About AKR
Nomenclature
Structures
Families
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Nomenclature
The general format for AKR names is as follows: the root symbol ‘AKR’ for Aldo-Keto Reductase; an Arabic number designating the family; a letter indicating the subfamily when multiple subfamilies exist; and an Arabic numeral representing the unique protein sequence. Under the system, the protein AKR1A1 would be the first AKR in family 1, subfamily A, and in this instance corresponds to human aldehyde reductase.
Definition of Families
Delineation of families occurs at the 40% amino acid identity level. Members of an AKR family should have < 40% amino acid identity with any other family. At present, the sixteen families defined by our cluster analysis satisfy this criterion.
Definition of Subfamilies
Within a given family, subfamilies may be defined by a > 60% identity in amino acid sequence among subfamily members. By this definition, nine of sixteen AKR families include multiple subfamilies. For example, family AKR1 includes the following subfamilies: AKR1C1-AKR1C4 and AKR1D1, which play critical roles in the metabolism of all steroid hormones, conjugated steroids, synthetic therapeutic steroids, and the synthesis of neurosteroids and bile acids. Numbering of the known members of each subfamily was assigned in an arbitrary fashion. For example, AKR1A1, AKR1A2, and AKR1A3 are the aldehyde reductases from human, pig, and rat, respectively. Any new additions to a subfamily are numbered chronologically.
Allelic Variants versus Isoforms
Allelic variation may occur between superfamily members. We propose that proteins with > 97% amino acid sequence identity are alleles of the same gene unless: they have different enzyme activities; they are encoded by different cDNA’s, usually evident by a distinct 3’-untranslated region (UTR); and they are derived from genes of different structure. While AKR1C1 [human dihydrodiol dehydrogenases 1 (DD1)], and AKR1C2 [human dihydrodiol dehydrogenases 2 (DD2)] are 98% identical in amino acid sequence and have 3’-UTRs which are 97% identical, the substrate specificity and function of these proteins are quite different. AKR1C1 is predominantly a 20α-HSD while AKR1C2 is the major bile acid binding protein in human liver. Based on these functional differences, we have assigned AKR1C1 and AKR1C2 as unique members of the AKR superfamily.
Dimeric Proteins
Multimers are proteins which consist of multiple monomers. Although majority of all AKR proteins are monomeric proteins, approximately 320 amino acids in length, the AKR2 (which includes the xylose reductases), AKR6 (which includes the b-subunits of the voltage-gated potassium channel), and AKR7 (which contains the aflatoxin dialdehyde reductases) families have been shown to form multimers. To expand the nomenclature to accommodate multimers we recommend that the composition and stoichiometry be listed. For example, AKR7A1:AKR7A4 (1:3) would designate a tetramer of the composition indicated.
AKR Genes
The designation for an AKR superfamily gene should be noted in italics to distinguish between the gene and the protein. For example, the gene AKR1A1 encodes the protein AKR1A1.
The above nomenclature system was adopted at the 8th International Workshop on the Enzymology and Molecular Biology of Carbonyl Metabolism. It is similar to that for the cytochrome P450 superfamily, but, unlike that system, amino acid sequences are used for comparisons. For historical reasons, the AKR1A subfamily represents the aldehyde reductases and the AKR1B subfamily represents the aldose reductase. We recommend that authors referencing members of the AKR superfamily use any previous names along with the new designation in parenthesis - for example, human aldehyde reductase (AKR1A1).
Protein Structures
AKRs are characterized by an (αβ)8-barrel structure.
Loop Structure
Using the structure of AKR1C9W, CHO Reductase with NADP+, three large loops can be assigned.
Cofactor Binding Site
Cofactor binding site for 3α-HSD (AKR1C9). Distances are in angstroms.
Typical Catalytic Tetrad
Blue sphere indicates the position of a water molecule and the probable position of the substrate carbonyl. Taken from 3α-HSD (AKR1c9).
AKR Family Descriptions
AKR Family 1
AKR1 enzymes control the concentrations of active ligands for nuclear receptors and control their ligand occupancy and transactivation. Furthermore, AKR1 enzymes regulate the amount of neurosteroids that can regulate the activity of GABAa and NMDA receptors. Therefore, AKR1 enzymes are typically involved in the pre-receptor regulation of nuclear as well as membrane bound receptors. In addition, altered expression of individual AKR1C genes is related to the development of prostate, breast, and endometrial cancer. Mutations in AKR1C1 and AKR1C4 are responsible for sexual development dysgenesis, and mutation in AKR1D1 are causative in blie acid deficiency.
AKR Family 2
Members of the AKR2 family are categorized as enzymes consisting of xylose reductases. AKR2B1 - AKR2B6 are classified as yeasts, while AKR2C and AKR2D are classified as fungi. The function of xylose reductases is to catalyze the first step of xylose metabolism. During this process xylose reductase, which is an NADPH- or NADH- dependent enzyme, will oxidize xylose to xylitol. While this occurs, the NAD+ dependent enzyme xylitol dehydrogenase (XDH) reduces xylitol to xylulose. Under microaerophilic conditions, yeasts like Kluyveromyces, Pichia, and Pachysolen are capable of fermenting xylose to ethanol.
AKR Family 3
Similar to the AKR2 family, members of the AKR3 family are enzymes found in yeast. For example, AKR3A1, known as Gcylp, catalyzes the reduction of several aldehyde substrates including D,L-glyceraldehyde. In addition, YPRI (AKR3A2) has been shown to contribute 50% of in vivo 2-methylbutyraldehyde reductase activity. Furthermore, deletion of the GRE3 gene encoding S. cerevisiae aldose reductase (AKR2B6) leads to a decrease in xylitol formation from xylose by 50%.
AKR Family 4
Members of AKR Family 4 are classified as plant-based AKR’s. These AKRs have many functions including biotic and abiotic stress defense, production of commercially important secondary metabolites, iron acquisition from soil, and plant-microbe interactions. Plant AKR’s have not been well studied, however a few of AKR4’s functionality are known. For instance, the AKR4C family is known to be involved in aldehyde detoxification and stress defense, osmolyte production, secondary metabolism, and membrane transport. For example, AKR4C8 and AKR4C9 from Arabidopsis thaliana (Arabidopsis) can reduce a range of toxic compounds containing reactive aldehyde groups. In contrast, AKR4C7 from maize (Zea mays) catalyzes the oxidation of sorbitol to Glc.
AKR Family 5
AKR Family 5 contains the gluconic acid reductase enzymes. AKR5C, AKR5D, and AKR5B, are classified as bacteria; AKR5E and AKR5F are classified as yeasts; finally, AKR5E is classified as a fungi. While majority of the functionality of the AKR5 family is unknown, AKR5D is responsible for the NADPH-dependent stereospecific reduction of 2,5-diketo-D-gluconate to 2-keto-L-gulonate, a precursor in the industrial production of vitamin C.
AKR Family 6
The AKR6 family is found in humans, and contains the beta-subunits of the voltage-gated potassium channel. These AKR6 family members are structurally characterized by having an extra helix attached to a long loop between β9 and α7, and the proteins forms tetramers. Furthermore, In the AKR6 family, the N-terminal β1-β2 hairpin (Y39-G46) forms a part of the tetramer intersubunit interface: together with the closely located R109-S111 segment (Kvβ2-AKR6A5 numbering) from the α2-β5 loop at the bottom of the barrel it interacts with the loop β5-α3 (consisting of amino acid residues K124-R129) at the top (C-terminal end) of another barrel. Interestingly the regions involved in the intersubunit interaction are >92% conserved within the AKR6 family, but do not share homology with AKRs from other families.
AKR Family 7
The AKR7 family contains the aflatoxin dialdehyde reductases. Members of the AKR7 family can be found in several species. For example AKR7A2 and AKR7A3 are found in humans, AKR7A1 and AKR7A4 are found in rats, and AKR7A5 is found in mice. The purpose of the AKR7 family is typically to reduce aldehyde to alcohol, however some do have more specific functions. For example, AKR7A2 is involved in the metabolism of daunorubicin to the cardiotoxic daunorubicinol.
AKR Family 8
AKR Family 8 is also classified as a microbial AKR family. Both AKR8A1 and AKR8A2 are known as pyridoxal reductase and can be found in yeast. The function of pyridoxal reductase is to catalyze the NADPH-mediated reduction of pyridoxal to pyridoxine.
AKR Family 9
AKR Family 9 is classified as a microbial AKR family. For example, AKR9C falls under the archaebacteria division; AKR9B1-B4 falls under the yeasts division, and AKR9A1-A3 falls under the Fungi category. These enzymes vary immensely and have differing functions. For example, AKR9A1, known as a sterigmatocystin dehydrogenase is involved in the biosynthesis of a fungal secondary metabolite. Another example is AKR9A2, which is involved in aflatoxin biosynthesis. On the contrary, AKR9C, known as oxi reductase catalyzes the transfer of electrons from one molecule (the oxidant, the hydrogen or the electron donor) to another molecule (the reductant, the hydrogen or electron acceptor).
AKR Family 11
Members of the AKR11 family, which are AKR11A and AKR11B are both classified as bacterial AKR’s. Their respective enzyme names are IolS and GSP69, and they both have the same function of reducing substrates DL-glyceraldehyde, D-erythrose and methylglyoxal in the presence of NADPH.
AKR Family 12
Members of the AKR12 family are known as Streptomyces sugar aldehyde reductases. AKR12A from Streptomyces fradiae, andAKR12C from Streptomyces avermitilis, are also thought to play roles as reductases in L-mycarose and L-oleandrose biosynthesis respectively. However, a role for these latter two enzymes through the use of gene mutation/deletion has not been proven.
AKR Family 13
Members of AKR13 are classified as hyperthermophilic bacteria reductases. These enzymes are involved in protein thermostabilization, including ion pairs, hydrogen bonds, hydrophobic interactions, disulfide bridges, packing, decrease of the entropy of unfolding, and intersubunit interactions.