Bioinformatic and biochemical characterization of DCXR and DHRS2/4 from Caenorhabditis elegans

Crystal structure and catalytic characterization of the dehydrogenase/reductase SDR family member 4 (DHRS4) from Caenorhabditis elegans

“…In contrast to the human enzyme, the nematode DHRS4 is active with aliphatic aldehydes such as lipid peroxidation products 4‐ONE and trans ‐2‐hexenal (this study), as well as with the saturated aldehydes hexanal (Table ) and octanal (Table ). Conversely, no reductase activity was detected with the triose glyceraldehyde.…”

“…ROS can trigger the peroxidation of membrane lipids, releasing highly reactive carbonyl compounds such as α,β‐unsaturated aldehydes . Interestingly, the DHRS4 homolog from C. elegans shows activity with the lipid peroxidation product 4‐ONE, suggesting a function in the defense against oxidative stress . Moreover, the lack of activity of the human enzyme toward aliphatic aldehydes and the low but detectable activity of the nematode DHRS4 with hexanal, trans ‐2‐hexenal, and octanal suggests that one of the ‘original functions’ of this protein in primitive lineages such as nematodes could be the detoxification of endogenous lipid‐derived aldehydes.…”

“…Our previous initial catalytic characterization of the C. elegans DHRS4 document some shared properties with the human DHRS4 , such as excellent catalytic activity with the xenobiotic 9,10‐PQ, a major constituent of diesel exhaust particles. Also the model substrate isatin (1H‐indole‐2,3‐dione), an endogenous indole with reported metabolic and behavioral effects that has been detected in brain , is reduced by human DHRS4, however, with lower catalytic efficiency than 9,10‐PQ .…”

Identification of a novel isoform of DHRS4 protein with a nuclear localization signal

“…NRDRA2 protein contains the coenzyme-binding sequence of TASTDGIG at residues 38-45, while missing the catalytic domain (YNVSK) of NRDR due to lack of exon 4 and exon 6. The homologues of NRDR from humans and other animals have been shown to be active in an overlapped spectrum of carbonyl substrates (Endo et al, 2009;Huang and Ichikawa, 1997;Kisiela et al, 2011;Matsunaga et al, 2008). According to the previously reported substrates of NRDR, we tested the catalytic activity of NRDRA2 on retinal, isatin, and menadione, but found no obvious enzymatic activities.…”

“…Similarly, NRDR proteins in pig, mouse, and dog have also been found to be efficient at reducing retinal (Endo et al, 2007;Lei et al, 2003;Usami et al, 2003). The human ortholog of NRDR was initially termed peroxisomal 2,4-dienoyl CoA reductase-related protein (Fransen et al, 1999), which is significantly active for reducing various aromatic ketones and alpha-dicarbonyl compounds, including 3-ketosteroids and cytotoxic 9,10-phenanthrenequinone (Endo et al, 2009;Kisiela et al, 2011;Matsunaga et al, 2008). Moreover, NRDR is also expressed highly in the pig testis, and has been implicated in the production of steroid hormone (Moe et al, 2007;Rolland et al, 2009).…”