Design and synthesis of inositolphosphoglycan putative insulin mediators

López-Prados, Javier; Cuevas, Félix; Reichardt, Niels‐Christian; Paz, José L. de; Morales, Ezequiel Q.; Martín‐Lomas, Manuel

doi:10.1039/b418041k

Cited by 18 publications

(8 citation statements)

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“…[18][19][20][21][22] Sugars are only coupled to resins through C6 when it is used as a synthetic aid and are detached before the end of the synthesis. [23][24][25] Conjugation of galactose to a resin through C6 is key not only to minimise interference with enzyme binding but also to allow addition of the nucleotide uridine to C1. Hence, immobilisation of UDP-galactose on a resin presented the following challenges: selective addition of the linker at the C6 position for subsequent coupling to the resin; the sensitivity of the phosphate to acidic conditions; selective fluorination at C4; the low reaction rates of uridine morpholidate with galactose phosphate.…”

Section: Introductionmentioning

confidence: 99%

“…Most sugars are attached to solid‐phase supports or resins through C1 with no nucleotide present . Sugars are only coupled to resins through C6 when it is used as a synthetic aid and are detached before the end of the synthesis . Conjugation of galactose to a resin through C6 is key not only to minimise interference with enzyme binding but also to allow addition of the nucleotide uridine to C1.…”

Section: Introductionmentioning

confidence: 99%

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Immobilization of UDP‐Galactose on an Amphiphilic Resin

et al. 2018

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Nucleotide sugars are activated sugar precursors used by glycosyltransferases to form glycans. Here we report the first examples of resin‐bound nucleotide sugars: fluorinated UDP‐galactose and UDP‐galactose. They were conjugated to a polyethylene glycol resin through the C6 position with an SMCC linker in good to excellent yields. This synthesis represents an efficient method to access resin‐bound nucleotide sugars in a modular approach that enables modifications of the sugar or nucleotide before conjugation. The system has been conceived as a new chemistry‐based screening system for enzymes that use UDP‐galactose.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immobilization of UDP‐Galactose on an Amphiphilic Resin

et al. 2018

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“…Inositol hexosamines (IHs) have attracted attention as leads to antidiabetic therapies because of their ability to activate phosphatases involved in glucose metabolism (Scheme ). − Galactosyamino and glucosylamino glycosides of inositols 1 with varying stereochemistry have been examined. − One of the more well-known analogues is galactosamine-β-(1 → 4)-3- O -methyl- d - chiro -inositol (INS-2) 2 , which is reported to be both insulin-mimetic and insulin-sensitizing in diabetic rats. This activity was attributed to allosteric activation of pyruvate dehydrogenase phosphatase (PDHP) and protein phosphatase 2Cα (PP2Cα).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of C-Glycoinositols from C-Glycosylcrotylstannanes

Altiti

Mootoo

2018

J. Org. Chem.

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A strategy for the synthesis of C-pseudodisaccharides that centers on the reaction of a C-linked crotyltin and a substituted pent-4-enal and a ring-closing metathesis-alkene dihydroxylation sequence on the derived crotylation products is illustrated in the preparation of analogues of the insulin modulatory inositol galactosamine-β-(1 → 4)-3-O-methyl-d- chiro-inositol (β-INS-2). The modularity of this approach and versatility of the pivotal crotylation products make this a potentially general methodology for diverse libraries of C-glycoinositols.

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“…Synthetic Inositol Hexosamine Analogues-The following compounds were synthesized (31)(32)(33)(34)(35)(36)(37). Representative structures are shown in Figs.…”

Section: Methodsmentioning

confidence: 99%

Reciprocal Control of Pyruvate Dehydrogenase Kinase and Phosphatase by Inositol Phosphoglycans: Dynamic State Set by “Push-Pull” System

McLean

Kunjara

Greenbaum

et al. 2008

Journal of Biological Chemistry

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Reversible phosphorylation of proteins regulates numerous aspects of cell function, and abnormal phosphorylation is causal in many diseases. Pyruvate dehydrogenase complex (PDC) is central to the regulation of glucose homeostasis. PDC exists in a dynamic equilibrium between de-phospho-(active) and phosphorylated (inactive) forms controlled by pyruvate dehydrogenase phosphatases (PDP1,2) and pyruvate dehydrogenase kinases (PDK1-4). In contrast to the reciprocal regulation of the phospho-/de-phospho cycle of PDC and at the level of expression of the isoforms of PDK and PDP regulated by hormones and diet, there is scant evidence for regulatory factors acting in vivo as reciprocal "on-off" switches. Here we show that the putative insulin mediator inositol phosphoglycan P-type (IPG-P) has a sigmoidal inhibitory action on PDK in addition to its known linear stimulation of PDP. Thus, at critical levels of IPG-P, this sigmoidal/linear model markedly enhances the switchover from the inactive to the active form of PDC, a "push-pull" system that, combined with the developmental and hormonal control of IPG-P, indicates their powerful regulatory function. The release of IPGs from cell membranes by insulin is significant in relation to diabetes. The chelation of IPGs with Mn 2؉ and Zn 2؉ suggests a role as "catalytic chelators" coordinating the traffic of metal ions in cells. Synthetic inositol hexosamine analogues are shown here to have a similar linear/sigmoidal reciprocal action on PDC exerting push-pull effects, suggesting their potential for treatment of metabolic disorders, including diabetes. Pyruvate dehydrogenase complex (PDC),2 an enzyme at the interface between glycolysis and the citric acid cycle, is influenced by dietary and hormonal control and by phosphorylation/dephosphorylation reactions, the former regulated by pyruvate dehydrogenase kinases (PDK1-4) and the latter by dedicated mitochondrial pyruvate dehydrogenase phosphatases (PDP1,2) (1-4). Phosphorylation forms the basis of the dynamic state of cell cycling networks, thus the balance between the active (de-phospho-) and the inactive (phospho-) forms of PDC is dependent upon the regulation of PDK and PDP (2,5,6). Cycling between two phosphorylated states is, classically, one mode of control, permitting rapid alterations in catalytic activity, e.g. in response to insulin, adrenaline, shifts in Ca 2ϩ distribution, and effector molecules. In addition, adaptive changes due to altered hormonal or dietary states, such as diabetes, starvation, or high fat/high carbohydrate diets, and related changes in the expression of isoforms of PDK and PDP in a tissue-specific manner regulate the phosphorylation state of the PDC (2, 7-12). The profile of the regulation of PDK1-4 to activation by NADH and to NADH plus acetyl CoA and ATP, together with differences in the apparent K i values for ADP, confers upon tissues individual patterns of response to alterations in metabolite profile linked to hormonal and dietary changes (2, 3, 9 -12).Inositol phosphoglycans (IPGs) are bro...

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Design and synthesis of inositolphosphoglycan putative insulin mediators

Cited by 18 publications

References 65 publications

Immobilization of UDP‐Galactose on an Amphiphilic Resin

Immobilization of UDP‐Galactose on an Amphiphilic Resin

Synthesis of C-Glycoinositols from C-Glycosylcrotylstannanes

Reciprocal Control of Pyruvate Dehydrogenase Kinase and Phosphatase by Inositol Phosphoglycans: Dynamic State Set by “Push-Pull” System

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