{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:45:58Z","timestamp":1790829958667,"version":"4.1.0"},"reference-count":70,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2019,3,8]],"date-time":"2019-03-08T00:00:00Z","timestamp":1552003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Office of Fisheries Supervision and Management for the Yangtze River Basin, MARA, PRC","award":["171821301354051046"],"award-info":[{"award-number":["171821301354051046"]}]},{"name":"Yunnan Innovation and Enhancement Program of Provincial Science and Technology Department","award":["2016AB024"],"award-info":[{"award-number":["2016AB024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Serotonin is a neurotransmitter involved in various physiological processes in the central and peripheral nervous systems. Serotonin is also a precursor for melatonin biosynthesis, which mainly occurs in the pineal gland of vertebrates. Tryptophan hydroxylase (TPH) acts as the rate-limiting enzyme in serotonin biosynthesis and is the initial enzyme involved in the synthesis of melatonin. Recently, two enzymes\u2014TPH1 and TPH2\u2014were reported to form the TPH family in vertebrates and to play divergent roles in serotonergic systems. Here, we examined the evolution of the TPH family from 70 vertebrate genomes. Based on the sequence similarity, we extracted 184 predicted tph homologs in the examined vertebrates. A phylogenetic tree, constructed on the basis of these protein sequences, indicated that tph genes could be divided into two main clades (tph1 and tph2), and that the two clades were further split into two subgroups of tetrapods and Actinopterygii. In tetrapods, and some basal non-teleost ray-finned fishes, only two tph isotypes exist. Notably, tph1 in most teleosts that had undergone the teleost-specific genome duplication could be further divided into tph1a and tph1b. Moreover, protein sequence comparisons indicated that TPH protein changes among vertebrates were concentrated at the NH2-terminal. The tertiary structures of TPH1 and TPH2 revealed obvious differences in the structural elements. Five positively selected sites were characterized in TPH2 compared with TPH1; these sites may reflect the functional divergence in enzyme activity and substrate specificity. In summary, our current work provides novel insights into the evolution of tph genes in vertebrates from a comprehensive genomic perspective.<\/jats:p>","DOI":"10.3390\/genes10030203","type":"journal-article","created":{"date-parts":[[2019,3,8]],"date-time":"2019-03-08T11:21:59Z","timestamp":1552044119000},"page":"203","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Molecular Evolution of Tryptophan Hydroxylases in Vertebrates: A Comparative Genomic Survey"],"prefix":"10.3390","volume":"10","author":[{"given":"Junmin","family":"Xu","sequence":"first","affiliation":[{"name":"School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Li","sequence":"additional","affiliation":[{"name":"BGI-Shenzhen, Shenzhen 518083, China"},{"name":"Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen 518083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunyun","family":"Lv","sequence":"additional","affiliation":[{"name":"Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen 518083, China"},{"name":"BGI Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Bian","sequence":"additional","affiliation":[{"name":"Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen 518083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0136-7387","authenticated-orcid":false,"given":"Xinxin","family":"You","sequence":"additional","affiliation":[{"name":"Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen 518083, China"},{"name":"BGI Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7441-1097","authenticated-orcid":false,"given":"Daiji","family":"Endoh","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Teraoka","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6358-976X","authenticated-orcid":false,"given":"Qiong","family":"Shi","sequence":"additional","affiliation":[{"name":"BGI-Shenzhen, Shenzhen 518083, China"},{"name":"Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen 518083, China"},{"name":"BGI Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S0006-3223(98)00139-5","article-title":"The spectrum of behaviors influenced by serotonin","volume":"44","author":"Lucki","year":"1998","journal-title":"Biol. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1152\/physrev.1992.72.1.165","article-title":"Structure and function of the brain serotonin system","volume":"72","author":"Jacobs","year":"1992","journal-title":"Physiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1073\/pnas.0606722104","article-title":"Maternal serotonin is crucial for murine embryonic development","volume":"104","author":"Fligny","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"32991","DOI":"10.1074\/jbc.M005671200","article-title":"Characterization of the chicken serotonin N-acetyltransferase gene","volume":"275","author":"Chong","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0021-9258(18)81366-7","article-title":"Aromatic l-amino acid decarboxylase","volume":"237","author":"Lovenberg","year":"1962","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1046\/j.1471-4159.1997.68010213.x","article-title":"Avian melatonin synthesis: Photic and circadian regulation of serotonin N-acetyltransferase mRNA in the chicken pineal gland and retina","volume":"68","author":"Bernard","year":"1997","journal-title":"J. Neurochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1016\/S0021-9258(18)61591-1","article-title":"Molecular cloning and nucleotide sequence of cDNA encoding hydroxyindole o-methyltransferase of bovine pineal glands","volume":"262","author":"Ishida","year":"1987","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"15591","DOI":"10.1021\/bi015722x","article-title":"Conformation of the substrate and pterin cofactor bound to human tryptophan hydroxylase. Important role of Phe313 in substrate specificity","volume":"40","author":"McKinney","year":"2001","journal-title":"Biochemistry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1146\/annurev.biochem.68.1.355","article-title":"Tetrahydropterin-dependent amino acid hydroxylases","volume":"68","author":"Fitzpatrick","year":"1999","journal-title":"Annu. Rev. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2208","DOI":"10.1021\/bi992531+","article-title":"Crystal structure and site-specific mutagenesis of pterin-bound human phenylalanine hydroxylase","volume":"39","author":"Erlandsen","year":"2000","journal-title":"Biochemistry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.abb.2010.12.017","article-title":"Tyrosine hydroxylase and regulation of dopamine synthesis","volume":"508","author":"Daubner","year":"2011","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1016\/S0022-2836(02)00560-0","article-title":"Crystal structure of the ternary complex of the catalytic domain of human phenylalanine hydroxylase with tetrahydrobiopterin and 3-(2-thienyl)-l-alanine, and its implications for the mechanism of catalysis and substrate activation","volume":"320","author":"Andersen","year":"2002","journal-title":"J. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1126\/science.1078197","article-title":"Synthesis of serotonin by a second tryptophan hydroxylase isoform","volume":"299","author":"Walther","year":"2003","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/BF02761772","article-title":"Advances in the molecular characterization of tryptophan hydroxylase","volume":"10","author":"Mockus","year":"1998","journal-title":"J. Mol. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1007\/s00429-012-0412-7","article-title":"The sea lamprey tryptophan hydroxylase: New insight into the evolution of the serotonergic system of vertebrates","volume":"218","author":"Rodicio","year":"2013","journal-title":"Brain Struct. Funct."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.jchemneu.2011.05.009","article-title":"The serotonergic system in fish","volume":"41","author":"Lillesaar","year":"2011","journal-title":"J. Chem. Neuroanat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1101\/gr.640303","article-title":"Genome duplication, a trait shared by 22,000 species of ray-finned fish","volume":"13","author":"Taylor","year":"2003","journal-title":"Genome Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1038\/nature03025","article-title":"Genome duplication in the teleost fish Tetraodon nigroviridis reveals the early vertebrate proto-karyotype","volume":"431","author":"Jaillon","year":"2004","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1093\/genetics\/151.4.1531","article-title":"Preservation of duplicate genes by complementary, degenerative mutations","volume":"151","author":"Force","year":"1999","journal-title":"Genetics"},{"key":"ref_20","first-page":"S215","article-title":"Cloning of two tryptophan hydroxylase genes expressed in the diencephalon of the developing zebrafish brain","volume":"119","author":"Bellipanni","year":"2002","journal-title":"Gene Expr. Patterns"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6855","DOI":"10.1073\/pnas.0500063102","article-title":"Engineering of protease variants exhibiting high catalytic activity and exquisite substrate selectivity","volume":"102","author":"Varadarajan","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1093\/molbev\/msm053","article-title":"Positive selection for single amino acid change promotes substrate discrimination of a plant volatile-producing enzyme","volume":"24","author":"Barkman","year":"2007","journal-title":"Mol. Biol. Evol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/S0169-5347(00)01994-7","article-title":"Statistical methods for detecting molecular adaptation","volume":"15","author":"Yang","year":"2000","journal-title":"Trends Ecol. Evol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1038\/4151022a","article-title":"Adaptive protein evolution in Drosophila","volume":"415","author":"Smith","year":"2002","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5322","DOI":"10.1073\/pnas.97.10.5322","article-title":"Rapid evolution in plant chitinases: Molecular targets of selection in plant-pathogen coevolution","volume":"97","author":"Bishop","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1101\/gr.170720.113","article-title":"Efficient de novo assembly of highly heterozygous genomes from whole-genome shotgun short reads","volume":"24","author":"Kajitani","year":"2014","journal-title":"Genome Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"31900","DOI":"10.1038\/srep31900","article-title":"Dbg2olc: Efficient assembly of large genomes using long erroneous reads of the third generation sequencing technologies","volume":"6","author":"Ye","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Mount, D.W. (2007). Using the basic local alignment search tool (blast). CSH Protoc., 2007.","DOI":"10.1101\/pdb.top17"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Slater, G.S.C., and Birney, E. (2005). Automated generation of heuristics for biological sequence comparison. BMC Bioinform., 6.","DOI":"10.1186\/1471-2105-6-31"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1093\/molbev\/msw054","article-title":"Mega7: Molecular evolutionary genetics analysis version 7.0 for bigger datasets","volume":"33","author":"Kumar","year":"2016","journal-title":"Mol. Biol. Evol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1093\/bioinformatics\/btr088","article-title":"Prottest 3: Fast selection of best-fit models of protein evolution","volume":"27","author":"Darriba","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1080\/10635150390235520","article-title":"A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood","volume":"52","author":"Guindon","year":"2003","journal-title":"Syst. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1093\/sysbio\/sys029","article-title":"Mrbayes 3.2: Efficient bayesian phylogenetic inference and model choice across a large model space","volume":"61","author":"Ronquist","year":"2012","journal-title":"Syst. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Drummond, A.J., and Rambaut, A. (2007). Beast: Bayesian evolutionary analysis by sampling trees. BMC Evol. Biol., 7.","DOI":"10.1186\/1471-2148-7-214"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1093\/bioinformatics\/16.2.135","article-title":"Texshade: Shading and labeling of multiple sequence alignments using latex2e","volume":"16","author":"Beitz","year":"2000","journal-title":"Bioinformatics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1093\/nar\/gkg520","article-title":"SWISS-MODEL: an automated protein homology-modeling server","volume":"31","author":"Schwede","year":"2003","journal-title":"Nucleic. Acids. Res."},{"key":"ref_37","first-page":"82","article-title":"Pymol: An open-source molecular graphics tool","volume":"40","author":"Delano","year":"2002","journal-title":"CCP4 News. On Prot. Crys."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1093\/molbev\/msm088","article-title":"Paml 4: Phylogenetic analysis by maximum likelihood","volume":"24","author":"Yang","year":"2007","journal-title":"Mol. Biol. Evol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1093\/oxfordjournals.molbev.a026236","article-title":"Estimating synonymous and nonsynonymous substitution rates under realistic evolutionary models","volume":"17","author":"Yang","year":"2000","journal-title":"Mol. Biol. Evol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1093\/molbev\/msi097","article-title":"Bayes empirical bayes inference of amino acid sites under positive selection","volume":"22","author":"Yang","year":"2005","journal-title":"Mol. Biol. Evol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"28105","DOI":"10.1074\/jbc.M602817200","article-title":"Functional domains of human tryptophan hydroxylase 2 (htph2)","volume":"281","author":"Flanagan","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1042\/BJ20071033","article-title":"Activation and stabilization of human tryptophan hydroxylase 2 by phosphorylation and 14-3-3 binding","volume":"410","author":"Winge","year":"2008","journal-title":"Biochem. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"24441","DOI":"10.1074\/jbc.M113.456863","article-title":"Structural and functional evolution of positively selected sites in pine glutathione s-transferase enzyme family","volume":"288","author":"Lan","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1101\/gr.101386.109","article-title":"Origins, evolution, and phenotypic impact of new genes","volume":"20","author":"Kaessmann","year":"2010","journal-title":"Genome Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2156-13-15","article-title":"A synthetic rainbow trout linkage map provides new insights into the salmonid whole genome duplication and the conservation of synteny among teleosts","volume":"13","author":"Guyomard","year":"2012","journal-title":"BMC Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1007\/s00438-014-0889-2","article-title":"Whole-genome duplication in teleost fishes and its evolutionary consequences","volume":"289","author":"Glasauer","year":"2014","journal-title":"Mol. Genet. Genom."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1002\/bies.20293","article-title":"From 2r to 3r: Evidence for a fish-specific genome duplication (fsgd)","volume":"27","author":"Meyer","year":"2005","journal-title":"Bioessays"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/nature05846","article-title":"The medaka draft genome and insights into vertebrate genome evolution","volume":"447","author":"Kasahara","year":"2007","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"20132881","DOI":"10.1098\/rspb.2013.2881","article-title":"A well-constrained estimate for the timing of the salmonid whole genome duplication reveals major decoupling from species diversification","volume":"281","author":"Macqueen","year":"2014","journal-title":"Proc. R. Soc. B Biol. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/nature17164","article-title":"The Atlantic salmon genome provides insights into rediploidization","volume":"533","author":"Lien","year":"2016","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1038\/ng.3098","article-title":"Genome sequence and genetic diversity of the common carp, Cyprinus carpio","volume":"46","author":"Xu","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1016\/j.ympev.2006.09.008","article-title":"Age and biogeography of major clades in sturgeons and paddlefishes (pisces: Acipenseriformes)","volume":"42","author":"Peng","year":"2007","journal-title":"Mol. Phylogenet. Evol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Hellsten, U., Khokha, M.K., Grammer, T.C., Harland, R.M., Richardson, P., and Rokhsar, D.S. (2007). Accelerated gene evolution and subfunctionalization in the pseudotetraploid frog Xenopus laevis. BMC Biol., 5.","DOI":"10.1186\/1741-7007-5-31"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1146\/annurev-animal-030117-014821","article-title":"The divergent genomes of teleosts","volume":"6","author":"Ravi","year":"2018","journal-title":"Annu. Rev. Anim. Biosci."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Li, Y., Lv, Y., Bian, C., You, X., Deng, L., and Shi, Q. (2018). A comparative genomic survey provides novel insights into molecular evolution of l-aromatic amino acid decarboxylase in vertebrates. Molecules, 23.","DOI":"10.3390\/molecules23040917"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Li, J., You, X., Bian, C., Yu, H., Coon, S.L., and Shi, Q. (2015). Molecular evolution of aralkylamine N-acetyltransferase in fish: A genomic survey. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17010051"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Zhang, K., Ruan, Z., Li, J., Bian, C., You, X., Coon, S.L., and Shi, Q. (2017). A comparative genomic and transcriptomic survey provides novel insights into N-acetylserotonin methyltransferase (asmt) in fish. Molecules, 22.","DOI":"10.3390\/molecules22101653"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/ng.3526","article-title":"The spotted gar genome illuminates vertebrate evolution and facilitates human-teleost comparisons","volume":"48","author":"Braasch","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1534\/genetics.111.127324","article-title":"Genome evolution and meiotic maps by massively parallel DNA sequencing: Spotted gar, an outgroup for the teleost genome duplication","volume":"188","author":"Amores","year":"2011","journal-title":"Genetics"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Ravi, V., Bhatia, S., Gautier, P., Loosli, F., Tay, B.H., Tay, A., Murdoch, E., Coutinho, P., van Heyningen, V., and Brenner, S. (2013). Sequencing of pax6 loci from the elephant shark reveals a family of pax6 genes in vertebrate genomes, forged by ancient duplications and divergences. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003177"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1038\/nature04607","article-title":"Designed divergent evolution of enzyme function","volume":"440","author":"Yoshikuni","year":"2006","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1093\/molbev\/msp310","article-title":"Positions under positive selection--key for selectivity and potency of scorpion \u03b1-toxins","volume":"27","author":"Weinberger","year":"2009","journal-title":"Mol. Biol. Evol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1002\/anie.198800791","article-title":"Flexibility and rigidity of proteins and protein\u2013pigment complexes","volume":"27","author":"Huber","year":"2010","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"16246","DOI":"10.1073\/pnas.0407066101","article-title":"Evolving protein functional diversity in new genes of drosophila","volume":"101","author":"Zhang","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1053\/j.gastro.2007.05.019","article-title":"Serotonin mediates oxidative stress and mitochondrial toxicity in a murine model of nonalcoholic steatohepatitis","volume":"133","author":"Nocito","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1053\/j.gastro.2004.10.002","article-title":"Autocrine\/paracrine regulation of the growth of the biliary tree by the neuroendocrine hormone serotonin","volume":"128","author":"Marzioni","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1126\/science.1123842","article-title":"Platelet-derived serotonin mediates liver regeneration","volume":"312","author":"Lesurtel","year":"2006","journal-title":"Science"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1002\/hep.21516","article-title":"Platelets and platelet-derived serotonin promote tissue repair after normothermic hepatic ischemia in mice","volume":"45","author":"Nocito","year":"2007","journal-title":"Hepatology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S1470-2045(06)70622-2","article-title":"Use of antidepressants and risk of colorectal cancer: A nested case-control study","volume":"7","author":"Xu","year":"2006","journal-title":"Lancet Oncol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5152","DOI":"10.1158\/0008-5472.CAN-08-0202","article-title":"Serotonin regulates macrophage-mediated angiogenesis in a mouse model of colon cancer allografts","volume":"68","author":"Nocito","year":"2008","journal-title":"Cancer Res."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/10\/3\/203\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:37:26Z","timestamp":1760186246000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/10\/3\/203"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,8]]},"references-count":70,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2019,3]]}},"alternative-id":["genes10030203"],"URL":"https:\/\/doi.org\/10.3390\/genes10030203","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,8]]}}}