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

Mohammad Tauqeer Alam, Viridiana Olin-Sandoval, Anna Stincone, Markus A. Keller, Aleksej Zelezniak, Ben F. Luisi and Markus Ralser ()
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Mohammad Tauqeer Alam: University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
Viridiana Olin-Sandoval: University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
Anna Stincone: University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
Markus A. Keller: University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
Aleksej Zelezniak: University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
Ben F. Luisi: University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
Markus Ralser: University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms16018

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