Synthesis of C-glycoside analogues of beta-galactosamine-(1-->4)-3-O-methyl-D-chiro-inositol and assay as activator of protein phosphatases PDHP and PP2Calpha.
The glycan beta-galactosamine-(1-4)-3-O-methyl-D-chiro-inositol, called INS-2, was previously isolated from liver as a putative second messenger-modulator for insulin. Synthetic INS-2 injected intravenously in rats is both insulin-mimetic and insulin-sensitizing. This bioactivity is attributed to allosteric activation of pyruvate dehydrogenase phosphatase (PDHP) and protein phosphatase 2Calpha (PP2Calpha). Towards identification of potentially metabolically stable analogues of INS-2 and illumination of the mechanism of enzymatic activation, C-INS-2, the exact C-glycoside of INS-2, and C-INS-2-OH the deaminated analog of C-INS-2, were synthesized and their activity against these two enzymes evaluated. C-INS-2 activates PDHP comparable to INS-2, but failed to activate PP2Calpha. C-INS-2-OH was inactive against both phosphatases. These results and modeling of INS-2, C-INS-2 and C-INS-2-OH into the 3D structure of PDHP and PP2Calpha, suggest that INS-2 binds to distinctive sites on the two different phosphatases to activate insulin signaling. Thus the carbon analog could selectively favor glucose disposal via oxidative pathways.
Hans
Sunej K
SK
Department of Chemistry, Hunter College, 695 Park Avenue, New York, NY 10065, United States.
Camara
Fatoumata
F
Altiti
Ahmad
A
Martín-Montalvo
Alejandro
A
Brautigan
David L
DL
Heimark
Douglas
D
Larner
Joseph
J
Grindrod
Scott
S
Brown
Milton L
ML
Mootoo
David R
DR
D000818:Animals; D004187:Disaccharides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006027:Glycosides; D051379:Mice; D008958:Models, Molecular; D009005:Monosaccharides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D000071636:Protein Phosphatase 2C; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase / Q000737:chemistry / Q000378:metabolism*; D051381:Rats
C476439:4-(2-amino-2-deoxygalactopyranosyl)-3-O-methylinositol; C438934:C-glycoside; D004187:Disaccharides; D006027:Glycosides; D009005:Monosaccharides; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase