Molecular evolution of multiple-level control of heme biosynthesis pathway in animal kingdom

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, pr...

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Bibliographic Details
Published in:PloS one 2014-01, Vol.9 (1), p.e86718-e86718
Main Authors: Tzou, Wen-Shyong, Chu, Ying, Lin, Tzung-Yi, Hu, Chin-Hwa, Pai, Tun-Wen, Liu, Hsin-Fu, Lin, Han-Jia, Cases, Ildeofonso, Rojas, Ana, Sanchez, Mayka, You, Zong-Ye, Hsu, Ming-Wei
Format: Article
Language:English
Subjects:
5' Untranslated Regions - genetics
Amino Acid Motifs
Amino Acid Sequence
Amino acids
Amino Acids - genetics
Animals
Base Sequence
Bioinformatics
Biological evolution
Biological products
Biology
Biosynthesis
Biosynthetic Pathways - genetics
Biotechnology
Cancer
Catalysis
Conserved Sequence - genetics
Control stability
Deoxyribonucleases - metabolism
Enzymes
Evolution
Evolution, Molecular
Evolutionary biology
Exons - genetics
Feedback control
Gene sequencing
Genes
Genomes
Genomics
Heme
Heme - biosynthesis
Hemoglobin synthesis
Introns - genetics
Iron
Kinases
Life sciences
Medicine
Metabolism
Mitochondria
Molecular evolution
Molecular Sequence Data
Negative feedback
Phylogenetics
Precision medicine
Product inhibition
Proteins
Response Elements - genetics
RNA
Selection, Genetic
Sequence Alignment
Splicing
Transcription (Genetics)
Transcription activation
Translation (Genetics)
Ubiquitin
Vertebrates
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0086718