The self-inhibitory nature of metabolic networks and its alleviation through compartmentalization
Artikel i vetenskaplig tidskrift, 2017

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.

Bacillus-Subtilis

Substrate

6-Bisphosphate

Fructose 2

Triosephosphate Isomerase

Escherichia-Coli

Lactate-Dehydrogenase

Yeast

Enzyme Function

Glycolysis

Genome

Pyruvate-Kinase

Författare

M. T. Alam

University of Cambridge

Warwick Medical School

V. Olin-Sandoval

Instituto Nacional de la Nutricion Salvador Zubiran

University of Cambridge

A. Stincone

University of Cambridge

Discuva Ltd.

M. A. Keller

Medizinische Universitat Innsbruck

University of Cambridge

Aleksej Zelezniak

Chalmers, Biologi och bioteknik, Systembiologi

B. F. Luisi

University of Cambridge

M. Ralser

The Francis Crick Institute

University of Cambridge

Nature Communications

2041-1723 (ISSN)

Vol. 8 Article no 16018- 16018

Ämneskategorier

Biokemi och molekylärbiologi

DOI

10.1038/ncomms16018