Pareto-optimal synthesis of multiple glycans in Golgi compartments

Abstract

Tree-shaped sugar chains called glycans are covalently attached to proteins in the plasma membrane of eukaryotic cells. They engage in multiple functions such as adhesion, signaling, etc. at the cell surface, so their correct manufacture is of vital importance. Glycans are assembled step by step through enzyme-catalyzed monomer addition reactions as they transit through compartments of the Golgi apparatus. The constraint of fixed residence times across Golgi compartments creates tradeoffs: a short residence time does not give complex glycans enough time for reactions to run to completion, while a long residence time might execute undesirable reactions, which inevitably occur due to enzyme promiscuity. It is not clear how the Golgi reconciles this trade-off. To study this, we devise a from-first-principles model of glycan manufacture with a focus on maximizing glycan yield. Pareto-optimal solutions are a class of solutions that reconcile trade-offs in simultaneously maximizing the yield of multiple glycans. We explore Pareto-optimal solutions for multiple glycan manufacture, and show that small changes in residence times or relative glycan yields can change the optimal enzyme distribution. Together, these results establish Pareto optimality as a unifying framework for interpreting Golgi compartment organization, and for controlling glycan outputs in industrial settings such as manufacture of biotherapeutics, many of which are glycosylated.