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A mechanism for bistability in glycosylation | PLOS Computational Biology

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Author summary While enzymes tend to have a narrow substrate specificity, there are a number of enzymes that are promiscuous, acting on a wide range of substrates. In this article we derive expressions for general multi-substrate competitive inhibition for the class of transferases, with particular emphasis on glycosylation. By extending the enzyme reaction mechanism to include inhibition by high substrate concentrations, we show that switching behaviour (bistability) is possible within a thermodynamically open systems of glycosylation enzymes. The biological implication of this finding is that small changes to a predictor variable may induce abrupt changes in the secreted products.

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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.

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Enzyme inhibitors,Enzymes,Glycosylation,Competitive inhibitors,Glycosyltransferases,Enzyme kinetics,Enzyme metabolism,Cancers and neoplasms

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https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1006348

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A mechanism for bistability in glycosylation

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Author summary While enzymes tend to have a narrow substrate specificity, there are a number of enzymes that are promiscuous, acting on a wide range of substrates. In this article we derive expressions for general multi-substrate competitive inhibition for the class of transferases, with particular emphasis on glycosylation. By extending the enzyme reaction mechanism to include inhibition by high substrate concentrations, we show that switching behaviour (bistability) is possible within a thermodynamically open systems of glycosylation enzymes. The biological implication of this finding is that small changes to a predictor variable may induce abrupt changes in the secreted products.

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https://journals.plos.org/ploscompbiol/article/figure/image?id=10.1371/journal.pcbi.1006348.g005&size=inline

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A mechanism for bistability in glycosylation

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A mechanism for bistability in glycosylation

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