Functional Analogy in Human Metabolism: Enzymes with Different Biological Roles or Functional Redundancy?

Abstract

Since enzymes catalyze almost all chemical reactions that occur in living organisms, it is crucial that genes encoding such activities are correctly identified and functionally characterized. Several studies suggest that the fraction of enzymatic activities in which multiple events of independent origin have taken place during evolution is substantial. However, this topic is still poorly explored, and a comprehensive investigation of the occurrence, distribution, and implications of these events has not been done so far. Fundamental questions, such as how analogous enzymes originate, why so many events of independent origin have apparently occurred during evolution, and what are the reasons for the coexistence in the same organism of distinct enzymatic forms catalyzing the same reaction, remain unanswered. Also, several isofunctional enzymes are still not recognized as nonhomologous, even with substantial evidence indicating different evolutionary histories. In this work, we begin to investigate the biological significance of the cooccurrence of nonhomologous isofunctional enzymes in human metabolism, characterizing functional analogous enzymes identified in metabolic pathways annotated in the human genome. Our hypothesis is that the coexistence of multiple enzymatic forms might not be interpreted as functional redundancy. Instead, these enzymatic forms may be implicated in distinct (and probably relevant) biological roles.

Mining of potential drug targets through the identification of essential and analogous enzymes in the genomes of pathogens of Glycine max, Zea mays and Solanum lycopersicum

“…In addition to this practical importance, these enzymes represent important evolutionary phenomenon, existence shows that for various biochemical problems, evolutionarily independent solutions may appear [ 35 ]. The main works on the practical application of analogous enzymes describes studies of metabolic pathways and inhibitory targets for human pathogens [ 42 , 69 – 70 ]. In the case of our study, we sought a practical application, focused on the solution of an agronomic problem.…”

“…Convergent evolution, initially thought to be a rare phenomenon in enzyme evolution, has been demonstrated for several enzymes including superoxide dismutase [ 36 – 38 ] and proteases [ 39 ]. Later, cases of functional analogy were found in most biochemical pathways [ 40 – 42 ]. Most importantly, the structural differences found between analogous enzymes from the plant and the phytopathogen, a consequence of their different evolutionary origins, may be exploited for the design of specific molecules that will interact only with the form found in the phytopathogen, leaving the plant and other important species, particularly men itself and Apis mellifera , one of the most important pollinators [ 43 , 44 ], unharmed.…”

Mutation severity spectrum of rare alleles in the human genome is predictive of disease type

“…Metabolic enzymes exhibit similar tendency towards mutation-tolerance as the ORs ( Fig 5E). One explanation for the greater tolerance of metabolic genes to mutations might be the redundancy not only in gene duplications, but also in non-homologous proteins that can serve as functional analogs of the same reactions [86]. Metabolites can also be acquired through transport mechanisms, relieving the evolutionary constraints on certain metabolic enzymes.…”

Mutation severity spectrum of rare alleles in the human genome is predictive of disease type

“…Metabolic enzymes exhibit similar tendency towards mutation-tolerance as the ORs (Figure 5D). One explanation for the greater tolerance of metabolic genes to mutations might be the redundancy not only in gene duplications, but also in non-homologous proteins that can serve as functional analogs of the same reactions [76]. Metabolites can also be acquired through transport mechanisms, relieving the evolutionary constraints on certain metabolic enzymes.…”