Figure 1. A genome-scale network of enzyme inhibition.

(a) construction of a genomic-scale enzyme-inhibition network by mapping inhibitor information curated from the BRENDA database¹⁶, to the human metabolic reconstruction (Recon2 (ref. ¹⁷)). (b) enzyme-inhibition network (non-directional illustration), in which 82% of enzymatic reactions are inhibited by 26% of Recon2 metabolites. Enzymes are coloured and grouped according to enzyme commission (EC) category, inhibitors according to their HMDB chemical classification²², node size is scaled numerically. (c) The enzyme-inhibition network is scale-free, and follows a power-law and a log-normal distribution (P value for comparing power-law distribution with log-normal, Poisson and exponential are 0.36, 8.7e-05, 0.077 respectively), in comparison to a random network of the same size which is not scale-free (P value for comparing power-law distribution with log-normal, Poisson and exponential are 0.42, 0.78, 0.44, respectively). Ninety per cent of enzymes and metabolites have 20 or less connections (blue line). (d) Top: Enzyme classes (EC classifications) according to their occurrence in the genome, in relation to their representation in the inhibition network. Bottom: Metabolites categorized according to HMDB superclass²², and the percentage, and to which extent they are inhibitors in b. (e) Fifty most frequently inhibiting metabolites illustrated as word-cloud, scaled to the number of inhibitory interactions annotated for each inhibitor. (f) Enzyme classes are inhibited dependent on the metabolite’s chemistry. Size of the nodes is scaled according the number of inhibitor/enzymes within each class. The edge thickness is scaled according to the occurrence of significant inhibitory interactions between the inhibitor’s superclass, and enzyme class. Nodes are connected if P value<0.05. FDR values are highlighted over edges. Abbreviations refer to HMDB categories: Amino acids, Amino Acids, Peptides and Analogues; Aliphatic comp., Aliphatic Acyclic Compounds; Aromatic comp., Aromatic Cyclic Compounds; Carbohydrates, Carbohydrates and Carbohydrate Conjugates; Organic acids, Organic Acids and Derivatives; Nucleotides, Nucleosides, Nucleotides and Analogues.