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Abstract

Significance: Alongside well-characterized permanent multimeric enzymes and multi-enzyme complexes relatively unstable transient enzyme-enzyme assemblies, including metabolons, provide an important mechanism for the regulation of energy and redox metabolism. Critical Issues: Despite the fact that enzyme-enzyme assemblies have been proposed for many decades and experimentally analyzed for at least 40 years there are very few pathways for which unequivocal evidence for the presence of metabolite channeling, the most frequently evoked reason for their formation, has been provided. Furthermore, in contrast to the stronger, permanent interactions for which a deep understanding of the subunit interface exists the mechanism(s) underlying transient enzyme-enzyme interactions remain poorly studied. Recent advances: The widespread adoption of proteomic and cell biological approaches to characterize protein-protein interaction is defining an ever-increasing number of enzyme-enzyme assemblies as well as enzyme protein interactions that likely identify factors which stabilize such complexes. Moreover, the use of microfluidic technologies provided compelling support of a role for substrate-specific chemotaxis in complex assemblies. Future Directions: Embracing current and developing technologies should render the delineation of metabolons from other enzyme-enzyme complexes more facile. In parallel, attempts to confirm that the findings reported in microfluidic systems are indeed representative of the cellular situation will be critical to understanding the physiological circumstances requiring and evoking dynamic changes in the levels of the various transient enzyme-enzyme assemblies of the cell.