Abstract
The synthesis of eukaryotic glycans - branched sugar oligomers attached to cell-surface proteins and lipids - is organized like a factory assembly line. Specific enzymes within successive compartments of the Golgi apparatus determine where new monomer building blocks are linked to the growing oligomer. These enzymes act promiscuously and stochastically, causing microheterogeneity (molecule-to-molecule variability) in the final oligomer products. However, this variability is tightly controlled: a given eukaryotic protein type is typically associated with a narrow, specific glycan oligomer profile. Here, we use ideas from the mathematical theory of self-assembly to enumerate the enzymatic causes of oligomer variability and show how to eliminate each cause. We rigorously demonstrate that cells can specifically synthesize a larger repertoire of glycan oligomers by partitioning promiscuous enzymes across multiple Golgi compartments. This places limits on biomolecular assembly: glycan microheterogeneity becomes unavoidable when the number of compartments is limited, or enzymes are excessively promiscuous.
Highlights
A N algorithm converts distinct inputs to corresponding unique outputs through a sequence of deterministic or stochastic actions
Eukaryotic glycan oligomers are assembled by collections of glycosyltransferase (GTase) enzymes in the ER and Golgi apparatus, a process known as glycosylation
We focus on the class of eukaryotic O-glycans [3, Chapter 10], whose synthesis begins in the Golgi apparatus when a root monomer is attached to a serine or threonine on the substrate protein
Summary
A N algorithm converts distinct inputs (e.g. a list of n numbers) to corresponding unique outputs (e.g. the same numbers sorted in increasing order) through a sequence of deterministic or stochastic actions (e.g. swaps of numbers at two positions). The process by which an egg is converted to an adult during organismal development is plausibly algorithmic [2]: distinct genomes produce distinct unique adults; and the genome encodes a recipe to make an adult, it is not a homunculus of the adult In this spirit we define a biosynthetic system as implementing a non-trivial algorithm if: (a) it can accept many distinct inputs; (b) it converts each input to a corresponding unique output; and (c) this is achieved without requiring a template of the output. Different protein types encounter different subsets of GTase enzymes via sequence-specific interactions, and acquire distinct glycan profiles [3, Chapter 5,6]. How can this stochastic and heterogeneous biosynthetic process generate narrow and reproducible glycan profiles?. If glycan biosynthesis could be made algorithmic, cells could suppress unwanted byproducts and generate only desired glycan oligomers with high yield
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