AKR1A1

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Aldo keto reductase family 1, member A1
Aldo keto reductase family 1, member A1
according to PDB  1AE4
other names
  • Alcohol: NADP + oxidoreductase ( NC-IUBMB )
  • Alcohol dehydrogenase (NADP + )
  • Aldehyde reductase

Existing structural data : 2ALR

Properties of human protein
Mass / length primary structure 36,573 daltons / 325 amino acids
Cofactor zinc
Identifier
Gene names AKR1A1; ALDR1, ALR, ARM, DD3, HEL-S-6
External IDs
Enzyme classification
EC, category 1.1.1.2
Occurrence
Parent taxon Bacteria , eukaryotes
Orthologue
human House mouse
Entrez 10327 58810
Ensemble ENSG00000117448 ENSMUSG00000028692
UniProt P14550 Q9JII6
Refseq (mRNA) NM_001202413 NM_021473
Refseq (protein) NP_001189342 NP_067448
Gene locus Chr 1: 45.55 - 45.57 Mb Chr 4: 116.64 - 116.65 Mb
PubMed search 10327 58810

Aldo-keto reductase family 1, member A1 , also known as alcohol dehydrogenase (NADP + ) , or aldehyde reductase is an enzyme that in eukaryotes the gene AKR1A1 is encoded. The enzyme belongs to the family of aldo-keto-reductases , which contain a large number of related monomeric NADPH -dependent oxidoreductases .

properties

AKR1A1 catalyzes the NADPH -dependent reduction of various aliphatic and aromatic aldehydes to alcohols as well as of mevaldate to mevalonic acid and of glyceraldehyde to glycerol . Mutations in the AKR1A1 gene occur in some non-Hodgkin lymphomas . The gene is particularly strongly expressed in many different organs - predominantly in the kidney, cortex, liver, thyroid and small intestine.

Gene structure

AKR1A1 contains a total of 10 exons . The gene is located on the short chromosome arm (p arm) between chromosome bands 1p33 and 1p32 of chromosome 1 .

function

The enzyme is involved in the reduction of biogenic and xenobiotic aldehydes and is present in almost every tissue . Alternative splicing of this gene results in two different transcript variants that encode the same protein.

Interaction with other proteins

AKR1A1 interacts with a total of 22 proteins:

Medical importance

The enzyme is important for the metabolism of γ-hydroxybutyrate (GHB) in human astrocytes . In addition, the enzyme is implicated in diabetic complications by catalyzing the reduction of glucose to sorbitol .

The enzyme is also responsible for the reduction of 3-deoxyoson , which is a major intermediate and potential crosslinking agent for the Maillard reaction . In a glycation or a reduction in enzyme activity can lead to a metabolic imbalance among diabetic conditions.

Lung cancer

Metabolic activation of polycyclic aromatic hydrocarbons with the help of aldo-keto-reductases

Polycyclic aromatic hydrocarbons (PAH) are primarily known as pollutants that can get into the lungs when smoking tobacco. One product that accumulates in the body is the carcinogenic benzo [ a ] pyrene (B [ a ] P). After conversion of B [ a ] P into B [ a ] P-7,8-dihydrodiol, it is converted into B [ a ] P-7,8-catechol by aldo-keto reductases such as AKR1A1 , creating reactive oxygen species such as the hyperoxide -Anion (O 2 · - ) and DNA adducts such as 8-hydroxydesoxyguanosine , which arise from B [ a ] P-7,8-dione, arise and can damage the DNA. Above all, the damage done by a G → T - transversion in the protein p53 coding tumor suppressor gene . A mutation or deletion of a gene coding for a tumor suppressor increases the likelihood of malignant tumor formation such as lung cancer.

Animal model

Research has shown that the mitochondria of the rat liver and renal cortex contain the enzyme alcohol dehydrogenase (NADP + ) to catalyze the oxidation of NADPH by aldehydes, p -nitrobenzaldehyde , methylglyoxal and glyceraldehyde .

Web links

Wikibooks: Biochemistry and Pathobiochemistry: Alcohol Dehydrogenase (NADP +)  - Learning and Teaching Materials
Wikibooks: Biochemistry and Pathobiochemistry: Alcohol Metabolism  - Learning and Teaching Materials
Wikibooks: Biochemistry and Pathobiochemistry: Fructose, Mannose and Fucose Metabolism  - Learning and Teaching Materials

Individual evidence

  1. ↑ UniProt P14550
  2. ↑ Palackal NT, Burczynski ME, Harvey RG, Penning TM: Metabolic activation of polycyclic aromatic hydrocarbon trans-dihydrodiols by ubiquitously expressed aldehyde reductase (AKR1A1) . In: Chemico-Biological Interactions . 130-132, No. 1-3, January 2001, pp. 815-24. PMID 11306097 .
  3. ↑ Lan Q, Zheng T, Shen M, Zhang Y, Wang SS, Zahm SH, Holford TR, Leaderer B, Boyle P, Chanock S: Genetic polymorphisms in the oxidative stress pathway and susceptibility to non-Hodgkin lymphoma . In: Human Genetics . 121, No. 2, April 2007, pp. 161-8. doi : 10.1007 / s00439-006-0288-9 . PMID 17149600 .
  4. ↑ a b AKR1A1. In: GeneCards (English).
  5. ↑ a b AKR1A1 aldo-keto reductase family 1, member A1 (aldehyde reductase) Homo sapiens (human). In: National Center for Biotechnology Information (NCBI) , accessed December 30, 2015 .
  6. ↑ S. Alzeer, EM Ellis: The role of aldehyde reductase AKR1A1 in the metabolism of γ-hydroxybutyrate in 1321N1 human astrocytoma cells . In: ScienceDirect (Ed.): Chemico-Biological Interactions . 191, No. 1-3, May 30, 2011, pp. 303-307. doi : 10.1016 / j.cbi.2011.01.018 . PMID 21276435 .
  7. ↑ KM Bohren, B. Bullock: The aldo-keto reductase superfamily. cDNAs and deduced amino acid sequences of human aldehydes and aldose reductases . In: The Journal of Biological Chemistry (JCB) . 264, No. 16, June 5, 1989, pp. 9547-9551. PMID 2498333 .
  8. ↑ M. Takahashi, YB Lu: In vivo glycation of aldehyde reductase, a major 3-deoxyglucosone reducing enzyme: identification of glycation sites . In: ACS Publications (Ed.): Biochemistry . 34, No. 4, January 31, 1995, pp. 1433-1438. doi : 10.1021 / bi00004a038 . PMID 7827091 .
  9. ↑ TE Smithgall, RG Harvey, TM Penning: Regio- and stereospecificity of homogeneous 3 alpha-hydroxysteroid-dihydrodiol dehydrogenase for trans-dihydrodiol metabolites of polycyclic aromatic hydrocarbons. In: The Journal of biological chemistry. Volume 261, Number 14, May 1986, pp. 6184-6191, PMID 3457793 .
  10. ↑ TE Smithgall, RG Harvey, TM Penning: Spectroscopic identification of ortho-quinones as the products of polycyclic aromatic trans-dihydrodiol oxidation catalyzed by dihydrodiol dehydrogenase. A potential route of proximate carcinogen metabolism. In: The Journal of biological chemistry. Volume 263, Number 4, February 1988, pp. 1814-1820, PMID 3276678 .
  11. ↑ Trevor M. Penning, S. Tsuyoshi Ohnishi, Tomoki Ohnishi, Ronald G. Harvey: Generation of Reactive Oxygen Species during the Enzymatic Oxidation of Polycyclic Aromatic Hydrocarbon trans-Dihydrodiols Catalyzed by Dihydrodiol Dehydrogenase. In: Chemical Research in Toxicology. 9, 1996, p. 84, doi : 10.1021 / tx950055s .
  12. ↑ EA Udovikova, L. Wojtczak: Mitochondrial aldehyde reductase: identification and characterization in rat liver and kidney cortex . In: ScienceDirect (Ed.): The International Journal of Biochemistry & Cell Biology . 30, No. 5, May 1998, pp. 597-608. PMID 9693960 .