AKR7A2

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Aldo-keto reductase

Figure 1. Structure of AKRs.

Mechanism

Since many human AKRs genes are upregulated by NRF2 transcription factors, this leads to a feed-forward mechanism to enhance drug resistance. Major chemotherapeutic agents (anthracyclines, mitomycin, cisplatin, anti-microtubulin agents, vincristine and cyclophosphamide) generate resistance through this mechanism. Human AKRs also catalyze the synthesis of androgens and estrogens and the elimination of progesterone and are involved in hormone-dependent malignant tumorigenesis. They are upregulated by antihormonal therapy, which provides a second mechanism of cancer drug resistance. inhibitors of the NRF2 system or PAN-AKR1C inhibitors are expected to overcome cancer drug resistance and/or synergize the effects of existing drugs.

Human Aldo-keto reductase

There are 15 human AKRs, and although their carbonyl substrates may be different, these proteins share some common features. b-chains form the horizontal bars of the barrel, and at the bottom of the barrel there are catalytic tetramers of Y55, K84, D40 and H117. At the back of the barrel, there are three large loops that help determine substrate specificity, where different amino acids are recruited into the substrate based binding pocket.

Correlation with cancer

AKR is overexpressed in a wide range of human cancers, such as prostate cancer, breast cancer, glioma, neuroblastoma, non-small and small cell lung cancer, colon cancer, small bowel cancer and acute myeloid leukemia. Tumor-specific expression of AKR isoforms has been observed, for example, in non-small cell lung cancer (AKR1C1, AKR1C2, AKR1C3, and AKR1B10), colon cancer (AKR1B10), breast and prostate cancer (AKR1C3), and acute myeloid leukemia (AKR1C3). Overexpression of AKRs has led to their availability as tumor biomarkers The high overexpression of AKRs has led to their use as tumor biomarkers.

AKR7A2

Aflatoxin B1 aldehyde reductase member 2 is an enzyme that in humans is encoded by the AKR7A2 gene. Aldo-keto reductases, such as AKR7A2, are involved in the detoxification of aldehydes and ketones.

Figure 2. Structure of AKR7A2.

Stress response genes

AKR7A2 are also stress response genes that respond to pro-electrical stress, oxidative stress, osmotic stress and steroid hormones. They are induced by the nuclear factor-red lineage 2P45-associated factor 2 (NFE2L2)-Kelch-like ECH-associated protein 1 (Keap1) (Keap1) pathway and are regulated by steroid hormone receptors through steroid response elements.AP-1 transcription factor is a tonic response enhancer that is a tonic response enhancer that is induced by the nuclear factor-red lineage 2P45-associated factor 2 (NFE2L2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is induced. As they respond to electrophilic and oxidative stress stimuli generated by chemotherapeutic drugs, they are upregulated by these drugs, which leads to the development of drug resistance. Because they also play a role in steroid hormone conversion, they are associated with chemoresistance to hormonal ablative therapies.