting as 17β/20α-HSD, 11,12) AKR1C29 (that is identical to 3-hydroxyhexobarbital dehydrogenase and exhibits 3α/3β/17β/20α-HSD activity), 13) AKR1C30 (that is identical to naloxone reductase type 1 and acts as 17β-HSD), AKR1C31 (that acts as 3α/17β/20α-HSD), AKR1C32 (that is identical to loxoprofen reductase and acts as 3α/20α-HSD) and AKR1C33 (that is identical to naloxone reductase type 2 and mainly acts as 3α-HSD).14) The rabbit AKRs share more than 73% amino acid sequence identity, which is 94% between AKR1C30 and AKR1C31. Despite of the high sequence identity, AKR1C30 and AKR1C31 differ in their specificity for dr...

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Enzymatic characteristics of an aldo–keto reductase family protein (AKR1C15) and its localization in rat tissues

Cited by 22 publications

References 60 publications

9,10-Phenanthrenequinone promotes secretion of pulmonary aldo-keto reductases with surfactant

9,10-Phenanthrenequinone promotes secretion of pulmonary aldo-keto reductases with surfactant

Biological Role of Aldo–Keto Reductases in Retinoic Acid Biosynthesis and Signaling

Probing AKR1C30 and AKR1C31 with Site-Directed Mutagenesis: Identifying the Roles of Residues 54 and 56 in the Binding of Substrates and Inhibitors

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