The self-inhibitory nature of metabolic networks and its alleviation through compartmentalization.

Alam MT, Olin-Sandoval V, Stincone A, Keller MA, Zelezniak A, Luisi BF, Ralser M

Nat Commun 8 (-) 16018 [2017-07-10; online 2017-07-10]

Metabolites can inhibit the enzymes that generate them. To explore the general nature of metabolic self-inhibition, we surveyed enzymological data accrued from a century of experimentation and generated a genome-scale enzyme-inhibition network. Enzyme inhibition is often driven by essential metabolites, affects the majority of biochemical processes, and is executed by a structured network whose topological organization is reflecting chemical similarities that exist between metabolites. Most inhibitory interactions are competitive, emerge in the close neighbourhood of the inhibited enzymes, and result from structural similarities between substrate and inhibitors. Structural constraints also explain one-third of allosteric inhibitors, a finding rationalized by crystallographic analysis of allosterically inhibited L-lactate dehydrogenase. Our findings suggest that the primary cause of metabolic enzyme inhibition is not the evolution of regulatory metabolite-enzyme interactions, but a finite structural diversity prevalent within the metabolome. In eukaryotes, compartmentalization minimizes inevitable enzyme inhibition and alleviates constraints that self-inhibition places on metabolism.

Aleksej Zelezniak

SciLifeLab Fellow

PubMed 28691704

DOI 10.1038/ncomms16018

Crossref 10.1038/ncomms16018

pii: ncomms16018
pmc: PMC5508129

Publications 9.5.0