Harnessing iron‑sulfur enzymes for synthetic biology

Shomar, Helena; Bokinsky, G.E.

doi:10.1016/j.bbamcr.2024.119718

Harnessing iron‑sulfur enzymes for synthetic biology

Title

Harnessing iron‑sulfur enzymes for synthetic biology

Author

Shomar, Helena (Université Paris Cité)
Bokinsky, G.E. (TU Delft BN/Greg Bokinsky Lab; Kavli institute of nanoscience Delft)

Date

2024

Abstract

Reactions catalysed by iron-sulfur (Fe-S) 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, Fe-S 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 Fe-S enzyme-dependent pathways. Here, we identify and review three core challenges in harnessing Fe-S enzyme activity, which all stem from the properties of Fe-S clusters: 1) limited Fe-S cluster supply within the host cell, 2) Fe-S cluster instability, and 3) lack of specialized reducing cofactor proteins often required for Fe-S enzyme activity, such as enzyme-specific flavodoxins and ferredoxins. We highlight successful methods developed for a variety of Fe-S 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 Fe-S enzymes in engineered metabolic pathways will accelerate the development of industry-ready Fe-S enzyme-dependent biosynthesis pathways.

Subject

Biotechnology
Ferredoxin
Iron‑sulfur protein
Metabolic engineering
Synthetic biology

To reference this document use:

http://resolver.tudelft.nl/uuid:c5869a7d-bbdb-425f-abd0-8908457c78f1

DOI

https://doi.org/10.1016/j.bbamcr.2024.119718

ISSN

0167-4889

Source

Biochimica et Biophysica Acta - Molecular Cell Research, 1871 (5)

Part of collection

Institutional Repository