Rat Aldose Reductase-Like Protein (AKR1B14) Efficiently Reduces the Lipid Peroxidation Product 4-Oxo-2-nonenal

Abstract

The aldo-keto reductase (AKR) superfamily is a rapidly growing group of pyridine nucleotide-dependent oxidoreductases that metabolize carbohydrates, steroids, prostaglandins, and other endogenous aldehydes and ketones, as well as xenobiotic compounds.1,2) Aldose reductase (AR), which belongs to the AKR1B subfamily, is a nicotinamide adenine dinucleotide phosphate reduced form (NADPH)-dependent enzyme that catalyses the first step in the polyol pathway and has been implicated in the onset of secondary complications of diabetes in humans.3,4) AR shows broad substrate specificity for various aldehydes and aldoses, and is involved in various physiological roles, including the metabolism of retinoids, steroids and xenobiotics, and defensive mechanisms for oxidative stress. [5][6][7][8] Beside AR, multiple AR-like proteins (ARLPs) that show high sequence similarity (67-71%) to ARs have been identified in human and rodent tissues. While one ARLP (AKR1B10) is ubiquitously expressed in human tissues, 8,9) two ARLPs, androgen-dependent vas deferens protein (AKR1B7) 10) and fibroblast growth factor-inducible protein (AKR1B8), 11) are distributed tissue-specifically in mice. The two mouse ARLPs reduce aldehydes, but are clearly distinct from mouse AR in their poor efficiency in reducing glucose.12,13) AKR1B7 and AKR1B8 differ in their substrate specificity and inhibitor sensitivity. Compared to AKR1B7, 10,12) AKR1B8 exhibits high catalytic efficiency for cytotoxic 4-hydroxynonenal (HNE) derived from lipid peroxidation, 13) but has poor reactivity towards isocaproaldehyde resulting from the side chain cleavage of cholesterol during steroidogenesis.10) AKR1B7 is insensitive to AR inhibitors (ARIs) 10) and exhibits prostaglandin (PG) F 2a synthase activity, which is not detected in the ARI-sensitive AKR1B8. 14)In rats, two ARLPs, AKR1B13 and AKR1B14, have been identified, 15,16) and are thought to be orthologs of mouse AKR1B8 and AKR1B7, respectively, based on high sequence identity of 95% (AKR1B13 versus AKR1B8) and 87% (AKR1B14 versus AKR1B7). AKR1B13 is distributed in almost all rat tissues, and exhibits similar substrate specificity and inhibitor sensitivity to AKR1B8. 17) AKR1B14 and AKR1B7 are similar in their high expression in the adrenal glands and induction by adrenocorticotropic hormone, 10,16,18) but differ in their distribution and gene regulation in other tissues. AKR1B7 is also expressed in mouse vas deferens, intestine and liver, and is up-regulated by androgen, pituitary tropic hormones and agonists of nuclear receptors (liver X receptor-a, pregnane X receptor and constitutive androstane receptor). 10,19,20) In contrast, AKR1B14 is highly expressed in female rat liver through female-specific secretion pattern of growth hormone, 21) and its expression in male rat liver is up-regulated by oxidative stress. 22) Thus, these differences have suggested that AKR1B14 plays a physiological role distinct from its mouse ortholog, AKR1B7. However, there is no report on the detailed properties of AKR1B14, except for its ro...

Characterization of AKR1B16, a novel mouse aldo-keto reductase

“…No NADH dependent reductase activity was observed. The K m value for NADPH (0.5 μM, Table 2) was similar to that reported for other members of this family [16,[46][47][48][49]. Therefore, we tested the AKR1B16 activity with typical AKR substrates in the presence of NADPH ( Table 2).…”

Human and rodent aldo–keto reductases from the AKR1B subfamily and their specificity with retinaldehyde

“…In Table 2, we compare their kinetic properties with retinoids, including recently published data for rat 1B13 [32], 1B14 [33] and 1B17 [26]. All the enzymes showed similar k cat values with glyceraldehyde (~30 min −1 ), with the exception of 1B7, 1B14 and 1B17, which usually displayed lower k cat values with all the substrates [22, 26].…”

“…Units: K m (mM with d,l -glyceraldehyde, µM with retinoids), k cat (min −1 ), k cat / K m (mM −1 ·min −1 ). Activities were determined in 0.1 M sodium phosphate, pH 7.5, 0.2 mM NADPH, 25°C, with d,l -glyceraldehyde, and in 90 mM KH 2 PO 4 , 40 mM KCl, pH 7.4, 0.5 mM NADP/H, 37°C, with retinoids, N.A., No activity; N.D., Not determined. a Data taken from [33]. …”

Oxidative and reductive metabolism of lipid-peroxidation derived carbonyls

“…In addition, AKR1B14 metabolizes furfural and 5-hydroxyfurfural while being unable to reduce D-glucose and D-xylose. ONE has been identified as a major substrate for AKR1B14 [78, 79], which is a particularly toxic byproduct of lipid-peroxidation (vide supra).…”