Effect of diabetes on the sugar nucleotides in several tissues of the rat

Spiro, Mary Jane

doi:10.1007/bf00252267

Cited by 31 publications

(18 citation statements)

References 53 publications

(40 reference statements)

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“…Concerning wild-type mouse tissues, GDP-D-Man concentrations varying from about 7 to 25 nmol/g of tissue (wet weight) were measured; liver was the organ with the highest levels of this GDP-hexose (Table 3). These values were similar to GDP-D-Man concentrations found previously in rat tissues (26). GDP-D-Glc levels were very low in all of the mouse tissues analyzed.…”

Section: Gdp-d-glc Is Present At Low Levels In Nematode and Mouse Tissupporting

confidence: 89%

A Novel GDP-d-glucose Phosphorylase Involved in Quality Control of the Nucleoside Diphosphate Sugar Pool in Caenorhabditis elegans and Mammals

Adler¹,

Gomez²,

Clarke³

et al. 2011

Journal of Biological Chemistry

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The plant VTC2 gene encodes GDP-L-galactose phosphorylase, a rate-limiting enzyme in plant vitamin C biosynthesis. Genes encoding apparent orthologs of VTC2 exist in both mammals, which produce vitamin C by a distinct metabolic pathway, and in the nematode worm Caenorhabditis elegans where vitamin C biosynthesis has not been demonstrated. We have now expressed cDNAs of the human and worm VTC2 homolog genes (C15orf58 and C10F3.4, respectively) and found that the purified proteins also display GDP-hexose phosphorylase activity. However, as opposed to the plant enzyme, the major reaction catalyzed by these enzymes is the phosphorolysis of GDP-D-glucose to GDP and D-glucose 1-phosphate. We detected activities with similar substrate specificity in worm and mouse tissue extracts. The highest expression of GDP-D-glucose phosphorylase was found in the nervous and male reproductive systems. A C. elegans C10F3.4 deletion strain was found to totally lack GDP-D-glucose phosphorylase activity; this activity was also found to be decreased in human HEK293T cells transfected with siRNAs against the human C15orf58 gene. These observations confirm the identification of the worm C10F3.4 and the human C15orf58 gene expression products as the GDP-D-glucose phosphorylases of these organisms. Significantly, we found an accumulation of GDP-D-glucose in the C10F3.4 mutant worms, suggesting that the GDP-D-glucose phosphorylase may function to remove GDP-D-glucose formed by GDP-D-mannose pyrophosphorylase, an enzyme that has previously been shown to lack specificity for its physiological D-mannose 1-phosphate substrate. We propose that such removal may prevent the misincorporation of glucosyl residues for mannosyl residues into the glycoconjugates of worms and mammals.The last missing enzyme of the plant vitamin C biosynthesis pathway was recently identified as a GDP-L-galactose phosphorylase encoded by the Arabidopsis VTC2 gene (1, 2). In this 10-step metabolic pathway from D-glucose to L-ascorbate, GDP-L-Gal 4 phosphorylase catalyzes the formation of L-Gal-1-P in the first committed (and highly regulated) step to vitamin C biosynthesis (2-5). Intriguingly, the VTC2 gene appears to be conserved in vertebrates, which are known to synthesize vitamin C via a different metabolic pathway than plants that does not include GDP-L-Gal as an intermediate (6), and in invertebrates such as Caenorhabditis elegans that may lack the ability to synthesize vitamin C (1). The physiological functions of these apparent orthologs are thus unclear. One clue may be that the Arabidopsis VTC2 enzyme can also use GDP-D-glucose as a substrate (1). Although the role of this activity in plants is unclear, such an activity may be important in other species. Whereas GDP-L-Gal is most probably absent from mammalian tissues, the presence of GDP-D-Glc in bovine mammary gland and the existence of a mammalian GDP-D-Glc pyrophosphorylase have been reported (7,8). More recent observations suggest that GDP-D-Glc formation can be catalyzed by the mammalian GDP-D-mannose pyroph...

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Section: Gdp-d-glc Is Present At Low Levels In Nematode and Mouse Tissupporting

confidence: 89%

A Novel GDP-d-glucose Phosphorylase Involved in Quality Control of the Nucleoside Diphosphate Sugar Pool in Caenorhabditis elegans and Mammals

Adler¹,

Gomez²,

Clarke³

et al. 2011

Journal of Biological Chemistry

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“…A UDP-Glc deficiency has been reported in the skeletal muscle of diabetic animals (42)(43)(44). This deficiency could be a consequence of the defective transport and/or phosphorylation of glucose in cells from diabetic subjects (45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

UDP-glucose Deficiency Causes Hypersensitivity to the Cytotoxic Effect of Clostridium perfringens Phospholipase C

Flores-Dı́az

Alape-Girón

Titball

et al. 1998

Journal of Biological Chemistry

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A Chinese hamster cell line with a mutation in the UDP-glucose pyrophosphorylase (UDPG:PP) gene leading to UDP-glucose deficiency as well as a revertant cell were previously isolated. We now show that the mutant cell is 10 5 times more sensitive to the cytotoxic effect of Clostridium perfringens phospholipase C (PLC) than the revertant cell. To clarify whether there is a connection between the UDP-glucose deficiency and the hypersensitivity to C. perfringens PLC, stable transfectant cells were prepared using a wild type UDPG:PP cDNA. Clones of the mutant transfected with a construct having the insert in the sense orientation had increased their UDPglucose level, whereas those of the revertant transfected with a UDPG:PP antisense had reduced their level of UDP-glucose compared with control clones transfected with the vector. Exposure of these two types of transfectant clones to C. perfringens PLC demonstrated that a cellular UDP-glucose deficiency causes hypersensitivity to the cytotoxic effect of this phospholipase. Further experiments with genetically engineered C. perfringens PLC variants showed that the sphingomyelinase activity and the C-domain are required for its cytotoxic effect in UDP-glucose-deficient cells.

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“…Cortes (4) and Spiro (5) and their co-workers have reported an increase in uridine diphosphohexoses in rat kidneys after experimentally induced diabetes. In particular, levels of UDP-Glc were demonstrated to be consistently increased in early diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…Increases in UDP-hexose levels have been reported in the kidney and other organs in association with experimental diabetes (4,5). These changes have been postulated to increase the expression of glycoproteins and glycosaminoglycans in the basement membranes of diabetic tissues.…”

Section: Introductionmentioning

confidence: 99%

A role for glycosphingolipid accumulation in the renal hypertrophy of streptozotocin-induced diabetes mellitus.

Zador¹,

Deshmukh²,

Kunkel³

et al. 1993

J. Clin. Invest.

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Glucosylceramide (GIcCer) and related glycosphingolipids have been implicated as causal elements in both the growth of cells and in the regulation of hormonal signaling. We therefore studied whether the renal hypertrophy induced by diabetes was associated with enhanced synthesis of glycosphingolipids. 16 d after the induction of diabetes, increases in renal size and concentration of glucocerebroside and ganglioside GM3 were observed paralleling an increase in UDP-Glc concentration. GlcCer synthase and R-glucosidase-specific activities were no different between control and diabetic kidneys. The apparent K. of the GlcCer synthase with respect to UDP-Glc was 250 rgM and was unchanged in the diabetic kidneys. The observed concentrations of UDP-Glc were 149 and 237 ,M in control and diabetic kidneys, respectively. The UDP-Glc level is thus rate limiting with regard to GIcCer synthesis. To determine whether the changes in glycolipid content were functionally significant, diabetic and control groups were treated with the GlcCer synthase inhibitor, D-threo-l-phenyl-2-decanoylamino-3-morpholino-1-propanol, 2 wk after the induction of diabetes. Kidney weights in the diabetic rats treated with Dthreo-l-phenyl-2-decanoylamino-3-morpholino-l-propanol were no different than the control groups. Morphometric analysis of glomerular volumes paralleled changes in renal growth. Glycosphingolipid formation may therefore represent a significant pathway for glucose utilization in early diabetic nephropathy. (J. Clin. Invest. 1993. 91:797-803.)

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Effect of diabetes on the sugar nucleotides in several tissues of the rat

Cited by 31 publications

References 53 publications

A Novel GDP-d-glucose Phosphorylase Involved in Quality Control of the Nucleoside Diphosphate Sugar Pool in Caenorhabditis elegans and Mammals

A Novel GDP-d-glucose Phosphorylase Involved in Quality Control of the Nucleoside Diphosphate Sugar Pool in Caenorhabditis elegans and Mammals

UDP-glucose Deficiency Causes Hypersensitivity to the Cytotoxic Effect of Clostridium perfringens Phospholipase C

A role for glycosphingolipid accumulation in the renal hypertrophy of streptozotocin-induced diabetes mellitus.

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