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Gene Review

DHRS2  -  dehydrogenase/reductase (SDR family) member 2

Homo sapiens

Synonyms: Dehydrogenase/reductase SDR family member 2, mitochondrial, Dicarbonyl reductase HEP27, HEP27, Protein D, SDR25C1

Molecular and cellular characteristics of the Hep27 protein

Hep27 protein (initially called protein D) has been identified as a nuclear cell-cycle regulated protein in cultured human hepatoblastoma cells. Its synthesis is inhibited during the DNA synthesis and activated when DNA synthesis is inhibited [1]. Hep27 protein was cloned and its full sequence inferred from Hep27 orf sequence [2]. The amino acid sequence, which included a nuclear-entrance motif, revealed that Hep27 protein belonged to the Short-Chain Dehydrogenase-Reductase enzyme family (SDR family) [2]. Hep27 is localized in several human normal tissue cells [3], [4], [3] and its subcellular localization includes nuclei, soluble cytoplasm and mitochondria [4],[5], [6].


Molecular and cellular activity of the Hep27 protein.

Hep27 protein is an NADPH-dependent dicarbonyl reductase active on dicarbonyl compounds (like

3,4-hexanedione, 2,3-heptanedione and 1-phenyl-1,2-propanedione) [7]. These substrates of the Hep27 enzyme are cytotoxic xenobiotics and their toxic effects include mitotic chromosome loss, inflammation and cell sclerotic complications. The three xenobiotics are generated during the course of metabolic process and oxidative stress, and are present in dietary constituents.

The reductive reaction of the Hep27 enzyme can specifically quench the toxic action of the three xenobiotics by converting them in no or less toxic compounds [7], [5]. Hep27 protein has also a non-enzymatic molecular activity to regulate apoptosis [8], [5], [6]. The cytoplasmic Hep27 can migrate into mitochondria where a fraction of it, after having proteolytically lost the N-terminal mitochondria-targeting signal, migrates into nuclei and binds to the Mdm2 protein. Mdm2 has the function to inhibit p53 transcription and activate its degradation. Mdm2, when complexed with Hep27, loses its negative actions on p53 and by this mechanism, Hep27 nuclear concentration can control the onset of the cell cycle arrest and apoptosis (Deisenroth et al., 2010; Thorner et al., 2010).


DHRS2 Gene

The gene coding for the Hep27 protein (named DHRS2) has been cloned and cytogenetically and physically mapped on Chr14q11.2 and its intron-exon structure determined [4]. The genomic structure of the DHRS2 gene includes two alternative promoter regions: a hepato-specific promoter (inducible by histone deacetylase inhibitor Na-butyrate) [1] and a second upstream promoter specifically active in monocyte-derived dendritic cells [3].

DHRS2 gene is also activated by c-Myb [9] and ETV5 [5] oncogenic transcription factors.


Molecular and functional evolution of mammalian DHRS2 Gene

DHRS2 gene originated from a duplication of the DHRS4 gene that took place before the formation of the mammalian clade. Mammalian DHRS2 genes have eight coding exons, a highly conserved intron-exon organization and intron phases. Vertebrate ortholog exons codes for polypeptides having high sequence similarity and three amino acids, in specific sequence positions, are diagnostic of DHRS2 enzymes. After duplication, DHRS2 gene evolved more rapidly and underwent positive selection on more sites than the DHRS4 gene. DHRS2 sites under positive selection were mainly located on the enzyme active site thus showing that substrate specificity drove the divergence from the DHRS4 enzyme. Rapid divergent evolution brought the human DHRS2 enzyme to have subcellular localization, synthesis regulation and specialized cellular functions very different from those of the human DHRS4 enzyme. Evolution of the DHRS2 protein may have started from a mutation that caused the inactivation of DHRS4 peroxisome targeting signal, which allowed DHRS2 protein to diffuse in different subcellular compartments and interact with new or more concentrated molecules. The capability of DHRS4 and newly duplicated DHRS2 enzymes to be active on multiple substrates likely acts as an important forge for a rapid functional divergence in such enzymes. Changing one or very few amino acids in an active site, which accepts molecular species having different structures and charges, can change its affinity towards some of the original substrates and trigger a new evolution of the active site. The enzyme can acquire new substrate specificities just by nullifying its affinity towards some of its original substrates and different specificities are expected depending on the position in the active site of the substituted residues. The necessity of the enzyme to adapt to the new metabolite environment can be the driving force of an accelerated evolution operated by positive selection [10].



  1. Identification of a novel nuclear protein synthesized in growth-arrested human hepatoblastoma HepG2 cells. Donadel, G., Garzelli, C., Frank, R., Gabrielli, F. Eur. J. Biochem. (1991) [Pubmed]
  2. A nuclear protein, synthesized in growth-arrested human hepatoblastoma cells, is a novel member of the short-chain alcohol dehydrogenase family. Gabrielli, F., Donadel, G., Bensi, G., Heguy, A., Melli, M. Eur. J. Biochem. (1995) [Pubmed]
  3. Genomic organization of the human gene HEP27: alternative promoter usage in HepG2 cells and monocyte-derived dendritic cells. Heinz, S., Krause, S.W., Gabrielli, F., Wagner, H.M., Andreesen, R., Rehli, M. Genomics. (2002) [Pubmed]
  4. A human short-chain dehydrogenase/reductase gene: structure, chromosomal localization, tissue expression and subcellular localization of its product. Pellegrini, S., Censini, S., Guidotti, S., Iacopetti, P., Rocchi, M., Bianchi, M., Covacci, A., Gabrielli, F. Biochim. Biophys. Acta. (2002) [Pubmed]
  5. Proteomic approach to ETV5 during endometrial carcinoma invasion reveals a link to oxidative stress. Monge, M., Colas, E., Doll, A., Gil-Moreno, A., Castellvi, J., Diaz, B., Gonzalez, M., Lopez-Lopez, R., Xercavins, J., Carreras, R., Alameda, F., Canals, F., Gabrielli, F., Reventos, J., Abal, M. Carcinogenesis. (2009) [Pubmed]
  6. Mitochondrial Hep27 is a c-Myb target gene that inhibits Mdm2 and stabilizes p53. Deisenroth, C., Thorner, A.R., Enomoto, T., Perou, C.M., Zhang, Y. Mol. Cell. Biol. (2010) [Pubmed]
  7. Hep27, a member of the short-chain dehydrogenase/reductase family, is an NADPH-dependent dicarbonyl reductase expressed in vascular endothelial tissue. Shafqat, N., Shafqat, J., Eissner, G., Marschall, H.U., Tryggvason, K., Eriksson, U., Gabrielli, F., Lardy, H., Jörnvall, H., Oppermann, U. Cell. Mol. Life. Sci. (2006) [Pubmed]
  8. Potential tumor suppressor role for the c-Myb oncogene in luminal breast cancer. Thorner, A.R., Parker, J.S., Hoadley, K.A., Perou, C.M. PLoS. One. (2010) [Pubmed]
  9. Distinct changes in gene expression induced by A-Myb, B-Myb and c-Myb proteins. Rushton, J.J., Davis, L.M., Lei, W., Mo, X., Leutz, A., Ness, S.A. Oncogene. (2003) [Pubmed]
  10. Molecular and functional evolution of human DHRS2 and DHRS4 duplicated genes. Gabrielli, F., Tofanelli, S. Gene. (2012) [Pubmed]
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