Extracellular and intracellular esterase processing of SCFA-hexosamine analogs: implications for metabolic glycoengineering and drug delivery.

Mathew MP, Tan E, Shah S, Bhattacharya R, Adam Meledeo M, Huang J, Espinoza FA, Yarema KJ. (2012) Extracellular and intracellular esterase processing of SCFA-hexosamine analogs: implications for metabolic glycoengineering and drug delivery. Bioorg Med Chem Lett. 22(22):6929-33. PMID: 23041156. PMCID: PMC3530194

Abstract

This report provides a synopsis of the esterase processing of short chain fatty acid (SCFA)-derivatized hexosamine analogs used in metabolic glycoengineering by demonstrating that the extracellular hydrolysis of these compounds is comparatively slow (e.g., with a t(1/2) of ∼4 h to several days) in normal cell culture as well as in high serum concentrations intended to mimic in vivo conditions. Structure-activity relationship (SAR) analysis of common sugar analogs revealed that O-acetylated and N-azido ManNAc derivatives were more refractory against extracellular inactivation by FBS than their butanoylated counterparts consistent with in silico docking simulations of Ac(4)ManNAc and Bu(4)ManNAc to human carboxylesterase 1 (hCE1). By contrast, all analogs tested supported increased intracellular sialic acid production within 2h establishing that esterase processing once the analogs are taken up by cells is not rate limiting.

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