Elsevier

Chemico-Biological Interactions

Volume 234, 5 June 2015, Pages 236-246
Chemico-Biological Interactions

The aldo-keto reductases (AKRs): Overview

https://doi.org/10.1016/j.cbi.2014.09.024Get rights and content

Highlights

  • Aldo-keto reductases (AKRs) are a major superfamily of NAD(P)H-dependent oxidoreductases.

  • They use a conserved catalytic mechanism and rate is often governed by cofactor release.

  • There are 15 human AKRs implicated in health and disease.

  • Inhibitor programs exist world-wide to develop therapeutics and chemical probes for AKRs.

  • Natural mutations in human AKRs are responsible for disease phenotypes.

Abstract

The aldo-keto reductase (AKR) protein superfamily contains >190 members that fall into 16 families and are found in all phyla. These enzymes reduce carbonyl substrates such as: sugar aldehydes; keto-steroids, keto-prostaglandins, retinals, quinones, and lipid peroxidation by-products. Exceptions include the reduction of steroid double bonds catalyzed by AKR1D enzymes (5β-reductases); and the oxidation of proximate carcinogen trans-dihydrodiol polycyclic aromatic hydrocarbons; while the β-subunits of potassium gated ion channels (AKR6 family) control Kv channel opening. AKRs are usually 37 kDa monomers, have an (α/β)8-barrel motif, display large loops at the back of the barrel which govern substrate specificity, and have a conserved cofactor binding domain. AKRs catalyze an ordered bi bi kinetic mechanism in which NAD(P)H cofactor binds first and leaves last. In enzymes that favor NADPH, the rate of release of NADP+ is governed by a slow isomerization step which places an upper limit on kcat. AKRs retain a conserved catalytic tetrad consisting of Tyr55, Asp50, Lys84, and His117 (AKR1C9 numbering). There is conservation of the catalytic mechanism with short-chain dehydrogenases/reductases (SDRs) even though they show different protein folds. There are 15 human AKRs of these AKR1B1, AKR1C1–1C3, AKR1D1, and AKR1B10 have been implicated in diabetic complications, steroid hormone dependent malignancies, bile acid deficiency and defects in retinoic acid signaling, respectively. Inhibitor programs exist world-wide to target each of these enzymes to treat the aforementioned disorders. Inherited mutations in AKR1C and AKR1D1 enzymes are implicated in defects in the development of male genitalia and bile acid deficiency, respectively, and occur in evolutionarily conserved amino acids. The human AKRs have a large number of nsSNPs and splice variants, but in many instances functional genomics is lacking. AKRs and their variants are now poised to be interrogated using modern genomic and informatics approaches to determine their association with human health and disease.

Introduction

The reduction of aldehydes and ketones to primary and secondary alcohols, respectively are formal functionalization reactions and are involved in the phase 1 metabolism of endogenous compounds and xenobiotics bearing these carbonyl groups. These reactions are often catalyzed by proteins that belong to two protein superfamilies, the short-chain dehydrogenases/reductases (SDRs) and the aldo-keto reductases (AKRs) [1], [2].

AKRs exist in nearly all phyla, they are mainly monomeric soluble proteins (34–37 kDa), NAD(P)(H) dependent oxidoreductases [3]. While a search of the genome data bases can reveal a large number of in silico sequences that are AKRs, the protein superfamily contains 190 annotated proteins which fall into 16 families [4]. The enzymes have broad substrate specificity and will transform sugar [5] and lipid aldehydes [6], [7], keto-steroids [8], keto-prostaglandins [9], [10], and chemical carcinogens, e.g., nicotine derived nitrosamines [11] as well as carcinogen metabolites e.g., polycyclic aromatic hydrocarbon trans-dihydrodiols [12], [13] and aflatoxin dialdehyde [14]. Each enzyme is characterized by the same protein fold, a triose-phosphate isomerase TIM barrel or (α/β)8-barrel with the insertion of several additional helices [15], [16]. At the back of the barrel there are three large loops that define substrate specificity. There are currently 119 AKR structures and their complexes in the PDB (as of August 2014). Sequence alignment and structural comparison identifies a common cofactor binding domain which permits pro-R-hydride transfer to the acceptor group, and a conserved catalytic tetrad of Tyr, Lys, His, Asp [3].

Sequence alignment also allows the identification of the AKR families and sub-families, where related members become grouped based on protein function. In this nomenclature <40% sequence identity of an AKR identifies the protein as belonging to a new family. Greater than 60% identity between members groups them as members of the same subfamily and a numeral identifies the exact protein member [17]. Thus aldehyde reductase is defined as AKR1A1. The 16 AKR families include: AKR1 (aldehyde reductases, aldose reductases, hydroxysteroid dehydrogenases, and steroid 5β-reductases); AKR2 (mannose and xylose reductases); AKR3 (yeast AKRs); AKR4 (chalcone and codeinone reductases); AKR5 (gluconic acid reductases); AKR6 (β-subunits of the potassium gated voltage channels); AKR7 (aflatoxin dialdehyde and succinic semialdehyde reductases); AKR8 (pyridoxal reductases); AKR9 (aryl alcohol dehydrogenases); AKR10 (Streptomyces AKRs); AKR11 (Bacillus AKRs); AKR12 (Streptomyces sugar aldehyde reductases); AKR13 (hyperthermophilic bacteria reductases); AKR14 (E. coli reductases), AKR15 (Mycobacterium reductases) and AKR16 (V. cholera reductases) (Fig. 1; www.med.upenn.edu/akr). This overview will review common features of the enzymatic properties of the AKRs and on the role of human AKRs in health and disease.

Section snippets

Enzymological properties

All AKRs catalyze a sequential ordered bi–bi reaction in which cofactor binds first and leaves last [18], [19]. This has raised issues relating to the identity of the rate-determining step; is the step cofactor binding and release? Substrate binding and product release? Or the chemical step?

Human AKRs and disease

There are 15 human AKRs see Table 1. These include aldehyde reductase (AKR1A1); aldose reductase and aldose-like reductase proteins (AKR1B1, AKR1B10 and AKR1B15); the hydroxysteroid dehydrogenases (AKR1C1–AKR1C4); steroid 5β-rductase (AKR1D1); 1,5-anhydro-d-fructose reductase (AKR1E2); the β-subunits of the potassium voltage gated channels (AKR6A3, AKR6A5, and AKR6A9) (which form tetramers); and the dimeric aflatoxin aldehyde reductases (AKR7A2 and AKR7A3). These human AKRs are implicated in a

Summary

AKRs are pluripotent enzymes that play a role in phase 1 metabolism of endogenous substrates and xenobiotics. Rate-determination is substrate dependent and may be driven by cofactor release, the chemical step or by a combination of these events. The catalytic Tyr and Glu acid residues conduct chemistry in violation of their pKa values at physiological pH. Determination of their pKa values in the protein microenvironment by NMR will be an important undertaking to further elucidate the AKR

Conflict of interest

This work was supported by grants from the National Institutes of Health as follows: 1R01-CA39504 and P30-ES013508 awarded to TMP.

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