Minimal cut sets in metabolic networks: from conceptual foundations to applications in metabolic engineering and biomedicine

23.04.2025

Steffen Klamt, Jürgen Zanghellini, and Axel von Kamp

Published in Briefings in Bioinformatics, Volume 26, Issue 2, March 2025, bbaf188.

https://doi.org/10.1093/bib/bbaf188

Minimal cut sets (MCSs) have emerged as an important branch of constraint-based metabolic modeling, offering a versatile framework for analyzing and engineering metabolic networks.

Over the past two decades, MCSs have evolved from a theoretical concept into a powerful tool for identifying tailored metabolic intervention strategies and studying robustness and failure modes of metabolic networks. Successful (experimental) applications range from designing highly efficient microbial cell factories to targeting cancer cell metabolism.

This review highlights key conceptual and algorithmic advancements that have transformed MCSs into a flexible methodology applicable to metabolic models of any size. It also provides a comprehensive overview of their applications and concludes with a perspective on future research directions.

The review aims to equip both newcomers and experts with the knowledge needed to effectively leverage MCSs for metabolic network analysis and design, therapeutic targeting, and beyond.

Relationships between MCSs, EMs, primal and dual network/system, and different ways of computing MCSs and EMs. Full (bold) lines represent routes that have been used for computations while dashed lines represent routes that are in principle possible but have not been utilized so far.

Evolution of major concepts of MCSs based on target (red) and desired (green) regions of the flux space. The regions can be defined either via linear inequalities (as indicated here) or via appropriate sets of elementary modes/elementary flux vectors, from which the MCSs can then be computed via the duality-based or the Berge algorithm, respectively.