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ENZYMOLOGY

Channeling a complex question

Nature Chemical Biology volume 16, pages 935–937 (2020)Cite this article

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It is generally believed that large protein complexes provide a catalytic advantage due to substrate channeling between enzymatic domains. However, the structure and function of the pentafunctional AROM complex suggests a noteworthy exception.

Metabolic pathways passage substrates and products through a series of transformations as they interconvert, synthesize, or degrade molecules. In the context of the cell, the enzymes catalyzing these sequential reactions often maintain permanent or transient interactions between them. Through these interactions, metabolic enzymes may participate in substrate channeling, in which the product of one enzyme is passed directly to the next enzyme in the sequence. By limiting diffusion to bulk solvent, substrate channeling increases metabolic flux, protects metabolic intermediates from off-pathway modification, enhances reaction rates, and raises effective substrate concentrations1. Substrate channeling is considered a fixture of many natural metabolic pathways, and it has been coopted in metabolic engineering and biocatalytic applications. In both natural and engineered systems, the simplest strategy for functionally connecting enzymes is through gene fusion, generating a single large protein comprised of multiple individual active sites2. Natural examples of these multifunctional enzymes include intensively studied systems such as fatty acid synthase, polyketide synthase, and tryptophan synthase. But do natural fusions that create large, polyfunctional enzymes necessarily impart the system with the advantages of substrate channeling? Arora Verasztó et al. offer new insights into this question through a detailed structural and kinetic study of the multi-enzyme AROM complex3. Their study reveals that, despite the natural occurrence of a tightly linked pentafunctional enzyme, the individual domains move and function independently, offering none of the substrate-channeling advantages expected of a multifunctional complex.

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Fig. 1: The pentafunctional AROM complex does not channel substrates in vitro.

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  1. Department of Biological Sciences, Marquette University, Milwaukee, WI, USA

    Martin St. Maurice

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  1. Martin St. Maurice
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Correspondence to Martin St. Maurice.

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St. Maurice, M. Channeling a complex question. Nat Chem Biol 16, 935–937 (2020). https://doi.org/10.1038/s41589-020-0619-5

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