Origins of specificity and promiscuity in metabolic networks

Abstract

How enzymes have evolved to their present form is linked to the question of how pathways emerged and evolved into extant metabolic networks. To investigate this mechanism, we have explored the chemical diversity present in a largely unbiased data set of catalytic reactions processed by modern enzymes across the tree of life. In order to get a quantitative estimate of enzyme chemical diversity, we measure enzyme multispecificity or promiscuity using the reaction molecular signatures. Our main finding is that reactions that are catalyzed by a highly specific enzyme are shared by poorly divergent species, suggesting a later emergence of this function during evolution. In contrast, reactions that are catalyzed by highly promiscuous enzymes are more likely to appear uniformly distributed across species in the tree of life. From a functional point of view, promiscuous enzymes are mainly involved in amino acid and lipid metabolisms, which might be associated with the earliest form of biochemical reactions. In this way, results presented in this paper might assist us with the identification of primeval promiscuous catalytic functions contributing to life's minimal metabolism.

FIGURE 1.

Relationship between latent promiscuity and reaction diversity. A, relationship between latent promiscuity and substrate chemical diversity; B, comparison between the measure of promiscuity at the annotation level (EC number) and based on EC dissimilarity in digits.

FIGURE 2.

Relationship between reaction chemical diversity and reaction phylogenetic diversity. A, phylogenetic distances from pairwise genetic distances calculated from multiple alignments; B, phylogenetic distances calculated from pairwise taxonomic node count in the tree of life. C, relationship between latent enzyme promiscuity and phylogenetic diversity of catalytic functions (EC numbers).

FIGURE 3.

Enzyme promiscuity at different levels of taxonomic grouping. A and B, distribution of reaction chemical diversity; C and D, latent enzyme promiscuity at two different levels of taxonomic grouping.

FIGURE 4.

Scatter plot of latent enzyme promiscuity and reaction chemical diversity in organisms. A, grouping by taxonomic groups; B, grouping at the organism level.

FIGURE 5.

Distribution of metabolic functions on enzymes depending on their latent promiscuity. A, KEGG orthologies; B, E. coli based on clusters of ortholog groups.