Role of oligosaccharides in the pharmacokinetics of tissue-derived and genetically engineered cholinesterases.
Abstract: To understand the role of glycosylation in the circulation of cholinesterases, we compared the mean residence time of five tissue-derived and two recombinant cholinesterases (injected intravenously in mice) with their oligosaccharide profiles. Monosaccharide composition analysis revealed differences in the total carbohydrate, galactose, and sialic acid contents. The molar ratio of sialic acid to galactose residues on tetrameric human serum butyrylcholinesterase, recombinant human butyrylcholinesterase, and recombinant mouse acetylcholinesterase was found to be approximately 1.0. For Torpedo californica acetylcholinesterase, monomeric and tetrameric fetal bovine serum acetylcholinesterase, and equine serum butyrylcholinesterase, this ratio was approximately 0.5. However, the circulatory stability of cholinesterases could not be correlated with the sialic acid-to-galactose ratio. Fractionation of the total pool of oligosaccharides obtained after neuraminidase digestion revealed one major oligosaccharide for human serum butyrylcholinesterase and three or four major oligosaccharides in other cholinesterases. The glycans of tetrameric forms of plasma cholinesterases (human serum butyrylcholinesterase, fetal bovine serum acetylcholinesterase, and equine serum butyrylcholinesterase) clearly demonstrated a reduced heterogeneity and higher maturity compared with glycans of monomeric fetal bovine serum acetylcholinesterase, dimeric tissue-derived T. californica acetylcholinesterase, and recombinant cholinesterases. T. californica acetylcholinesterase, recombinant cholinesterases, and monomeric fetal bovine serum acetylcholinesterase showed a distinctive shorter mean residence time (44-304 min) compared with tetrameric forms of plasma cholinesterases (1902-3206 min). Differences in the pharmacokinetic parameters of cholinesterases seem to be due to the combined effect of the molecular weight and charge- and size-based heterogeneity in glycans.
Publication Date: 1998-01-28 PubMed ID: 9443938DOI: 10.1124/mol.53.1.112Google Scholar: Lookup
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- Journal Article
Summary
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This study examines the role of glycosylation in the circulation of cholinesterases, by comparing the residence time of several tissue-derived and recombinant cholinesterases with their oligosaccharide profiles. The researchers found that differences in pharmacokinetic parameters of cholinesterases appear to be associated with the combined effect of molecular weight and heterogeneity of glycans.
Objective and Methodology
- This research seeks to understand how glycosylation influences the circulation of cholinesterases. This is achieved by comparing the mean residence time (the time that a drug stays in the body before being metabolized or eliminated) of five tissue-derived and two recombinant cholinesterases. All substances were injected intravenously in mice and their corresponding oligosaccharide profiles analyzed.
Results
- An analysis of the composition of monosaccharides revealed significant differences in the total carbohydrate, galactose, and sialic acid contents of different cholinesterases.
- The molar ratio of sialic acid to galactose residues reported relatively similar values for some factorials: around 1.0 for tetrameric human serum butyrylcholinesterase, recombinant human butyrylcholinesterase, and recombinant mouse acetylcholinesterase, and about 0.5 for Torpedo californica acetylcholinesterase, monomeric and tetrameric fetal bovine serum acetylcholinesterase, and equine serum butyrylcholinesterase.
- However, it wasn’t possible to establish a link between a cholinesterase’s circulatory stability and its sialic acid-to-galactose ratio.
- The fractionation of the total pool of oligosaccharides after digestion with neuraminidase revealed one major oligosaccharide for human serum butyrylcholinesterase and between three or four major oligosaccharides in other cholinesterases.
- In comparison to others, the glycans of tetrameric forms of plasma cholinesterases showed a reduced heterogeneity and a higher maturity.
- Differences were found in the mean residence time of different cholinesterases with some having shorter residence times (44-304 minutes) than the tetrameric forms of plasma cholinesterases (1902-3206 minutes).
Conclusion
- Particularly, the variations in the pharmacokinetic parameters of cholinesterases seem to be influenced by a combination of factors: the molecular weight and the heterogeneity (based on charge and size) in glycans.
- This research provides valuable insight into the role of glycosylation in the pharmacokinetics of cholinesterases, which could be pivotal for understanding and improving drug delivery mechanisms and effectiveness.
Cite This Article
APA
Saxena A, Ashani Y, Raveh L, Stevenson D, Patel T, Doctor BP.
(1998).
Role of oligosaccharides in the pharmacokinetics of tissue-derived and genetically engineered cholinesterases.
Mol Pharmacol, 53(1), 112-122.
https://doi.org/10.1124/mol.53.1.112 Publication
Researcher Affiliations
- Division of Biochemistry, Walter Reed Army Institute of Research, Washington D. C. 20307-5100, USA.
MeSH Terms
- Acetylcholinesterase / blood
- Acetylcholinesterase / pharmacokinetics
- Animals
- Butyrylcholinesterase / blood
- Butyrylcholinesterase / pharmacokinetics
- CHO Cells
- Cattle
- Centrifugation, Density Gradient
- Cholinesterases / analysis
- Cholinesterases / blood
- Cholinesterases / pharmacokinetics
- Cricetinae
- Enzyme Stability
- Glycosylation
- Horses
- Humans
- Injections, Intravenous
- Mice
- Oligosaccharides / analysis
- Oligosaccharides / metabolism
- Recombinant Proteins / pharmacokinetics
- Torpedo
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