A New Nomenclature for the Aldo-Keto Reductase Superfamily
The system we propose is similar to the nomenclature for the cytochrome P450 superfamily, but, unlike that system, uses amino acid sequence comparisons. The general format for new AKR names will be 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 this 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 fourteen families defined by our cluster analysis satisfies 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 the fourteen AKR families include multiple subfamilies. For example, family AKR1 includes the following subfamilies: A) mammalian aldehyde reductases; B) mammalian aldose reductases; C) hydroxysteroid dehydrogenases (HSDs); and D) Δ4-3-ketosteroid-5β-reductase. 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 dehydrogenase 1 (DD1)] and AKR1C2 [human dihydrodiol dehydrogenase 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- Currently, the AKR2, AKR6 and AKR7 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.
At the 8th International Workshop on the Enzymology and Molecular Biology of Carbonyl Metabolism, the proposed nomenclature system was adopted. For historical reasons, the AKR1A subfamily represents the aldehyde reductases and the AKR1B subfamily represents the aldose reductases. To ease the adoption of the nomenclature system, we recommend that authors referencing members of the AKR superfamily use the old name with the new designation in parenthesis until universal adoption of the system occurs — for example, human aldehyde reductase (AKR1A1).
Scheme showing the nomenclature system can be found here.