The Metabolic Basis of Inherited Diseases

Winkelmann, R. K.

doi:10.1001/archderm.1972.01620110090032

Cited by 91 publications

(7 citation statements)

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“…As in the liver [3], the limiting step at low concentrations of fructose (below 10 mM) is at the level of its uptake by a carrier-mediated transport system with a high K, (Fig. 3), which contrasts with the high affinity of fructokinase for its substrate.…”

Section: Conversion Of Fructose To Glucose In the Intestinementioning

confidence: 99%

“…The observation made by Gopher et al [4] that isotopically pure [U-'3C]fructose administered to children by nasogastric drip at a rate of 0.26-0.5 mgkg-' (dissolved in 1 ml) . min-' for 60 min (to be compared to the dose of 200mgkg given in tolerance tests for Hereditary Fructose Intolerance [3]) is converted 40-50% to [U-'3C]glucose can now be reinterpreted. The same group of investigators extended their observations to the monkey and the rabbit, showing then that the formation of [U-'3C]glucose could only be observed after nasogastric infusion but not when fructose was given intravenously [5].…”

Section: An Explanation For the Direct Pathwaymentioning

confidence: 99%

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Conversion of fructose to glucose in the rabbit small intestine

Bismut

Hers

Schaftingen

1993

European Journal of Biochemistry

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Gopher et al [Gopher, A., Vaisman, N., Mandel, H. & Lapidot, A. (1990) Proc. Natl Acad. Sci. USA 87, 5449–5453] recently reported that about 50% of the glucose formed from [U‐13C]fructose infused nasogastrically in children contained 13C3 adjacent to 13C4. Assuming a high isotopic dilution of the triosephosphate pool, the authors concluded that about 50% of the fructose converted to glucose in liver and intestine bypassed the classical aldolase pathway, utilizing a hypothetical direct pathway that would involve the phosphorylation of fructose 1‐phosphate to fructose 1,6‐bisphosphate. The present work was undertaken in order to establish to what extent the conversion of fructose to glucose in the intestine could account for this unexpected isotopic distribution. The technique of everted sleeves was used to define the rate of conversion of [U‐14C]glucose and [U‐14C]fructose in the small intestine of 24‐h‐fasted rabbits. It appeared that, at the low concentration of fructose used by Gopher et al., almost as much fructose was converted to glucose as remained unmodified in the tissue. Fractose uptake was not inhibited by glucose, and the presence of all the necessary enzymes in the tissue indicated that the fructose to glucose conversion occurred by the aldolase pathway. Remarkably, this conversion operated with an isotopic dilution not exceeding 25%, due to the low rate of glucose metabolism and the near absence of gluconeogenesis from lactate. It can, therefore, be postulated that, in the presence of pure [U13C]fructose, the triosephosphate pool is highly enriched in 13C with little dilution by 12C, essentially giving rise to [U‐13C]glucose, as reported by Gopher et al. There is, therefore, no need to postulate the participation of a direct pathway.

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Section: Conversion Of Fructose To Glucose In the Intestinementioning

confidence: 99%

Section: An Explanation For the Direct Pathwaymentioning

confidence: 99%

Conversion of fructose to glucose in the rabbit small intestine

Bismut

Hers

Schaftingen

1993

European Journal of Biochemistry

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“…Considerable research has been focused on designing small-molecule inhibitors of FBPase, since patients with hereditary fructose 1,6-bisphosphatase deficiency seem to develop normally after early childhood [9]. Wright et al [10] reported a series of anilinoquinazolines as allosteric inhibitors of FBPase, identified by screening a library of compounds.…”

Section: Introductionmentioning

confidence: 99%

Designing inhibitors against fructose 1,6-bisphosphatase: Exploring natural products for novel inhibitor scaffolds

Heng

Harris

Kantrowitz

2010

European Journal of Medicinal Chemistry

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Natural products often contain unusual scaffold structures that may be elaborated by combinatorial methods to develop new drug-like molecules. Visual inspection of more than 128 natural products with some type of anti-diabetic activity suggested that a subset might provide novel scaffolds for designing potent inhibitors against fructose 1,6-bisphosphatase (FBPase), an enzyme critical in the control of gluconeogenesis. Using in silico docking methodology, these were evaluated to determine those that exhibited affinity for the AMP binding site. Achyrofuran from the South American plant Achyrocline satureoides, was selected for further investigation. Using the achyrofuran scaffold, inhibitors against FBPase were developed. Compounds 15 and 16 inhibited human liver and pig kidney FBPases at IC 50 values comparable to that of AMP, the natural allosteric inhibitor.

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“…It should be mentioned that fructose constitutes the main sugar of seminal fluid. Three inherited abnormalities in fructose metabolism have been identified: essential fructosuria, hereditary fructose intolerance and hereditary fructose-1,6-bisphosphatase deficiency (Baerlocher et al,1978;Gitzelmann et al, 1989;Froesch, 1978). After absorption by the proces of facilitated diffusion, fructose enters hepatocytes , by the portal blood.…”

Section: The Inherited Abnormalities In Fructose Metabolismmentioning

confidence: 99%

“…The F1,6BPase reaction is a major point of control of gluconeogenesis. Fructose-1,6-diphosphatase (FDPase) deficiency is an autosomal recessive disorder caused by a mutation of the FDP1 gene and results in impaired gluconeogenesis ( Froesch, 1978;Gitzelmann et al, 1989;Hellerud, 2010). Patients with FDPase deficiency typically present in the newborn period with symptoms or signs related to hypoglycemia and metabolic acidosis following ingestion of fructose.…”

Section: Fructose-16-diphosphatase (Fdpase) Deficiencymentioning

confidence: 99%