Why Optimal States Recruit Fewer Reactions in Metabolic Networks

TL;DR

This paper demonstrates that optimized metabolic networks tend to have fewer active reactions, especially due to irreversible reactions, and that maximizing flux can paradoxically reduce active reactions, supported by mathematical bounds and simulations.

Contribution

It provides rigorous bounds on active reactions in metabolic networks and reveals the impact of irreversibility and optimization on network activity.

Findings

Optimized networks have fewer active reactions than non-optimized ones.

Irreversible reactions significantly influence the number of active reactions.

Maximizing total flux can decrease the number of active reactions.

Abstract

The metabolic network of a living cell involves several hundreds or thousands of interconnected biochemical reactions. Previous research has shown that under realistic conditions only a fraction of these reactions is concurrently active in any given cell. This is partially determined by nutrient availability, but is also strongly dependent on the metabolic function and network structure. Here, we establish rigorous bounds showing that the fraction of active reactions is smaller (rather than larger) in metabolic networks evolved or engineered to optimize a specific metabolic task, and we show that this is largely determined by the presence of thermodynamically irreversible reactions in the network. We also show that the inactivation of a certain number of reactions determined by irreversibility can generate a cascade of secondary reaction inactivations that propagates through the network. The mathematical results are complemented with numerical simulations of the metabolic networks of the bacterium Escherichia coli and of human cells, which show, counterintuitively, that even the maximization of the total reaction flux in the network leads to a reduced number of active reactions.