Abstract
The goal of our research is to increase our understanding of how biology works at the molecular level, with a particular focus on how enzymes evolve their functions through adaptations to generate new specificities and mechanisms. FunTree (Sillitoe and Furnham, Nucleic Acids Res 44:D317–D323, 2016) is a resource that brings together sequence, structure, phylogenetic, and chemical and mechanistic information for 2340 CATH superfamilies (Sillitoe et al., Nucleic Acids Res 43:D376–D381, 2015) (which all contain at least one enzyme) to allow evolution to be investigated within a structurally defined superfamily.
We will give an overview of FunTree’s use of sequence and structural alignments to cluster proteins within a superfamily into structurally similar groups (SSGs) and generate phylogenetic trees augmented by ancestral character estimations (ACE). This core information is supplemented with new measures of functional similarity (Rahman et al., Nat Methods 11:171–174, 2014) to compare enzyme reactions based on overall bond changes, reaction centers (the local environment atoms involved in the reaction), and the structural similarities of the metabolites involved in the reaction. These trees are also decorated with taxonomic and Enzyme Commission (EC) code and GO annotations, forming the basis of a comprehensive web interface that can be found at http://www.funtree.info. In this chapter, we will discuss the various analyses and supporting computational tools in more detail, describing the steps required to extract information.
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References
Sillitoe I, Furnham N (2016) FunTree: advances in a resource for exploring and contextualising protein function evolution. Nucleic Acids Res 44:D317–D323. https://doi.org/10.1093/nar/gkv1274
Sillitoe I, Lewis TE, Cuff A et al (2015) CATH: comprehensive structural and functional annotations for genome sequences. Nucleic Acids Res 43:D376–D381. https://doi.org/10.1093/nar/gku947
Rahman SA, Cuesta SM, Furnham N et al (2014) EC-BLAST: a tool to automatically search and compare enzyme reactions. Nat Methods 11:171–174. https://doi.org/10.1038/nmeth.2803
Ruan J, Li H, Chen Z et al (2007) TreeFam: 2008 update. Nucleic Acids Res 36:D735–D740. https://doi.org/10.1093/nar/gkm1005
Bostock M (2017) https://d3js.org
Tamuri AU, Laskowski RA (2010) ArchSchema: a tool for interactive graphing of related Pfam domain architectures. Bioinformatics 26:1260–1261. https://doi.org/10.1093/bioinformatics/btq119
Uniprot Consortium (2009) The universal protein resource (UniProt) 2009. Nucleic Acids Res 37:D169–D174. https://doi.org/10.1093/nar/gkn664
Valdar WSJ (2002) Scoring residue conservation. Proteins Struct Funct Genet 48:227–241. https://doi.org/10.1002/prot.10146
Gutmanas A, Alhroub Y, Battle GM et al (2014) PDBe: Protein Data Bank in Europe. Nucleic Acids Res 42:D285–D291. https://doi.org/10.1093/nar/gkt1180
Suzuki R, Shimodaira H (2006) Pvclust: an R package for assessing the uncertainty in hierarchical clustering. Bioinformatics 22:1540–1542. https://doi.org/10.1093/bioinformatics/btl117
Rahman S, Bashton M, Holliday GL et al (2009) Small Molecule Subgraph Detector (SMSD) toolkit. J Cheminform 1:12. https://doi.org/10.1186/1758-2946-1-12
Yachdav G, Goldberg T, Wilzbach S et al (2015) Anatomy of BioJS, an open source community for the life sciences. elife 4:e07009. https://doi.org/10.7554/eLife.07009
Ribeiro AJM, Holliday GL, Furnham N et al (2018) Mechanism and Catalytic Site Atlas (M-CSA): a database of enzyme reaction mechanisms and active sites. Nucleic Acids Res 46(D1):D618–D623
Furnham N, Dawson NL, Rahman SA et al (2016) Large-scale analysis exploring evolution of catalytic machineries and mechanisms in enzyme superfamilies. J Mol Biol 428:253–267. https://doi.org/10.1016/j.jmb.2015.11.010
Tyzack JD, Furnham N, Sillitoe I et al (2017) Understanding enzyme function evolution from a computational perspective. Curr Opin Struct Biol 47:131–139. https://doi.org/10.1016/j.sbi.2017.08.003
Furnham N, Sillitoe I, Holliday GL et al (2012) Exploring the evolution of novel enzyme functions within structurally defined protein superfamilies. PLoS Comput Biol 8:e1002403. https://doi.org/10.1371/journal.pcbi.1002403
Holliday GL, Bartlett GJ, Almonacid DE et al (2005) MACiE: a database of enzyme reaction mechanisms. Bioinformatics 21:4315–4316. https://doi.org/10.1093/bioinformatics/bti693
Furnham N, Holliday GL, de Beer TAP et al (2014) The catalytic site atlas 2.0: cataloging catalytic sites and residues identified in enzymes. Nucleic Acids Res 42:D485–D489. https://doi.org/10.1093/nar/gkt1243
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Tyzack, J.D., Furnham, N., Sillitoe, I., Orengo, C.M., Thornton, J.M. (2019). Exploring Enzyme Evolution from Changes in Sequence, Structure, and Function. In: Sikosek, T. (eds) Computational Methods in Protein Evolution. Methods in Molecular Biology, vol 1851. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8736-8_14
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DOI: https://doi.org/10.1007/978-1-4939-8736-8_14
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