A mechanism for bistability in glycosylation

PLoS Comput Biol. 2018 Aug 3;14(8):e1006348. doi: 10.1371/journal.pcbi.1006348. eCollection 2018 Aug.

Abstract

Glycosyltransferases are a class of enzymes that catalyse the posttranslational modification of proteins to produce a large number of glycoconjugate acceptors from a limited number of nucleotide-sugar donors. The products of one glycosyltransferase can be the substrates of several other enzymes, causing a combinatorial explosion in the number of possible glycan products. The kinetic behaviour of systems where multiple acceptor substrates compete for a single enzyme is presented, and the case in which high concentrations of an acceptor substrate are inhibitory as a result of abortive complex formation, is shown to result in non-Michaelian kinetics that can lead to bistability in an open system. A kinetic mechanism is proposed that is consistent with the available experimental evidence and provides a possible explanation for conflicting observations on the β-1,4-galactosyltransferases. Abrupt switching between steady states in networks of glycosyltransferase-catalysed reactions may account for the observed changes in glycosyl-epitopes in cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biophysical Phenomena / physiology
  • Catalysis
  • Enzyme Activation
  • Feedback, Physiological / physiology
  • Galactosyltransferases / metabolism
  • Glycosylation
  • Glycosyltransferases / metabolism*
  • Glycosyltransferases / pharmacokinetics*
  • Glycosyltransferases / physiology
  • Humans
  • Kinetics
  • Substrate Specificity / physiology

Substances

  • Glycosyltransferases
  • Galactosyltransferases

Grants and funding

This work was part supported by an EU Initial Training Network, Project No. 608381 - Training in Neurodegeneration, Therapeutics Intervention and Neurorepair (TINTIN) awarded to GPD. URL: http://ec.europa.eu/research/fp7/index_en.cfm; and Science Foundation Ireland Grant No. SFI-13/SP SSPC/I2893 URL: http://www.sfi.ie. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.