The Enzymatic Defect in Essential Pentosuria

Wang, Y. M.; Eys, Jan Van

doi:10.1056/nejm197004162821604

Cited by 33 publications

(16 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, no abnormality in fertilization was observed in mice lacking the dcxr gene. 3 Furthermore, the deficiency of L-xylulose reductase, which is demonstrated here to be identical with DCXR, has been known to result in essential pentosuria, and individuals with this disorder are normal at least in their reproductive function, as has been demonstrated in a family study of the pentosuria allele (37,38). In terms of a genetic disorder, the identification of the variant gene resulting in essential pentosuria will be an important study in the future.…”

Section: Discussionsupporting

confidence: 54%

See 1 more Smart Citation

Molecular Characterization of Mammalian Dicarbonyl/l-Xylulose Reductase and Its Localization in Kidney

Nakagawa¹,

Ishikura²,

Asami³

et al. 2002

Journal of Biological Chemistry

144

View full text Add to dashboard Cite

In this report, we first cloned a cDNA for a protein that is highly expressed in mouse kidney and then isolated its counterparts in human, rat hamster, and guinea pig by polymerase chain reaction-based cloning. The cDNAs of the five species encoded polypeptides of 244 amino acids, which shared more than 85% identity with each other and showed high identity with a human sperm 34-kDa protein, P34H, as well as a murine lungspecific carbonyl reductase of the short-chain dehydrogenase/reductase superfamily. In particular, the human protein is identical to P34H, except for one amino acid substitution. The purified recombinant proteins of the five species were about 100-kDa homotetramers with NADPH-linked reductase activity for ␣-dicarbonyl compounds, catalyzed the oxidoreduction between xylitol and L-xylulose, and were inhibited competitively by nbutyric acid. Therefore, the proteins are designated as dicarbonyl/L-xylulose reductases (DCXRs). The substrate specificity and kinetic constants of DCXRs for dicarbonyl compounds and sugars are similar to those of mammalian diacetyl reductase and L-xylulose reductase, respectively, and the identity of the DCXRs with these two enzymes was demonstrated by their co-purification from hamster and guinea pig livers and by protein sequencing of the hepatic enzymes. Both DCXR and its mRNA are highly expressed in kidney and liver of human and rodent tissues, and the protein was localized primarily to the inner membranes of the proximal renal tubules in murine kidneys. The results imply that P34H and diacetyl reductase (EC 1.1.1.5) are identical to Lxylulose reductase (EC 1.1.1.10), which is involved in the uronate cycle of glucose metabolism, and the unique localization of the enzyme in kidney suggests that it has a role other than in general carbohydrate metabolism.

show abstract

Section: Discussionsupporting

confidence: 54%

“…ducts. Although pentosuric individuals are clinically healthy apart from their chronic excretion of L-xylulose (37), some disorders in the metabolism of dicarbonyl compounds and renal function may be gleaned from the proposed roles of DCXR, which will be tested by generating transgenic and knockout animals of the dcxr gene.…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization of Mammalian Dicarbonyl/l-Xylulose Reductase and Its Localization in Kidney

Nakagawa¹,

Ishikura²,

Asami³

et al. 2002

Journal of Biological Chemistry

144

View full text Add to dashboard Cite

show abstract

“…In 1970, the critical enzyme deficiency was identified as L-xylulose reductase (7). The phenotype results from a defect in the glucuronic acid oxidation pathway (8).…”

mentioning

confidence: 99%

Garrod's fourth inborn error of metabolism solved by the identification of mutations causing pentosuria

Pierce

Spurrell

Mandell³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Pentosuria is one of four conditions hypothesized by Archibald Garrod in 1908 to be inborn errors of metabolism. Mutations responsible for the other three conditions (albinism, alkaptonuria, and cystinuria) have been identified, but the mutations responsible for pentosuria remained unknown. Pentosuria, which affects almost exclusively individuals of Ashkenazi Jewish ancestry, is characterized by high levels of the pentose sugar l -xylulose in blood and urine and deficiency of the enzyme l -xylulose reductase. The condition is autosomal-recessive and completely clinically benign, but in the early and mid-20th century attracted attention because it was often confused with diabetes mellitus and inappropriately treated with insulin. Persons with pentosuria were identified from records of Margaret Lasker, who studied the condition in the 1930s to 1960s. In the DCXR gene encoding l -xylulose reductase, we identified two mutations, DCXR c.583ΔC and DCXR c.52(+1)G > A , each predicted to lead to loss of enzyme activity. Of nine unrelated living pentosuric subjects, six were homozygous for DCXR c.583ΔC , one was homozygous for DCXR c.52(+1)G > A , and two were compound heterozygous for the two mutant alleles. l -Xylulose reductase was not detectable in protein lysates from subjects’ cells and high levels of xylulose were detected in their sera, confirming the relationship between the DCXR genotypes and the pentosuric phenotype. The combined frequency of the two mutant DCXR alleles in 1,067 Ashkenazi Jewish controls was 0.0173, suggesting a pentosuria frequency of approximately one in 3,300 in this population. Haplotype analysis indicated that the DCXR c.52(+1)G > A mutation arose more recently than the DCXR c.583ΔC mutation.

show abstract

“…The xylitol concentration was estimated to be 13 mg per 100 ml red blood cell after a single injection of xylitol. The NADP-linked xylitol dehydrogenase has a low Km for xylitol (5). Although the xylitol content of the red cell increased after repeated injection, it is unlikely that the intracellular xylitol concentration reached saturating levels for the enzyme.…”

Section: Methodsmentioning

confidence: 99%

“…The red cell hemolysate can utilize xylitol and produce L-xylulose and NADPH (reduced form of triphosphopyridine nucleotide) (5). It thus seems possible that xylitol might be able to replace glucose-6-phosphate for the maintenance of NADPH in the G6PD-deficient state.…”

Section: Introductionmentioning

confidence: 99%

The potential use of xylitol in glucose-6-phosphate dehydrogenase deficiency anemia

Wang¹,

Patterson²,

Eys³

1971

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

The Enzymatic Defect in Essential Pentosuria

Cited by 33 publications

References 18 publications

Molecular Characterization of Mammalian Dicarbonyl/l-Xylulose Reductase and Its Localization in Kidney

Molecular Characterization of Mammalian Dicarbonyl/l-Xylulose Reductase and Its Localization in Kidney

Garrod's fourth inborn error of metabolism solved by the identification of mutations causing pentosuria

The potential use of xylitol in glucose-6-phosphate dehydrogenase deficiency anemia

Contact Info

Product

Resources

About