Hep27, a member of the short-chain dehydrogenase/reductase family, is an NADPH-dependent dicarbonyl reductase expressed in vascular endothelial tissue

Abstract

Human Hep27 was originally isolated from growth-arrested HepG2 cells and identified as a member of the superfamily of short-chain dehydrogenases/reductases (SDR). Its substrate specificity has not been determined, but a cross-species comparison suggests that it occurs in widely divergent species, such as human, Cenorhabditis elegans, Drosophila and Arabidopsis thaliana. In this study, Hep27 was expressed as a His(6) fusion protein, and subjected to a substrate screen, using a compound library of SDR substrates, comprising steroids, retinoids, sugars and carbonyl compounds. Whereas no steroid dehydrogenase or retinoid activity was detected, it was found that Hep27 catalyzed the NADPH-dependent reduction of dicarbonyl compounds, like 3,4-hexanedione and 1-phenyl-1,2-propanedione with similar turnover numbers as DCXR (a mitochondrial dicarbonyl reductase/xylulose reductase). In contrast, Hep27 does not convert sugar substrates like xylulose or threose. Based on its substrate specificity and expression in endothelial tissues, it is suggested that Hep27 functions as a dicarbonyl reductase in enzymatic inactivation of reactive carbonyls, involved in covalent modification of cellular components.

Efficient eradication of hormone‐resistant human prostate cancers by inactivated Sendai virus particle

“…The function of the enzyme doesn't seem to be related with anti-tumor activity. 53 Thus, many genes activated with HVJ-E are interferon-inducible and appears to promote anti-tumor activity of HVJ-E.…”

Identification and Characterization of Arabidopsis Indole-3-Butyric Acid Response Mutants Defective in Novel Peroxisomal Enzymes

“…Human HEP27 (also known as DHRS2) is the most characterized member of this cluster and is 45% identical to IBR1. HEP27 is a nuclear protein (Pellegrini et al 2002) and can reduce dicarbonyl compounds, but not sugars, steroids, or retinoids (Shafqat et al 2006). The mammalian protein NRDR (also known as DHRS4, HEP27-like, RRD, PHCR, SDR-SRL, and SCAD-SRL) is a closely related homolog that acts as a retinol dehydrogenase and a retinal reductase regulating retinoid metabolism (Lei et al 2003).…”

Mitochondrial HEP27 Is a c-Myb Target Gene That Inhibits Mdm2 and Stabilizes p53

“…The mature protein accumulates primarily in the mitochondria, potentially performing "housekeeping" functions on unknown substrates within the matrix space. Previous screening for potential mitochondrial substrates of Hep27 suggested an NADPH-dependent carbonyl reductase function (46). Further experimentation is necessary to determine the precise mitochondrial function of Hep27.…”

“…Sequence alignment of Hep27 reveals considerable evolutionary conservation from plants to humans (46), with significant homology to short-chain alcohol dehydrogenase/reductase (SDR) enzymes; a superfamily of primarily NAD/NAD(P)-dependent oxidoreductases involved in a host of intermediate metabolic processes (19). Further characterization of Hep27 revealed a gene localized to chromosome 14q11.2 (36), a region characterized by high-frequency loss of heterozygosity in a number of different tumor types, including nasopharyngeal carcinoma (4,29), malignant mesothelioma (3), gastrointestinal stromal tumors (7,10), and metastatic lung adenocarcinomas (13).…”