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.
Highlights
With the ready availability both of computing power and software tools for numerical simulation, the mathematical modelling of metabolic systems has become a core component of cell biology
Experimental evidence for the existence such complexes can be the appearance of inhibition at high substrate concentrations; in the case of glycosyltransferases, the inhibition is usually that of the acceptor [26,27,28,29], but can be that of the donor [30]
We have extended the treatment of multi-substrate enzymes obeying rapid-equilibrium random-order kinetics to systems exhibiting inhibition at high substrate concentrations
Summary
With the ready availability both of computing power and software tools for numerical simulation, the mathematical modelling of metabolic systems has become a core component of cell biology. Models of classical metabolic pathways, such as glycolysis [1,2,3], the citric-acid cycle [4], the urea cycle [5] and biosynthetic pathways such as N-linked and O-linked glycosylation [6, 7], have been developed as a way to understand how such processes are regulated. Online repositories of such models, such as the BioModels database [8], allow many of these models to be examined without the need for programming ability on the part of the user.
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