title: Extracellular and intracellular esterase processing of SCFA-hexosamine analogs: implications for metabolic glycoengineering and drug delivery.
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.
authors.affiliation: Department of Biomedical Engineering and the Translational Tissue Engineering Center, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Mohit P
authors.initials: MP
authors.lastname: Mathew
authors.forename: Elaine
authors.initials: E
authors.lastname: Tan
authors.forename: Shivam
authors.initials: S
authors.lastname: Shah
authors.forename: Rahul
authors.initials: R
authors.lastname: Bhattacharya
authors.forename: M
authors.initials: M
authors.lastname: Adam Meledeo
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.forename: Freddy A
authors.initials: FA
authors.lastname: Espinoza
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Yarema
mesh_terms: D001665:Binding Sites; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D005232:Fatty Acids, Volatile / Q000737:chemistry*; D006595:Hexosamines / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D062105:Molecular Docking Simulation; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D004337:Drug Carriers; D005232:Fatty Acids, Volatile; D006595:Hexosamines; C008322:mannosamine; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; D019158:N-Acetylneuraminic Acid