AKR1B1

Structure

Gene

The AKR1B1 gene lies on the chromosome location of 7q33 and consists of 10 exons. There are a few putative pseudogenes for this gene, and one of them has been confirmed and mapped to chromosome 3.

Protein

AKR1B1 consists of 316 amino acid residues and weighs 35853Da. It does not possess the traditional dinucleotide binding fold. The way it binds NADPH differs from other nucleotide adenine dinucleotide-dependent enzymes. The active site pocket of human aldose reductase is relatively hydrophobic, lined by seven aromatic and four other non-polar residues.

Function

AR belongs to the aldehyde-keto reductase superfamily, with a widely expression in human organs including the kidney, lens, retina, nerve, heart, placenta, brain, skeletal muscle, testis, blood vessels, lung, and liver. It is a reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-dependent enzyme catalyzing the reduction of various aldehydes and ketones to the corresponding alcohol. It also participates in glucose metabolism and osmoregulation and plays a protective role against toxic aldehydes derived from lipid peroxidation and steroidogenesis.

Clinical significance

Under diabetic conditions AR converts glucose into sorbitol, which is then converted to fructose. 20466987 It has been found to play an important role in many diabetes complications such as diabetes retinopathy and renopathy. It is also involved in many oxidative stress diseases, cell signal transduction, and cell proliferation process including cardiovascular disorders, sepsis, and cancer.

It has been reported that the action of AR contributes to the activation of retinal microglia, suggesting that inhibition of AR may be of a therapeutic importance to reduce inflammation associated with activation of RMG. Adapting AR inhibitors could as well prevent sepsis complications, prevent angiogenesis, ameliorate mild or asymptomatic diabetic cardiovascular autonomic neuropathy and may be a promising strategy for the treatment of endotoxemia and other ROS-induced inflammatory diseases.

Interactions

AKR1B1 has been found to interact with:

• ginsenoside 20(S)-Rh2
• alkaloid
• carboxylic acid derivatives
• spirohydantoins
• cyclic amides

References

References

1. (March 1991). "The human aldose reductase gene maps to chromosome region 7q35". Human Genetics.
2. "Entrez Gene: AKR1B1 aldo-keto reductase family 1, member B1 (aldose reductase)".
3. (August 1998). "The structure and function of yeast xylose (aldose) reductases". Yeast.
4. (October 1999). "Major differences exist in the function and tissue-specific expression of human aflatoxin B1 aldehyde reductase and the principal human aldo-keto reductase AKR1 family members". The Biochemical Journal.
5. (June 2004). "Decreased expression of cyclic adenosine monophosphate-regulated aldose reductase (AKR1B1) is associated with malignancy in human sporadic adrenocortical tumors". The Journal of Clinical Endocrinology and Metabolism.
6. (May 2014). "Tonicity-responsive enhancer binding protein regulates the expression of aldose reductase and protein kinase C δ in a mouse model of diabetic retinopathy". Experimental Eye Research.
7. (April 2015). "The Relationship Between Aldose Reductase C106T Polymorphism and Diabetic Retinopathy: An Updated Meta-Analysis". Investigative Ophthalmology & Visual Science.
8. (2016-01-01). "Updates on Aldose Reductase Inhibitors for Management of Diabetic Complications and Non-diabetic Diseases". Mini Reviews in Medicinal Chemistry.
9. (March 2015). "Targeting aldose reductase for the treatment of diabetes complications and inflammatory diseases: new insights and future directions". Journal of Medicinal Chemistry.
10. (May 2014). "Aldose reductase inhibition prevents endotoxin-induced inflammatory responses in retinal microglia". Investigative Ophthalmology & Visual Science.
11. (September 2014). "20(S)-Ginsenoside Rh2 as aldose reductase inhibitor from Panax ginseng". Bioorganic & Medicinal Chemistry Letters.
12. (March 2014). "Alkaloids as aldose reductase inhibitors, with special reference to berberine". Journal of Alternative and Complementary Medicine.