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, 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.
Department of Life Sciences, National Taiwan Ocean University, Keelung, Taiwan.
Wen-Shyong
WS
Tzou
Department of Life Sciences, National Taiwan Ocean University, Keelung, Taiwan.
Ying
Y
Chu
Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan.
Tzung-Yi
TY
Lin
Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan.
Chin-Hwa
CH
Hu
Department of Computer Science and Engineering, National Taiwan Ocean University, Keelung, Taiwan.
Tun-Wen
TW
Pai
Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan ; Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan.
Hsin-Fu
HF
Liu
Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan.
Han-Jia
HJ
Lin
Computational Cell Biology Group, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona, Spain.
Ildeofonso
I
Cases
Computational Cell Biology Group, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona, Spain.
Ana
A
Rojas
Cancer and Iron Group, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona, Spain.
Mayka
M
Sanchez
Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan.
Zong-Ye
ZY
You
Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan.
Ming-Wei
MW
Hsu
D020121:5' Untranslated Regions / Q000235:genetics; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D053898:Biosynthetic Pathways / Q000235:genetics*; D017124:Conserved Sequence / Q000235:genetics; D003851:Deoxyribonucleases / Q000378:metabolism; D019143:Evolution, Molecular; D005091:Exons / Q000235:genetics; D005796:Genes; D006418:Heme / Q000096:biosynthesis*; D007438:Introns / Q000235:genetics; D008969:Molecular Sequence Data; D020218:Response Elements / Q000235:genetics; D012641:Selection, Genetic; D016415:Sequence Alignment
D020121:5' Untranslated Regions; D000596:Amino Acids; D006418:Heme; D003851:Deoxyribonucleases