1. Gene Aliases

Aldo-Keto Reductase Family 7 Member A3, Aflatoxin B1 Aldehyde Reductase Member 3, Aflatoxin Aldehyde Reductase, AFB1 Aldehyde Reductase 2, AFB1-AR 2, AFAR2, Aldo-Keto Reductase Family 7, Member A3 (Aflatoxin Aldehyde Reductase), Epididymis Secretory Sperm Binding Protein, Aflatoxin B1 Aldehyde Reductase 2 [https://www.genecards.org/cgi-bin/carddisp.pl?gene=AKR7A3]

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

Interactions with text mining support

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

Aflatoxin activation and detoxification: Aflatoxins are among the principal mycotoxins produced as secondary metabolites by the molds Aspergillus flavus and Aspergillus parasiticus that contaminate economically important food and feed crops (Wild & Turner 2002). Aflatoxin B1 (AFB1) is the most potent naturally occurring carcinogen known and is also an immunosuppressant. It is a potent hepatocarcinogenic agent in many species, and has been implicated in the etiology of human hepatocellular carcinoma. Poultry, especially turkeys, are extremely sensitive to the toxic and carcinogenic action of AFB1 present in animal feed, resulting in multi-million dollar losses to the industry. Discerning the biochemical and molecular mechanisms of this extreme sensitivity of poultry to AFB1 will help with the development of new strategies to increase aflatoxin resistance (Rawal et al. 2010, Diaz & Murcia 2011).

AFB1 has one major genotoxic metabolic fate, conversion to AFXBO, and several others that are less mutagenic but that can still be quite toxic. AFB1 can be oxidised to the toxic AFB1 exo 8,9 epoxide (AFXBO) product by several cytochrome P450 enzymes, especially P450 3A4 in the liver. This 8,9 epoxide can react with the N7 atom of a guanyl base of DNA to produce adducts by intercalating between DNA base pairs. The exo epoxide is unstable in solution, however, and can react spontaneously to form a diol that is no longer reactive with DNA. The diol product in turn undergoes base-catalysed rearrangement to a dialdehyde that can react with protein lysine residues. AFB1 can also be metabolised to products (AFQ1, AFM1, AFM1E) which have far less genotoxic consequences than AFB1. The main route of detoxification of AFB1 is conjugation of its reactive 8,9-epoxide form with glutathione (GSH). This reaction is carried out by trimeric glutathione transferases (GSTs), providing a chemoprotective mechanism against toxicity. Glutathione conjugates are usually excreted as mercapturic acids in urine (Guengerich et al. 1998, Hamid et al. 2013) [https://reactome.org/PathwayBrowser/#/R-HSA-5423646].

Metapathway biotransformation Phase I and II: Biotransformation is the chemical modification (or modifications) made by an organism on a chemical compound. If this modification ends in mineral compounds like CO2, NH4+, or H2O, the biotransformation is called mineralisation. Biotransformation means chemical alteration of chemicals such as nutrients, amino acids, toxins, and drugs in the body. It is also needed to render non-polar compounds polar so that they are not reabsorbed in renal tubules and are excreted. Biotransformation of xenobiotics can dominate toxicokinetics and the metabolites may reach higher concentrations in organisms than their parent compounds [https://www.wikipathways.org/pathways/WP702.html].

GO terms:

aflatoxin catabolic process [The chemical reactions and pathways resulting in the breakdown of aflatoxin, a fungal metabolite found as a contaminant in moldy grains that induces liver cancer. Aflatoxin induces a G to T transversion at codon 249 of p53, leading to its inactivation. Aflatoxin is converted to a chemical carcinogen by P450. GO:0046223]

aflatoxin metabolic process [The chemical reactions and pathways involving aflatoxin, a fungal metabolite found as a contaminant in moldy grains that induces liver cancer. Aflatoxin induces a G to T transversion at codon 249 of p53, leading to its inactivation. Aflatoxin is converted to a chemical carcinogen by P450. GO:0046222]

MSigDB Signatures:

WP_AFLATOXIN_B1_METABOLISM: Aflatoxin B1 metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_AFLATOXIN_B1_METABOLISM.html]

WP_METAPATHWAY_BIOTRANSFORMATION_PHASE_I_AND_II: Metapathway biotransformation Phase I and II [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_METAPATHWAY_BIOTRANSFORMATION_PHASE_I_AND_II.html]

CARRILLOREIXACH_HEPATOBLASTOMA_VS_NORMAL_DN: Genes down-regulated in hepatoblastoma (HB) tumors as compared with non-tumor (NT) adjacent tissue. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/CARRILLOREIXACH_HEPATOBLASTOMA_VS_NORMAL_DN.html]

CARRILLOREIXACH_HEPATOBLASTOMA_VS_NORMAL_HYPERMETHYLATED_AND_DN: Genes hypermethylated and downexpressed in hepatoblastoma (HB) tumors as compared with non-tumor (NT) adjacent tissue assessed by Infinium MethylationEPIC 850K array and Human Transcriptome Array 2.0 & RNA-sequencing. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/CARRILLOREIXACH_HEPATOBLASTOMA_VS_NORMAL_HYPERMETHYLATED_AND_DN.html]

REACTOME_AFLATOXIN_ACTIVATION_AND_DETOXIFICATION: Aflatoxin activation and detoxification [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_AFLATOXIN_ACTIVATION_AND_DETOXIFICATION.html]

REACTOME_BIOLOGICAL_OXIDATIONS: Biological oxidations [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_BIOLOGICAL_OXIDATIONS.html]

IBRAHIM_NRF2_DOWN: Genes down-regulated in HEK293T cells overexpressing FLAG-NRF2 [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/IBRAHIM_NRF2_DOWN.html]

7. Gene Descriptions

NCBI Gene Summary: Aldo-keto reductases, such as AKR7A3, are involved in the detoxification of aldehydes and ketones.[supplied by OMIM, Apr 2004]

GeneCards Summary: AKR7A3 (Aldo-Keto Reductase Family 7 Member A3) is a Protein Coding gene. Diseases associated with AKR7A3 include Cytochrome P450 Oxidoreductase Deficiency. Among its related pathways are Metapathway biotransformation Phase I and II and Metabolism. Gene Ontology (GO) annotations related to this gene include electron transfer activity and aldo-keto reductase (NADP) activity. An important paralog of this gene is AKR7L.

UniProtKB/Swiss-Prot Summary: Can reduce the dialdehyde protein-binding form of aflatoxin B1 (AFB1) to the non-binding AFB1 dialcohol. May be involved in protection of liver against the toxic and carcinogenic effects of AFB1, a potent hepatocarcinogen.

8. Cellular Location of Gene Product

Mainly localized to the cytosol. In addition localized to the Golgi apparatus (based on antibodies targeting proteins from multiple genes). Predicted location: Intracellular [https://www.proteinatlas.org/ENSG00000162482/subcellular]

9. Mechanistic Information

Summary

The Akr7a3 gene encodes an enzyme crucial in the liver's detoxification process [CS: 8]. It specifically addresses the threat posed by aflatoxin B1 (AFB1), a harmful hepatocarcinogen [CS: 10]. AFB1 is activated by P4503A4 to a more dangerous epoxide form [CS: 8], which further converts into a dialdehyde [CS: 7]. Akr7a3's role is to metabolize this dialdehyde into less reactive mono- and dialcohols [CS: 8]. This action is vital as it prevents the dialdehyde from binding with proteins to form Schiff bases, a process that can cause significant cellular damage and lead to carcinogenesis [CS: 9].

In liver diseases like hepatocellular carcinoma (HCC), the dysregulation of Akr7a3 is linked to increased liver damage and a higher risk of cancer [CS: 7]. When Akr7a3 expression is reduced, the liver's capacity to detoxify AFB1 is impaired, resulting in the accumulation of more harmful substances [CS: 6]. This reduction in Akr7a3 expression weakens the liver's protective mechanisms, particularly its role in suppressing tumorigenicity and chemoresistance, by affecting critical signaling pathways like ERK, c-Jun, and NF-kB [CS: 5]. This weakened state makes the liver more vulnerable to disease and less capable of combating the toxic effects of substances like AFB1 [CS: 6].

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: intestine, liver, pancreas, stomach (tissue enhanced) [https://www.proteinatlas.org/ENSG00000162482/tissue]

Cell type enchanced: distal enterocytes, gastric mucus-secreting cells, proximal enterocytes, proximal tubular cells (cell type enhanced) [https://www.proteinatlas.org/ENSG00000162482/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

Compounds that decrease expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest

Most relevant biomarkers with lower score or lower probability of association with disease or organ of interest: