AKR1B1
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Aldo-keto reductase family 1, member B1 (AKR1B1) is an
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
in humans that encodes the
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
aldose reductase In enzymology, aldose reductase (or aldehyde reductase) () is an enzyme in humans encoded by the gene AKR1B1. It is an cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monos ...
. It is a reduced nicotinamide-adenine dinucleotide phosphate (
NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require N ...
)-dependent enzyme catalyzing the reduction of various
aldehydes In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...
and
ketones In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...
to the corresponding
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
. The involvement of AKR1B1 in
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
diseases, cell signal transduction, and cell proliferation process endows AKR1B1 with potential as a therapeutic target.


Structure


Gene

The ''AKR1B1'' gene lies on the
chromosome A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...
location of 7q33 and consists of 10
exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence i ...
. 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 Protein structure is the three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers specifically polypeptides formed from sequences of amino acids, which are the monomers of the polymer. A single amino acid m ...
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 A lens is a transmissive optical device that focuses or disperses a light beam by means of refraction. A simple lens consists of a single piece of transparent material, while a compound lens consists of several simple lenses (''elements'') ...
,
retina The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...
, 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 Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
metabolism and osmoregulation and plays a protective role against toxic aldehydes derived from
lipid peroxidation Lipid peroxidation, or lipid oxidation, is a complex chemical process that leads to oxidative degradation of lipids, resulting in the formation of peroxide and hydroperoxide derivatives.{{Cite journal , last1=Ayala , first1=Antonio , last2=Muñoz ...
and
steroidogenesis A steroid is an organic compound with four fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter memb ...
.


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 Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage of sepsis is followed by suppression of the immune system. Common signs and s ...
, and
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
. It has been reported that the action of AR contributes to the activation of retinal
microglia Microglia are a type of glia, glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about around 5–10% of cells found within the brain. As the resident macrophage cells, they act as t ...
, 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 Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
, 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 Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...
* carboxylic acid derivatives * spirohydantoins * cyclic amides


References


Further reading

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External links

* * {{Portal bar, Biology, border=no EC 1.1.1