Sticky enzymes: increasing metabolic efficiency via substrate-dependent enzyme clustering

It has long been appreciated that the enzymes of cellular metabolism are highly optimized. More recently, it has been recognized that coclustering multiple enzymes into compact agglomerates can accelerate the processing of metabolic intermediates, with benefits including increased pathway fluxes, reduced toxicity, and sensitive branch-point regulation. While the optimal organization of such clusters has been explored theoretically, little is known about how to achieve such organization inside cells. I will describe how phase-separating enzymes can self-organize into nearly-optimally sized and spaced clusters – provided their “stickiness” is allosterically regulated by local substrate availability. In a nutshell, enzyme clusters only form when and where they are needed to process substrate. Within a mathematical model that implements this scheme for simple metabolic pathways, pathway fluxes can be increased by approximately 50-fold at realistic enzyme densities. Finally, I will discuss ideas for how enzyme “stickiness” can be allosterically regulated. This strategy for self-organization goes beyond current paradigms for natural and engineered enzyme clusters, and thus represents a motivating challenge to the fields of synthetic biology and metabolic engineering.