Abstract
We provide an overview of the physiological roles of aldehyde reductase (AKR1A) and also discuss the functions of aldose reductase (AKR1B) and other family members when necessary. Many types of aldehyde compounds are cytotoxic and some are even carcinogenic. Such toxic aldehydes are detoxified via the action of AKR in an NADPH-dependent manner and the resulting products may exert anti-diabetic and anti-tumorigenic activity. AKR1A is capable of reducing 3-deoxyglucosone and methylglyoxal, which are reactive intermediates that are involved in glycation, a non-enzymatic glycosylation reaction. Accordingly, AKR1A is thought to suppress the formation of advanced glycation end products (AGEs) and prevent diabetic complications. AKR1A and, in part, AKR1B are responsible for the conversion of d-glucuronate to l-gulonate which constitutes a process for ascorbate (vitamin C) synthesis in competent animals. AKR1A is also involved in the reduction of S-nitrosylated glutathione and coenzyme A and thereby suppresses the protein S-nitrosylation that occurs under conditions in which the production of nitric oxide is stimulated. As the physiological functions of AKR1A are currently not completely understood, the genetic modification of Akr1a could reveal the latent functions of AKR1A and differentiate it from other family members.
Highlights
Carbonyl compounds are produced by either enzymatic reactions during a variety of metabolic processes or by non-enzymatic reactions
While AKR1B participates in the reduction of glucose to sorbitol in the polyol pathway which is a cause for diabetic complications, glucose is not good substrate for AKR1A [5]
In the polyol pathway that is stimulated under conditions of hyperglycemia, AKR1B catalyzes the oxidative conversion of glucose to sorbitol, which is reduced to fructose by the action of sorbitol dehydrogenase (SDH) (Figure 3)
Summary
Carbonyl compounds are produced by either enzymatic reactions during a variety of metabolic processes or by non-enzymatic reactions. The two splicing mRNA variants carrying different 50 -untranslated regions are transcribed from Akr1a1, but the translation of these variants produces identical AKR1A protein products. These splicing variants of mRNA are expressed in all tissues to similar extents [8], and the physiological significance of the alternative splicing of Akr1a1 has not been clearly understood until now. No alternative exon has been reported for the mouse Akr1a4 gene, which is a slightly smaller than Akr1a1 and contains slightly larger introns among the exons in the 30 -region. NRF2, Akr1a1 and some other AKRs are substantially increased via the knockdown of the Kelch-like ECH-associated protein 1 (Keap1), a suppressor of NRF2 [20] These observations suggest that Akr1a1 is involved in the amelioration of such stress conditions
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