Proteopedia

Aldo-keto reductase

(Redirected from AKR4C8)

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Function

Aldo-keto reductase (AKR) is a protein family which contains enzymes that reduce carbonyl substrates like sugar aldehyde, keto-steroid, keto-prostaglandin, retinal, quinones and lipid peroxidation by-products to primary alcohol[1]. AKR uses NADP as a cofactor. AKRs contain a conserved catalytic tetrad consisting of Tyr, Asp, Lys and His.

  • AKR1B10 reduces aliphatic and aromatic aldehydes. It is expressed in adrenal gland, small intestines and colon.
  • AKR1B14 is involved in synthesis of prostaglandin F and detoxification of products of lipid peroxidation.
  • AKR1C4 interconverts steroidal hormone between its active and inactive form[2].
  • AKR1C13 involved in detoxification of xenobiotics in the stomach[3].
  • AKR1D1 is responsible for the catalysis of 5-β-reduction of bile acid intermediates and steroid hormones carrying a δ(4)-3-one structure.
  • AKR2E4 is involved in regulation of the molting hormone ecdysone[4].
  • AKR4C8 and AKR4C9 detoxify sugar-derived reactive carbonyls[5].
  • AKR4C14 involved in detoxification of methylglyoxal and MDA [6].
  • AKR4C17 involved in glyphosate herbicide resistance [7].
  • AKR7A1 and AKR7A5 metabolize the environmental carcinogen aflatoxin B(1) [8].
  • AKR11C1 uses substrates with a long aliphatic tails [9].
  • AKR14A1 involved in metabolism of methylglyoxal [10].

Disease

Mutations in AKR1D1 cause a form of bile acid deficiency which can be fatal in newborns[11]. AKR1D1 inhibitor Finasteride is used as treatment for benign prostate hyperplasia.

Structural highlights

The active site of AKR1B10 contains the cofactor and a . Water molecules are shown as red spheres.

  • are part of the enzyme catalytic tetrad[12].
  • .

3D structures of aldo-keto reductase

Aldo-keto reductase 3D structures


Human AKR1B10 complex with polyfluorinated inhibitor and NADP 4icc

Drag the structure with the mouse to rotate


ReferencesReferences

  1. ↑ Penning TM. The aldo-keto reductases (AKRs): Overview. Chem Biol Interact. 2015 Jun 5;234:236-46. doi: 10.1016/j.cbi.2014.09.024. Epub, 2014 Oct 7. PMID:25304492 doi:http://dx.doi.org/10.1016/j.cbi.2014.09.024
  2. ↑ Brožič P, Turk S, Rižner TL, Gobec S. Inhibitors of aldo-keto reductases AKR1C1-AKR1C4. Curr Med Chem. 2011;18(17):2554-65. PMID:21568892 doi:10.2174/092986711795933713
  3. ↑ . PMID:110526179
  4. ↑ Yamamoto K, Wilson DK. Identification, characterization, and crystal structure of an aldo-keto reductase (AKR2E4) from the silkworm Bombyx mori. Arch Biochem Biophys. 2013 Oct 15;538(2):156-63. doi: 10.1016/j.abb.2013.08.018. , Epub 2013 Sep 6. PMID:24012638 doi:http://dx.doi.org/10.1016/j.abb.2013.08.018
  5. ↑ Saito R, Shimakawa G, Nishi A, Iwamoto T, Sakamoto K, Yamamoto H, Amako K, Makino A, Miyake C. Functional analysis of the AKR4C subfamily of Arabidopsis thaliana: model structures, substrate specificity, acrolein toxicity, and responses to light and [CO(2)]. Biosci Biotechnol Biochem. 2013;77(10):2038-45. PMID:24096666 doi:10.1271/bbb.130353
  6. ↑ Songsiriritthigul C, Narawongsanont R, Tantitadapitak C, Guan HH, Chen CJ. Structure-function study of AKR4C14, an aldo-keto reductase from Thai jasmine rice (Oryza sativa L. ssp. indica cv. KDML105). Acta Crystallogr D Struct Biol. 2020 May 1;76(Pt 5):472-483. doi:, 10.1107/S2059798320004313. Epub 2020 Apr 23. PMID:32355043 doi:http://dx.doi.org/10.1107/S2059798320004313
  7. ↑ Li H, Yang Y, Hu Y, Chen CC, Huang JW, Min J, Dai L, Guo RT. Structural analysis and engineering of aldo-keto reductase from glyphosate-resistant Echinochloa colona. J Hazard Mater. 2022 Aug 15;436:129191. PMID:35739721 doi:10.1016/j.jhazmat.2022.129191
  8. ↑ Ellis EM, Slattery CM, Hayes JD. Characterization of the rat aflatoxin B1 aldehyde reductase gene, AKR7A1. Structure and chromosomal localization of AKR7A1 as well as identification of antioxidant response elements in the gene promoter. Carcinogenesis. 2003 Apr;24(4):727-37. PMID:12727802 doi:10.1093/carcin/bgg016
  9. ↑ Marquardt T, Kostrewa D, Balakrishnan R, Gasperina A, Kambach C, Podjarny A, Winkler FK, Balendiran GK, Li XD. High-resolution crystal structure of AKR11C1 from Bacillus halodurans: an NADPH-dependent 4-hydroxy-2,3-trans-nonenal reductase. J Mol Biol. 2005 Nov 25;354(2):304-16. Epub 2005 Oct 10. PMID:16242712 doi:http://dx.doi.org/10.1016/j.jmb.2005.09.067
  10. ↑ Grant AW, Steel G, Waugh H, Ellis EM. A novel aldo-keto reductase from Escherichia coli can increase resistance to methylglyoxal toxicity. FEMS Microbiol Lett. 2003 Jan 21;218(1):93-9. PMID:12583903
  11. ↑ Drury JE, Mindnich R, Penning TM. Characterization of disease-related 5beta-reductase (AKR1D1) mutations reveals their potential to cause bile acid deficiency. J Biol Chem. 2010 Aug 6;285(32):24529-37. doi: 10.1074/jbc.M110.127779. Epub 2010, Jun 3. PMID:20522910 doi:http://dx.doi.org/10.1074/jbc.M110.127779
  12. ↑ Cousido-Siah A, Ruiz FX, Mitschler A, Porte S, de Lera AR, Martin MJ, Manzanaro S, de la Fuente JA, Terwesten F, Betz M, Klebe G, Farres J, Pares X, Podjarny A. Identification of a novel polyfluorinated compound as a lead to inhibit the human enzymes aldose reductase and AKR1B10: structure determination of both ternary complexes and implications for drug design. Acta Crystallogr D Biol Crystallogr. 2014 Mar;70(Pt 3):889-903. doi:, 10.1107/S1399004713033452. Epub 2014 Feb 27. PMID:24598757 doi:http://dx.doi.org/10.1107/S1399004713033452

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