Abstract
Adaptation of enzymes in a metabolic pathway can occur not only through changes in amino acid sequences but also through variations in transcriptional activation, mRNA splicing and mRNA translation. The heme biosynthesis pathway, a linear pathway comprised of eight consecutive enzymes in animals, provides researchers with ample information for multiple types of evolutionary analyses performed with respect to the position of each enzyme in the pathway. Through bioinformatics analysis, we found that the protein-coding sequences of all enzymes in this pathway are under strong purifying selection, from cnidarians to mammals. However, loose evolutionary constraints are observed for enzymes in which self-catalysis occurs. Through comparative genomics, we found that in animals, the first intron of the enzyme-encoding genes has been co-opted for transcriptional activation of the genes in this pathway. Organisms sense the cellular content of iron, and through iron-responsive elements in the 5′ untranslated regions of mRNAs and the intron-exon boundary regions of pathway genes, translational inhibition and exon choice in enzymes may be enabled, respectively. Pathway product (heme)-mediated negative feedback control can affect the transport of pathway enzymes into the mitochondria as well as the ubiquitin-mediated stability of enzymes. Remarkably, the positions of these controls on pathway activity are not ubiquitous but are biased towards the enzymes in the upstream portion of the pathway. We revealed that multiple-level controls on the activity of the heme biosynthesis pathway depend on the linear depth of the enzymes in the pathway, indicating a new strategy for discovering the molecular constraints that shape the evolution of a metabolic pathway.
Highlights
Molecular evolution has recently been a popular area of investigation, and through the advancement of technology and the maturation of analysis methods, this field continues to spawn important insights into the evolutionary processes affecting genes
Based on the M0 model, assuming a constant evolutionary rate for all branches and all codons of the eight genes encoding the enzymes of the metazoan heme biosynthesis pathway, the v values vary from 0.041 (FECH) to 0.127 (UROS), providing evidence that the sequences of the coding regions of these genes are under negative selection (Figure 2A)
The v values of genes located at positions four (UROS) and seven (PPO) were shown to be significantly higher than for the genes located at other positions (Wilcoxon rank sum test, P,0.0001)
Summary
Molecular evolution has recently been a popular area of investigation, and through the advancement of technology and the maturation of analysis methods, this field continues to spawn important insights into the evolutionary processes affecting genes. None of these genes or their encoded proteins exists in isolation, and the products of genes construct the metabolic pathways and networks underlying the cellular and metabolic processes of organisms. As an increasing number of studies are describing the rates of protein and pathway evolution over evolutionary time, there are more opportunities to clarify the patterns and principles of natural selection acting on the pathways involved in the metabolic networks of organisms. Selection is relaxed in the downstream enzymes, and nonsynonymous substitution rates as well as dN/dS ratios are higher in these pathway components
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