Aldo-keto reductase (AKR) superfamily is responsible for preventing mammalian cells from the toxic and carcinogenic effect of different genotoxic and non-genotoxic chemicals by reducing them, though the inducibility of these genes are different in different species. The aim of this paper is to compare the gene regulation mechanisms of AKR superfamily genes in different species and to identify the conserved areas, which are responsible for gene regulations in the presence of antioxidant, toxicants, and non-genotoxic carcinogens. At the beginning of the analysis AKR genes found in different species were divided into two groups based on their amino acid sequence similarities. Comparison of AKR7A gene clusters between different species revealed that Human AKR7A2 has orthologues in mammalians like rat, mouse, pigs, and other primates. On the other hand, AKR7A3 has orthologues only in rat and AKR7L is present only in primates. All the genes of AKR superfamily have a trend to stay in clusters in mammalian chromosomes having repeated sequences in between them. Transcription start site analysis revealed that genes like human AKR7A2 and rat Akr7a4 do not have conventional promoter regions such as TATA box, CAAT box and have several GC-rich regions, whereas gene like Akr7a1 contains a TATA box 25 bp upstream of transcription start site instead of having CpG islands. Putative orthologous genes i.e., rat AKR7A4, human AKR7A2, and mouse AKR7A5 share more common features such as common transcription factor binding site for specificity protein 1 (SP1), GATA binding factor family, Selenocysteine tRNA gene transcription activating factor (STAF) zinc finger protein, Krüppel-like C2H2 zinc finger (HICF) protein, negative glucocorticoid response element (NGRE) etc. Similarly, genes like rat AKR7A1, human AKR7A3, and human AKR7L share common sequence and transcription factor binding sites. Among those, Nuclear factor erythroid 2-related factor 2 (Nrf2) is thought to be responsible for the inducibility of these genes in the presence of antioxidants. Our analysis revealed that AKR7A gene family consists of genes having a large number of variations in them. Some of these, such as AKR7A2 are housekeeping genes, on the other hand, genes like AKR7A3 are highly inducible in the presence of antioxidants because of the presence of Nrf2 binding site in their promoter. AKR7A1 has a different promoter than others and function of AKR7L gene is still unknown.
Aldo-Keto reductase Chemoprevention Antioxidant response Nrf2 ARE
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The authors gratefully acknowledge Dr. Elizabeth Ellis, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde for her contribution.
Conceived and designed the experiments: SAR and MKSS. Analyzed the data: SAR. Wrote the first draft of the manuscript: SAR. Contributed to the writing of the manuscript: MKSS. Agree with manuscript results and conclusions: SAR and MKSS. Jointly developed the structure and arguments for the paper: SAR and MKSS. Made critical revisions and approved final version: SAR and MKSS. All authors reviewed and approved of the final manuscript.
The authors received no funding for the research.
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