Harnessing iron‑sulfur enzymes for synthetic biology.

Reactions catalysed by iron‑sulfur (FeS) enzymes appear in a variety of biosynthetic pathways that produce valuable natural products. Harnessing these biosynthetic pathways by expression in microbial cell factories grown on an industrial scale would yield enormous economic and environmental benefits. However, FeS enzymes often become bottlenecks that limits the productivity of engineered pathways. As a consequence, achieving the production metrics required for industrial application remains a distant goal for FeS enzyme-dependent pathways. Here, we identify and review three core challenges in harnessing FeS enzyme activity, which all stem from the properties of FeS clusters: 1) limited FeS cluster supply within the host cell, 2) FeS cluster instability, and 3) lack of specialized reducing cofactor proteins often required for FeS enzyme activity, such as enzyme-specific flavodoxins and ferredoxins. We highlight successful methods developed for a variety of FeS enzymes and electron carriers for overcoming these difficulties. We use heterologous nitrogenase expression as a grand case study demonstrating how each of these challenges can be addressed. We predict that recent breakthroughs in protein structure prediction and design will prove well-suited to addressing each of these challenges. A reliable toolkit for harnessing FeS enzymes in engineered metabolic pathways will accelerate the development of industry-ready FeS enzyme-dependent biosynthesis pathways.

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Copyright © 2024. Published by Elsevier B.V.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.