ABSTRACT
To support life, the osmolality of the cellular fluid is tightly regulated by various means, including osmolyte control. Dicarbonyl/L-xylulose reductase (DCXR) is a highly conserved enzyme reducing L-xylulose to xylitol, which serves as an effective osmolyte in various mammalian and human tissues such as lung epithelium, sperm, and lens. DHS-21 is the only DCXR ortholog in Caenorhabditis elegans, and DCXR null mutant worms accumulate eggs in the uterus. However, it has been unknown how and why the mutant worms impair egg retention. In this study, we tested whether the egg-retention in dhs-21 (jh129), the DCXR null mutant worm, is sensitive to changes in osmolarity. Low osmolality reverted the egg retention phenotype of dhs-21(jh129), while high osmolarity aggravated it. Also, knock-down of either one of osr-1, osm-7, or osm-11, osmoregulatory genes, also rescued egg-retention phenotypes of the null mutants. The study indicates that DCXR functions in fluid homeostasis by regulating cellular osmolality in C. elegans and provides insights into DCXR-involved clinical conditions, such as congenital cataracts and malfunctioning lung and kidney.
ABSTRACT
Dicarbonyl/L-xylulose reductase (DCXR) is a highly conserved and phylogenetically widespread enzyme converting L-xylulose into xylitol. It also reduces highly reactive α-dicarbonyl compounds, thus performing a dual role in carbohydrate metabolism and detoxification. Enzymatic properties of DCXR from yeast, fungi and mammalian tissue extracts are extensively studied. Deficiency of the DCXR gene causes a human clinical condition called pentosuria and low DCXR activity is implicated in age-related diseases including cancers, diabetes, and human male infertility. While mice provide a model to study clinical condition of these diseases, it is necessary to adopt a physiologically tractable model in which genetic manipulations can be readily achieved to allow the fast genetic analysis of an enzyme with multiple biological roles. Caenorhabditis elegans has been successfully utilized as a model to study DCXR. Here, we discuss the biochemical properties and significance of DCXR activity in various human diseases, and the utility of C. elegans as a research platform to investigate the molecular and cellular mechanism of the DCXR biology.
Subject(s)
Carbohydrate Metabolism, Inborn Errors/enzymology , Sugar Alcohol Dehydrogenases/deficiency , Amino Acid Sequence , Animals , Carbohydrate Metabolism, Inborn Errors/pathology , Humans , Models, Molecular , Molecular Sequence Data , Sugar Alcohol Dehydrogenases/chemistry , Sugar Alcohol Dehydrogenases/metabolism , XyluloseABSTRACT
Dicarbonyl/L-xylulose reductase (DCXR) converts l-xylulose into xylitol, and reduces various α-dicarbonyl compounds, thus performing a dual role in carbohydrate metabolism and detoxification. In this study, we identified DHS-21 as the only DCXR ortholog in Caenorhabditis elegans. The dhs-21 gene is expressed in various tissues including the intestine, gonadal sheath cells, uterine seam (utse) cells, the spermathecal-uterus (sp-ut) valve and on the plasma membrane of spermatids. Recombinant DHS-21 was shown to convert L-xylulose to xylitol using NADPH as a cofactor. Dhs-21 null mutants of C. elegans show defects in longevity, reproduction and egg-laying. Knock-down of daf-16 and elt-2 transcription factors affected dhs-21 expression. These results suggest that DHS-21 is a bona fide DCXR of C. elegans, essential for normal life span and reproduction.
