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Evaluating Functional Annotations of Enzymes Using the Gene Ontology [chapter]

Gemma L. Holliday, Rebecca Davidson, Eyal Akiva, Patricia C. Babbitt
2016 Msphere  
The Gene Ontology (GO) (Ashburner et al., Nat Genet 25(1):25-29, 2000) is a powerful tool in the informatics arsenal of methods for evaluating annotations in a protein dataset. From identifying the nearest well annotated homologue of a protein of interest to predicting where misannotation has occurred to knowing how confi dent you can be in the annotations assigned to those proteins is critical. In this chapter we explore what makes an enzyme unique and how we can use GO to infer aspects of
more » ... ein function based on sequence similarity. These can range from identifi cation of misannotation or other errors in a predicted function to accurate function prediction for an enzyme of entirely unknown function. Although GO annotation applies to any gene products, we focus here a describing our approach for hierarchical classifi cation of enzymes in the Structure-Function Linkage Database (SFLD) (Akiva et al., Nucleic Acids Res 42(Database issue):D521-530, 2014) as a guide for informed utilisation of annotation transfer based on GO terms.
doi:10.1007/978-1-4939-3743-1_9 pmid:27812939 pmcid:PMC5837055 fatcat:3tndsn64ffhrjbz57fftokvyky

Small Molecule Subgraph Detector (SMSD) toolkit

Syed Rahman, Matthew Bashton, Gemma L Holliday, Rainer Schrader, Janet M Thornton
2009 Journal of Cheminformatics  
L. Baldacci for his feedback on the tool. We would like to thank the Chemistry Development Kit (CDK) developers who were prompt in addressing our queries.  ...  Two labeled graphs G q and G t are isomorphic if there is an isomorphism f between them preserving the labels i.e. l(v) = l(f (v)) for all v ∈ V(G q and l(u, v) = l(f (u), f (v)) for all edges u, v ∈ E  ...  A molecular graph G = (V, E, l) consists of a set of vertices V(G) (i.e. atoms in a molecule), a set of edges E(G) (i.e. the bonds in a molecule) and l is a function that maps the union of V and E to natural  ... 
doi:10.1186/1758-2946-1-12 pmid:20298518 pmcid:PMC2820491 fatcat:s4zwn2whrfgabjstrhidpxzcvq

Using Reaction Mechanism to Measure Enzyme Similarity

Noel M. O'Boyle, Gemma L. Holliday, Daniel E. Almonacid, John B.O. Mitchell
2007 Journal of Molecular Biology  
annotated as an "Assisted Keto-Enol Based on the partial reactions given by the SFLD, the families contained in this superfamily are divided by the BC method into 4 sets: (a) galactonate dehydratase, L-fuconate  ... 
doi:10.1016/j.jmb.2007.02.065 pmid:17400244 pmcid:PMC3461574 fatcat:yzx56y2e2raqvlwx4sownabeny

Exploring the Biological and Chemical Complexity of the Ligases

Gemma L. Holliday, Syed Asad Rahman, Nicholas Furnham, Janet M. Thornton
2014 Journal of Molecular Biology  
There are several higher-order MDAs that also perform the N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine synthase (EC function.  ...  Using these structures, it is possible to build a model of the sequence with N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine synthase (EC function (data not shown).  ... 
doi:10.1016/j.jmb.2014.03.008 pmid:24657765 pmcid:PMC4018984 fatcat:okzzvfi425hjlfcp4zxei7luh4

EC-BLAST: a tool to automatically search and compare enzyme reactions

Syed Asad Rahman, Sergio Martinez Cuesta, Nicholas Furnham, Gemma L Holliday, Janet M Thornton
2014 Nature Methods  
We would thank L. Baldacci, F. Fenninger, G. Torrance, S. Choudhary, N. Gopal, and S. T. Williams for their technical contributions. We thank D. Schomburg and C.  ... 
doi:10.1038/nmeth.2803 pmid:24412978 pmcid:PMC4122987 fatcat:gzuingrmjzemfprulo7wvlk4oa

MACiE: exploring the diversity of biochemical reactions

Gemma L. Holliday, Claudia Andreini, Julia D. Fischer, Syed Asad Rahman, Daniel E. Almonacid, Sophie T. Williams, William R. Pearson
2011 Nucleic Acids Research  
D H Q6Q2C2 3.4e-09 34.6 133 F D W - - Q59695 4.7e-09 30.3 267 F S M D H O52866 6.7e-09 28.5 221 W D W - - P26174 0.00017 26.4 276 L  ...  S A D H Q15N09 0.00021 23.7 253 W S L D H The final columns of the table represent the conservation of the catalytic residues, the top line is the residue number in the sequence  ... 
doi:10.1093/nar/gkr799 pmid:22058127 pmcid:PMC3244993 fatcat:byhlceunrncahhkl6jvj2ufohu

Exploring the Evolution of Novel Enzyme Functions within Structurally Defined Protein Superfamilies

Nicholas Furnham, Ian Sillitoe, Gemma L. Holliday, Alison L. Cuff, Roman A. Laskowski, Christine A. Orengo, Janet M. Thornton, Yanay Ofran
2012 PLoS Computational Biology  
scale motions that are quenched upon PPACK binding. TROSY Hahn-echo and relaxation dispersion experiments reveal a large number of residues throughout the protein undergoing temporally correlated ms-ms motions. These include the Na þ -binding loop and the b-strand connecting exosite 1 and the active site, both of which are implicated in allosteric coupling of effector binding sites with the active site. The results show a network of slowly exchanging residues extends through the entire
more » ... bin molecule. 164-Symp Enzyme activity is essential for almost all aspects of life. With completely sequenced genomes, the full complement of enzymes in an organism can be defined, and 3D structures have been determined for many enzyme families. Traditionally each enzyme has been studied individually, but as more enzymes are characterised it is now timely to revisit the molecular basis of catalysis, by comparing different enzymes and their mechanisms, and to consider how complex pathways and networks may have evolved. New approaches to understanding enzymes mechanisms and how enzyme families evolve functional diversity will be described. 1.Martinez Cuesta S, Furnham N, Rahman SA, Sillitoe I, Thornton JM. The evolution of enzyme function in the isomerases.
doi:10.1371/journal.pcbi.1002403 pmid:22396634 pmcid:PMC3291543 fatcat:77jw2t4jjbgarjsgexccje34iy

Origin and Evolution of Protein Fold Designs Inferred from Phylogenomic Analysis of CATH Domain Structures in Proteomes

Syed Abbas Bukhari, Gustavo Caetano-Anollés, Gemma L. Holliday
2013 PLoS Computational Biology  
The spatial arrangements of secondary structures in proteins, irrespective of their connectivity, depict the overall shape and organization of protein domains. These features have been used in the CATH and SCOP classifications to hierarchically partition fold space and define the architectural make up of proteins. Here we use phylogenomic methods and a census of CATH structures in hundreds of genomes to study the origin and diversification of protein architectures (A) and their associated
more » ... gies (T) and superfamilies (H). Phylogenies that describe the evolution of domain structures and proteomes were reconstructed from the structural census and used to generate timelines of domain discovery. Phylogenies of CATH domains at T and H levels of structural abstraction and associated chronologies revealed patterns of reductive evolution, the early rise of Archaea, three epochs in the evolution of the protein world, and patterns of structural sharing between superkingdoms. Phylogenies of proteomes confirmed the early appearance of Archaea. While these findings are in agreement with previous phylogenomic studies based on the SCOP classification, phylogenies unveiled sharing patterns between Archaea and Eukarya that are recent and can explain the canonical bacterial rooting typically recovered from sequence analysis. Phylogenies of CATH domains at A level uncovered general patterns of architectural origin and diversification. The tree of A structures showed that ancient structural designs such as the 3-layer (aba) sandwich (3.40) or the orthogonal bundle (1.10) are comparatively simpler in their makeup and are involved in basic cellular functions. In contrast, modern structural designs such as prisms, propellers, 2-solenoid, super-roll, clam, trefoil and box are not widely distributed and were probably adopted to perform specialized functions. Our timelines therefore uncover a universal tendency towards protein structural complexity that is remarkable. Citation: Bukhari SA, Caetano-Anollés G (2013) Origin and Evolution of Protein Fold Designs Inferred from Phylogenomic Analysis of CATH Domain Structures in Proteomes. PLoS Comput Biol 9(3): e1003009.
doi:10.1371/journal.pcbi.1003009 pmid:23555236 pmcid:PMC3610613 fatcat:ythxoymd5jfxvdea6wzr2ie7sm

A global analysis of function and conservation of catalytic residues in enzymes

António J. M. Ribeiro, Jonathan D. Tyzack, Neera Borkakoti, Gemma L. Holliday, Janet M. Thornton
2019 Journal of Biological Chemistry  
The catalytic residues of an enzyme comprise the amino acids located in the active center responsible for accelerating the enzyme-catalyzed reaction. These residues lower the activation energy of reactions by performing several catalytic functions. Decades of enzymology research has established general themes regarding the roles of specific residues in these catalytic reactions, but it has been more difficult to explore these roles in a more systematic way. Here, we review the data on the
more » ... tic residues of 648 enzymes, as annotated in the Mechanism and Catalytic Site Atlas (M-CSA), and compare our results with those in previous studies. We structured this analysis around three key properties of the catalytic residues: amino acid type, catalytic function, and sequence conservation in homologous proteins. As expected, we observed that catalysis is mostly accomplished by a small set of residues performing a limited number of catalytic functions. Catalytic residues are typically highly conserved, but to a smaller degree in homologues that perform different reactions or are nonenzymes (pseudoenzymes). Cross-analysis yielded further insights revealing which residues perform particular functions and how often. We obtained more detailed specificity rules for certain functions by identifying the chemical group upon which the residue acts. Finally, we show the mutation tolerance of the catalytic residues based on their roles. The characterization of the catalytic residues, their functions, and conservation, as presented here, is key to understanding the impact of mutations in evolution, disease, and enzyme design. The tools developed for this analysis are available at the M-CSA website and allow for user specific analysis of the same data.
doi:10.1074/jbc.rev119.006289 pmid:31796628 pmcid:PMC6956550 fatcat:umxyfl7xvzbkngv6nuwrvghboy

Reaction Decoder Tool (RDT): extracting features from chemical reactions

Syed Asad Rahman, Gilliean Torrance, Lorenzo Baldacci, Sergio Martínez Cuesta, Franz Fenninger, Nimish Gopal, Saket Choudhary, John W. May, Gemma L. Holliday, Christoph Steinbeck, Janet M. Thornton
2016 Bioinformatics  
., 2014) , FunTree (Sillitoe and Furnham, 2016) , MACiE (Holliday et al., 2012) etc. use RDT in the background to mine and extract chemical information from thousands of enzyme reactions.  ... 
doi:10.1093/bioinformatics/btw096 pmid:27153692 pmcid:PMC4920114 fatcat:dkglyqt6zzaw7mrtk2ylndhfvq

The Catalytic Site Atlas 2.0: cataloging catalytic sites and residues identified in enzymes

Nicholas Furnham, Gemma L. Holliday, Tjaart A. P. de Beer, Julius O. B. Jacobsen, William R. Pearson, Janet M. Thornton
2013 Nucleic Acids Research  
Understanding which are the catalytic residues in an enzyme and what function they perform is crucial to many biology studies, particularly those leading to new therapeutics and enzyme design. The original version of the Catalytic Site Atlas (CSA) ( published in 2004, which catalogs the residues involved in enzyme catalysis in experimentally determined protein structures, had only 177 curated entries and employed a simplistic approach to expanding
more » ... these annotations to homologous enzyme structures. Here we present a new version of the CSA (CSA 2.0), which greatly expands the number of both curated (968) and automatically annotated catalytic sites in enzyme structures, utilizing a new method for annotation transfer. The curated entries are used, along with the variation in residue type from the sequence comparison, to generate 3D templates of the catalytic sites, which in turn can be used to find catalytic sites in new structures. To ease the transfer of CSA annotations to other resources a new ontology has been developed: the Enzyme Mechanism Ontology, which has permitted the transfer of annotations to Mechanism, Annotation and Classification in Enzymes (MACiE) and UniProt Knowledge Base (UniProtKB) resources. The CSA database schema has been re-designed and both the CSA data and search capabilities are presented in a new modern web interface.
doi:10.1093/nar/gkt1243 pmid:24319146 pmcid:PMC3964973 fatcat:jb465gitcjdgxkrr3lw3drfa6m

Characterizing the complexity of enzymes on the basis of their mechanisms and structures with a bio-computational analysis

Gemma L. Holliday, Julia D. Fischer, John B. O. Mitchell, Janet M. Thornton
2011 The FEBS Journal  
For example, in glutamine-fructose-6-phosphate transaminase (EC, M0082), the first part of the reaction (the conversion of l-glutamine to l-glutamate and ammonia) is performed in one domain (CATH  ...  These proteins are formed from a pool of the 20 standard amino acids plus the rarer selenocysteine and l-pyrrolysine, which are encoded in the genetic code of life.  ... 
doi:10.1111/j.1742-4658.2011.08190.x pmid:21605342 pmcid:PMC3258480 fatcat:gwyfpzuedzfj7ls7rdxu75eyqq

A strategy for large-scale comparison of evolutionary- and reaction-based classifications of enzyme function

Gemma L Holliday, Shoshana D Brown, David Mischel, Benjamin J Polacco, Patricia C Babbitt
2020 Database: The Journal of Biological Databases and Curation  
Determining the molecular function of enzymes discovered by genome sequencing represents a primary foundation for understanding many aspects of biology. Historically, classification of enzyme reactions has used the enzyme nomenclature system developed to describe the overall reactions performed by biochemically characterized enzymes, irrespective of their associated sequences. In contrast, functional classification and assignment for the millions of protein sequences of unknown function now
more » ... lable is largely done in two computational steps, first by similarity-based assignment of newly obtained sequences to homologous groups, followed by transferring to them the known functions of similar biochemically characterized homologs. Due to the fundamental differences in their etiologies and practice, 'how' these chemistry- and evolution-centric functional classification systems relate to each other has been difficult to explore on a large scale. To investigate this issue in a new way, we integrated two published ontologies that had previously described each of these classification systems independently. The resulting infrastructure was then used to compare the functional assignments obtained from each classification system for the well-studied and functionally diverse enolase superfamily. Mapping these function assignments to protein structure and reaction similarity networks shows a profound and complex disconnect between the homology- and chemistry-based classification systems. This conclusion mirrors previous observations suggesting that except for closely related sequences, facile annotation transfer from small numbers of characterized enzymes to the huge number uncharacterized homologs to which they are related is problematic. Our extension of these comparisons to large enzyme superfamilies in a computationally intelligent manner provides a foundation for new directions in protein function prediction for the huge proportion of sequences of unknown function represented in major databases. Interactive sequence, reaction, substrate and product similarity networks computed for this work for the enolase and two other superfamilies are freely available for download from the Structure Function Linkage Database Archive (
doi:10.1093/database/baaa034 pmid:32449511 fatcat:fnfgcszyqjfttb7ulzllwir2am

Mechanism and Catalytic Site Atlas (M-CSA): a database of enzyme reaction mechanisms and active sites

António J M Ribeiro, Gemma L Holliday, Nicholas Furnham, Jonathan D Tyzack, Katherine Ferris, Janet M Thornton
2017 Nucleic Acids Research  
M-CSA (Mechanism and Catalytic Site Atlas) is a database of enzyme active sites and reaction mechanisms that can be accessed at thornton-srv/m-csa. Our objectives with M-CSA are to provide an open data resource for the community to browse known enzyme reaction mechanisms and catalytic sites, and to use the dataset to understand enzyme function and evolution. M-CSA results from the merging of two existing databases, MACiE (Mechanism, Annotation and Classification in Enzymes), a
more » ... abase of enzyme mechanisms, and CSA (Catalytic Site Atlas), a database of catalytic sites of enzymes. We are releasing M-CSA as a new website and underlying database architecture. At the moment, M-CSA contains 961 entries, 423 of these with detailed mechanism information, and 538 with information on the catalytic site residues only. In total, these cover 81% (195/241) of third level EC numbers with a PDB structure, and 30% (840/2793) of fourth level EC numbers with a PDB structure, out of 6028 in total. By searching for close homologues, we are able to extend M-CSA coverage of PDB and UniProtKB to 51 993 structures and to over five million sequences, respectively, of which about 40% and 30% have a conserved active site.
doi:10.1093/nar/gkx1012 pmid:29106569 pmcid:PMC5753290 fatcat:sep5alggufdb7msnnlsx47dlmq

[FeFe]-Hydrogenase Maturation: Insights into the Role HydE Plays in Dithiomethylamine Biosynthesis

Jeremiah N. Betz, Nicholas W. Boswell, Corey J. Fugate, Gemma L. Holliday, Eyal Akiva, Anna G. Scott, Patricia C. Babbitt, John W. Peters, Eric M. Shepard, Joan B. Broderick
2015 Biochemistry  
Electron paramagnetic resonance and UV-visible spectroscopic studies demonstrate that reconstituted HydE binds two [4Fe-4S] clusters and copurifies with S-adenosyl-L-methionine.  ...  Incorporation of deuterium from D 2 O into 5'-deoxyadenosine, the cleavage product of S-adenosyl-L-methionine, coupled with molecular docking experiments suggests that the HydE substrate contains a thiol  ...  Similar experiments were carried out with L-Ser, L-Ala, D-Cys, and L-homocysteine (L-Hcy) in D 2 O, and revealed the importance of the thiol functionality.  ... 
doi:10.1021/bi501205e pmid:25654171 pmcid:PMC4839199 fatcat:mi7g4kshw5chrna6hjjjwrtbta
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