From elementary flux modes to elementary flux vectors: Metabolic pathway analysis with arbitrary linear flux constraints

Abstract

Elementary flux modes (EFMs) emerged as a formal concept to describe metabolic pathways and have become an established tool for constraint-based modeling and metabolic network analysis. EFMs are characteristic (support-minimal) vectors of the flux cone that contains all feasible steady-state flux vectors of a given metabolic network. EFMs account for (homogeneous) linear constraints arising from reaction irreversibilities and the assumption of steady state; however, other (inhomogeneous) linear constraints, such as minimal and maximal reaction rates frequently used by other constraint-based techniques (such as flux balance analysis [FBA]), cannot be directly integrated. These additional constraints further restrict the space of feasible flux vectors and turn the flux cone into a general flux polyhedron in which the concept of EFMs is not directly applicable anymore. For this reason, there has been a conceptual gap between EFM-based (pathway) analysis methods and linear optimization (FBA) techniques, as they operate on different geometric objects. One approach to overcome these limitations was proposed ten years ago and is based on the concept of elementary flux vectors (EFVs). Only recently has the community started to recognize the potential of EFVs for metabolic network analysis. In fact, EFVs exactly represent the conceptual development required to generalize the idea of EFMs from flux cones to flux polyhedra. This work aims to present a concise theoretical and practical introduction to EFVs that is accessible to a broad audience. We highlight the close relationship between EFMs and EFVs and demonstrate that almost all applications of EFMs (in flux cones) are possible for EFVs (in flux polyhedra) as well. In fact, certain properties can only be studied with EFVs. Thus, we conclude that EFVs provide a powerful and unifying framework for constraint-based modeling of metabolic networks.

Metabolic enzyme cost explains variable trade-offs between microbial growth rate and yield

“…Since non-EFMs can be optimal with additional flux constraints, the algorithm for finding the possible optimal flux modes will have to be adjusted. Since these new points can be found by interpolating between EFMs we expect that an efficient algorithm can be developed, perhaps building onto the concept of elementary flux vectors [54,55].…”

Getting there and staying there: supporting and enabling persistent human life on Mars using synthetic natural rubber, self-healing materials, and biological batteries

“…Elementary flux modes (EFMs) are a concept used to analyse metabolic networks. An EFM is defined formally as the " characteristic (support-minimal) vectors of the flux cone that contains all feasible steady-state flux vectors of a given metabolic network" (Klamt 2017). In other words, an EFM is essentially a representation of possible ways to use carbon, nitrogen, and other inputs to make metabolic products used to keep the organism "alive", or our desired product, cis-1,4 polyisoprene.…”

Expanding Metabolic Capabilities Using Novel Pathway Designs: Computational Tools and Case Studies

“…EFMs provide a natural framework for exploring metabolic pathways with the desired functionality, e.g., production of a specific compound from some determined sources; however, they are limited by the inherent complexity of the enumeration problem and the type of constraints they can capture. For instance, minimal and maximal reaction rates render the concept of EFMs inadequate, and thus, a different framework based on elementary flux vectors has been proposed to tackle this limitation . However, it is often the case where additional constraints, e.g., thermodynamic realizability and enzymatic cost, can be formulated to narrow the search space and arrive at more attractive solutions.…”