Synthesis of C-glycoside analogues of β-galactosamine-(1→4)-3-O-methyl-D-chiro-inositol and assay as activator of protein phosphatases PDHP and PP2Cα

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 2C alpha (PP2C alpha). 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 PP2Ca. 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 PP2Ca, 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. (C) 2009 Elsevier Ltd. All rights reserved.