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Controlling local concentrations of reactants, intermediates, and enzymes in synthetic pathways is critical for achieving satisfactory productivity of any desired products. An emerging approach to exert control over local concentrations is the use of synthetic biomolecular scaffolds to co-localize key molecules of synthetic pathways. These scaffolds bring the key molecules into close proximity by recruiting pathway enzymes via ligand binding and/or physically sequestrating enzymes and metabolites into isolated compartments. Novel scaffolds made of proteins, nucleic acids, and micro-compartments with increasingly complex architecture have recently been explored and applied to a variety of pathways, with varying degrees of success. Despite these strides, precise assembly of synthetic scaffolds remains a difficult task, particularly in vivo, where interactions both intended and unexpected can lead to unpredictable results. Additionally, because heterologous enzymes often have lowered activities in their new hosts, an ideal scaffold should provide a flexible platform that can adapt to kinetic imbalances in different contexts. In this review, we discuss some of the notable advances in the creation of these synthetic scaffolds and highlight the current challenges in their application.

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