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Gene Review

AKR1C3  -  aldo-keto reductase family 1, member C3

Homo sapiens

Synonyms: 17-beta-HSD 5, 17-beta-hydroxysteroid dehydrogenase type 5, 3-alpha-HSD type 2, 3-alpha-HSD type II, brain, 3-alpha-hydroxysteroid dehydrogenase type 2, ...
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Disease relevance of AKR1C3

  • Human hepatoma (HepG2) cells (which lack 3beta-HSD/Delta(5-4) ketosteroid isomerase mRNA expression, but express AKR1C1-AKR1C3) were able to convert DHT into 3alpha- and 3beta-Diol [1].
  • In human myeloid leukemia (HL-60) cells, ligand access to PPARgamma is regulated by AKR1C3, which diverts PGD(2) metabolism away from J-series prostanoids (Desmond et al., 2003) [2].
  • It is suggested that the expression of AKR1C1 and AKR1C3 in endometrial cancer will govern the ratio of P:E2 [3].
  • Oxidative damage-related genes AKR1C3 and OGG1 modulate risks for lung cancer due to exposure to PAH-rich coal combustion emissions [4].
  • Variable increases in immunoreactivity for AKR1C3 was also demonstrated in non-neoplastic changes in the prostate including chronic inflammation, atrophy and urothelial (transitional) cell metaplasia [5].

High impact information on AKR1C3


Chemical compound and disease context of AKR1C3


Biological context of AKR1C3


Anatomical context of AKR1C3


Associations of AKR1C3 with chemical compounds


Enzymatic interactions of AKR1C3

  • Prostaglandin F synthase (PGFS) was first purified from bovine lung and catalyzes the formation of 9 alpha,11 beta-PGF(2) from PGD(2) and PGF(2)(alpha) from PGH(2) in the presence of NADPH [12].

Regulatory relationships of AKR1C3


Other interactions of AKR1C3

  • AKR1C3 and AKR1C4 oxidized testosterone to Delta(4)-androstene-3,17-dione [11].
  • Human lung PGFS has been crystallized with the cofactor NADP(+) and the substrate PGD(2), and with the cofactor NADPH and the inhibitor rutin [12].
  • The activities of aldose reductase and 3 alpha-hydroxysteroid dehydrogenase type 2 (106 and 35 nmol/mg/min, respectively) were higher than those of the other enzymes (0.2-4.0 nmol/mg/min) [20].
  • Using the same primary tissue samples, increased levels of epidermal growth factor receptor (EGFR) expression were detected in only 32% of tumour tissues, suggesting hPGFS may have the potential to become a drug target or molecular marker for SCCHN [21].
  • CONCLUSIONS: Polymorphisms in HSD3B1, CYP19, AKR1C3 genes may be associated with an enlarged prostate in older men [13].

Analytical, diagnostic and therapeutic context of AKR1C3


  1. Human cytosolic 3alpha-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3beta-hydroxysteroid dehydrogenase activity: implications for steroid hormone metabolism and action. Steckelbroeck, S., Jin, Y., Gopishetty, S., Oyesanmi, B., Penning, T.M. J. Biol. Chem. (2004) [Pubmed]
  2. Development of nonsteroidal anti-inflammatory drug analogs and steroid carboxylates selective for human aldo-keto reductase isoforms: potential antineoplastic agents that work independently of cyclooxygenase isozymes. Bauman, D.R., Rudnick, S.I., Szewczuk, L.M., Jin, Y., Gopishetty, S., Penning, T.M. Mol. Pharmacol. (2005) [Pubmed]
  3. AKR1C1 and AKR1C3 may determine progesterone and estrogen ratios in endometrial cancer. Rizner, T.L., Smuc, T., Rupreht, R., Sinkovec, J., Penning, T.M. Mol. Cell. Endocrinol. (2006) [Pubmed]
  4. Oxidative damage-related genes AKR1C3 and OGG1 modulate risks for lung cancer due to exposure to PAH-rich coal combustion emissions. Lan, Q., Mumford, J.L., Shen, M., Demarini, D.M., Bonner, M.R., He, X., Yeager, M., Welch, R., Chanock, S., Tian, L., Chapman, R.S., Zheng, T., Keohavong, P., Caporaso, N., Rothman, N. Carcinogenesis (2004) [Pubmed]
  5. Increased expression of type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma. Fung, K.M., Samara, E.N., Wong, C., Metwalli, A., Krlin, R., Bane, B., Liu, C.Z., Yang, J.T., Pitha, J.V., Culkin, D.J., Kropp, B.P., Penning, T.M., Lin, H.K. Endocr. Relat. Cancer (2006) [Pubmed]
  6. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Stanbrough, M., Bubley, G.J., Ross, K., Golub, T.R., Rubin, M.A., Penning, T.M., Febbo, P.G., Balk, S.P. Cancer Res. (2006) [Pubmed]
  7. Selective loss of AKR1C1 and AKR1C2 in breast cancer and their potential effect on progesterone signaling. Ji, Q., Aoyama, C., Nien, Y.D., Liu, P.I., Chen, P.K., Chang, L., Stanczyk, F.Z., Stolz, A. Cancer Res. (2004) [Pubmed]
  8. Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin. Lovering, A.L., Ride, J.P., Bunce, C.M., Desmond, J.C., Cummings, S.M., White, S.A. Cancer Res. (2004) [Pubmed]
  9. The aldo-keto reductase AKR1C3 is a novel suppressor of cell differentiation that provides a plausible target for the non-cyclooxygenase-dependent antineoplastic actions of nonsteroidal anti-inflammatory drugs. Desmond, J.C., Mountford, J.C., Drayson, M.T., Walker, E.A., Hewison, M., Ride, J.P., Luong, Q.T., Hayden, R.E., Vanin, E.F., Bunce, C.M. Cancer Res. (2003) [Pubmed]
  10. A superfamily of NADPH-dependent reductases in eukaryotes and prokaryotes. Carper, D.A., Wistow, G., Nishimura, C., Graham, C., Watanabe, K., Fujii, Y., Hayashi, H., Hayaishi, O. Exp. Eye Res. (1989) [Pubmed]
  11. Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. Penning, T.M., Burczynski, M.E., Jez, J.M., Hung, C.F., Lin, H.K., Ma, H., Moore, M., Palackal, N., Ratnam, K. Biochem. J. (2000) [Pubmed]
  12. Crystal structure of human prostaglandin F synthase (AKR1C3). Komoto, J., Yamada, T., Watanabe, K., Takusagawa, F. Biochemistry (2004) [Pubmed]
  13. Polymorphisms in genes involved in sex hormone metabolism may increase risk of benign prostatic hyperplasia. Roberts, R.O., Bergstralh, E.J., Farmer, S.A., Jacobson, D.J., Hebbring, S.J., Cunningham, J.M., Thibodeau, S.N., Lieber, M.M., Jacobsen, S.J. Prostate (2006) [Pubmed]
  14. Androgen inactivation and steroid-converting enzyme expression in abdominal adipose tissue in men. Blouin, K., Richard, C., Brochu, G., Hould, F.S., Lebel, S., Marceau, S., Biron, S., Luu-The, V., Tchernof, A. J. Endocrinol. (2006) [Pubmed]
  15. Close kinship of human 20alpha-hydroxysteroid dehydrogenase gene with three aldo-keto reductase genes. Nishizawa, M., Nakajima, T., Yasuda, K., Kanzaki, H., Sasaguri, Y., Watanabe, K., Ito, S. Genes Cells (2000) [Pubmed]
  16. The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome. Nelson, V.L., Qin Kn, K.N., Rosenfield, R.L., Wood, J.R., Penning, T.M., Legro, R.S., Strauss, J.F., McAllister, J.M. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  17. Tibolone metabolism in human liver is catalyzed by 3alpha/3beta-hydroxysteroid dehydrogenase activities of the four isoforms of the aldo-keto reductase (AKR)1C subfamily. Steckelbroeck, S., Oyesanmi, B., Jin, Y., Lee, S.H., Kloosterboer, H.J., Penning, T.M. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  18. Structure-function aspects and inhibitor design of type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3). Penning, T.M., Burczynski, M.E., Jez, J.M., Lin, H.K., Ma, H., Moore, M., Ratnam, K., Palackal, N. Mol. Cell. Endocrinol. (2001) [Pubmed]
  19. Characterization of a monoclonal antibody for human aldo-keto reductase AKR1C3 (type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase); immunohistochemical detection in breast and prostate. Lin, H.K., Steckelbroeck, S., Fung, K.M., Jones, A.N., Penning, T.M. Steroids (2004) [Pubmed]
  20. Tetrahydrobiopterin is synthesized from 6-pyruvoyl-tetrahydropterin by the human aldo-keto reductase AKR1 family members. Iino, T., Tabata, M., Takikawa, S., Sawada, H., Shintaku, H., Ishikura, S., Hara, A. Arch. Biochem. Biophys. (2003) [Pubmed]
  21. Preferential expression of hPGFS in primary SCCHN and tumour cell lines derived from respiratory and digestive organs. Li, S., Hanna, E., Breau, R., Ratanatharathorn, V., Xia, X., Suen, J. Br. J. Cancer (2004) [Pubmed]
  22. Identification of a principal mRNA species for human 3alpha-hydroxysteroid dehydrogenase isoform (AKR1C3) that exhibits high prostaglandin D2 11-ketoreductase activity. Matsuura, K., Shiraishi, H., Hara, A., Sato, K., Deyashiki, Y., Ninomiya, M., Sakai, S. J. Biochem. (1998) [Pubmed]
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