SUMMARY: MACiE (mechanism, annotation and classification in enzymes) is a publicly available web-based database, held in CMLReact (an XML application), that aims to help our understanding of the evolution of enzyme catalytic mechanisms and also to create a classification system which reflects the actual chemical mechanism (catalytic steps) of an enzyme reaction, not only the overall reaction. AVAILABILITY: http://www-mitchell.ch.cam.ac.uk/macie/.EPSRC (G.L.H. and J.B.O.M.), the BBSRC (G.J.B. and J.M.T.—CASE studentship in association with Roche Products Ltd; N.M.O.B. and J.B.O.M.—grant BB/C51320X/1), the Chilean Government’s Ministerio de Planificacio´n y Cooperacio´n and
Cambridge Overseas Trust (D.E.A.) for funding and Unilever for supporting the Centre for Molecular Science Informatics.application note restricted to 2 printed pages web site: http://www-mitchell.ch.cam.ac.uk/macie

Bartlett

Berman

D. E. Almonacid

G. J. Bartlett

G. L. Holliday

J. B. O. Mitchell

J. M. Thornton

Kanehisa

N. M. O'Boyle

Nagano

Orengo

P. Murray-Rust

Porter

Schomburg

English

PubMed

MACiE (mechanism, annotation and classification in enzymes) is a publicly available web-based database, held in CMLReact (an XML application), that aims to help our understanding of the evolution of enzyme catalytic mechanisms and also to create a classification system which reflects the actual chemical mechanism (catalytic steps) of an enzyme reaction, not only the overall reaction.</p

Holliday, G L

Bartlett, G J

Almonacid, D E

O'Boyle, N M

Murray-Rust, P

Thornton, J M

Mitchell, John Blayney Owen

University of St. Andrews - Pure

MACiE: a database of enzyme reaction mechanisms

Crossref

University of St Andrews Research Portal

SUMMARY: MACiE (mechanism, annotation and classification in enzymes) is a publicly available web-based database, held in CMLReact (an XML application), that aims to help our understanding of the evolution of enzyme catalytic mechanisms and also to create a classification system which reflects the actual chemical mechanism (catalytic steps) of an enzyme reaction, not only the overall reaction. AVAILABILITY: http://www-mitchell.ch.cam.ac.uk/macie/

Apollo (Cambridge)

Vol. 21 no. 23 2005, pages 4315–4316doi:10.1093/bioinformatics/bti693BIOINFORMATICSAPPLICATIONS NOTEDatabases and ontologiesMACiE: a database of enzyme reaction mechanismsGemma L. Holliday1, Gail J. Bartlett2,†, Daniel E. Almonacid1, Noel M. O’Boyle1,Peter Murray-Rust1, Janet M. Thornton2 and John B. O. Mitchell1,1Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge,Lensfield Road, Cambridge, CB2 1EW, UK and 2EMBL-EBI, Wellcome Trust Genome Campus,Hinxton, Cambridge, CB10 1SD, UKReceived on July 21, 2005; revised on September 22, 2005; accepted on September 23, 2005Advance Access publication September 27, 2005ABSTRACTSummary: MACiE (mechanism, annotation and classification inenzymes) is a publicly available web-based database, held inCMLReact (an XML application), that aims to help our understandingof the evolution of enzyme catalytic mechanisms and also to create aclassification system which reflects the actual chemical mechanism(catalytic steps) of an enzyme reaction, not only the overall reaction.Availability: http://www-mitchell.ch.cam.ac.uk/macie/Contact: jbom1@cam.ac.ukA great deal of knowledge about enzymes, including structures,gene sequences, mechanisms, metabolic pathways and kineticdata, now exists. However, it is spread between many differentdatabases and throughout the literature. Here we announce thecompletion of the initial version of MACiE, a unique database ofthe chemical mechanisms of enzymatic reactions.Web resources such as BRENDA (Schomburg et al., 2004),KEGG (Kanehisa et al., 2004) and the International Union of Bio-chemistry and Molecular Biology (IUBMB) Enzyme Nomenclaturewebsite (IUBMB, 2005, http://www.chem.qmul.ac.uk/iubmb/enzyme/) contain descriptions of the overall reactions performedby enzymes, accompanied in some cases by a textual or graphicaldescription of the mechansim. MACiE is unique in combiningdetailed stepwise mechanistic information (including 2D anima-tions), a wide coverage of both chemical space and the proteinstructure universe, and the chemical intelligence of CMLReact(Holliday,C.L., Murray-Rust,P., and Rzepa,H.S., 2005, manuscriptsubmitted to J. Chem. Inf. Modeling). MACiE usefully complementsboth the mechanistic detail of the Structure–Function LinkageDatabase (SFLD) for a small number of enzyme superfamilies(Pegg et al., 2005) and the wider coverage with less chemicaldetail provided by EzCatDB (Nagano, 2005) which also containsa limited number of 3D animations.DESIGNThe MACiE dataset evolved from that published in the CatalyticSite Atlas (CSA) (Bartlett et al., 2002; Porter et al., 2004), and eachentry is selected so that it fulfils the following criteria:(1) There is a 3D crystal structure of the enzyme deposited in theProtein Databank (PDB) (Berman et al., 2000).(2) There is a relatively well-understood mechanism available.Taken from the literature, these cover a variety ofmethodologies, including chemical and biochemical studies,quantum mechanical calculations and structual biologyreports.(3) The enzyme is unique at the H level of the CATHclassification—a hierarchical classification system ofprotein domain structures (Orengo et al., 1997)—unlessthere is a homologue with a significantly different chemicalmechanism.(4) Where there are a number of possible PDB codes availablethe entry should be, if possible, a wild-type enzyme.All MACiE enzymes are also contained in the Enzyme Commis-sion (EC) classification system (IUBMB, 2005, http://www.chem.qmul.ac.uk/iubmb/enzyme/), that is, they all have four number codesdescribing their overall reaction. The first level (Class) describesthe basic reaction type. The second and third levels (subclass andsub-subclass, respectively) describe the reaction in further detailand the final level (serial number) describes substrate specificity.For example, the b-lactamases (Fig. 1) are assigned the EC number3.5.2.6, i.e. a hydrolase (3) acting on a C–N bond (5) in a cyclicamide (2) with a b-lactam as the substrate (6).In MACiE, the data centre on the catalytic steps involved in thechemical mechanism as well as the overall reaction. Each entryincludes the following steps: Enzyme name and EC number PDB code and CATH codes of all domains in the enzyme Diagram and annotation of the overall reaction Primary literature referencesTo whom correspondence should be addressed.†Present Address: Bioinformatics Support Service (Biochemistry Building),Centre for Bioinformatics, Division of Molecular Biosciences, Faculty ofLife Sciences, Imperial College London, London, SW7 2AZ, UK The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.orgThe online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open accessversion of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford UniversityPress are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in itsentirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org Diagram and annotation of all reaction steps, including:—The Ingold mechanism (Ingold, 1969)—Diagram and function of catalytic amino acid residues—Information on the reactive centres and bond changes Comments on the reaction (where applicable).CONTENTThe criteria defined in the Design section initially produced adataset of 100 entries. A single EC number may cover a pluralityof MACiE entries when different mechanisms bring about thesame overall chemical transformation, as with the two types of3-dehydroquinate dehydratase, and thus 100 MACiE entries spanonly 96 EC numbers.The 100 enzymes in Version 1 of MACiE incorporate domainsfrom 140 CATH homologous superfamilies. MACiE currently cov-ers 56 of the 174 EC sub-subclasses present in the PDB, thus, wefeel that we have a representative coverage of EC reaction space(comparative EC wheels are available at URL http://www-mitchell.ch.cam.ac.uk/macie/ECCoverage/). We anticipate that all 158 sub-subclasses for which both structures and reliable mechanisms areavailable will be represented in the forthcoming MACiE Version 2.SOFTWAREThe data are initially entered in MDL’s ISIS/Base, a database pack-age for chemical reactions, validated by at least two people, andthen converted into CMLReact using the Jumbo Toolkit (Wakelinet al., 2005) to create an information and semantically rich database.At this stage we add extra fields of information to the CMLReactversion of MACiE that are unavailable in the ISIS version,including the CATH code. Jumbo is a set of Java-based softwarewhich converts the MDL file format produced from ISIS/Base intoCMLReact. The MacieConverter section of Jumbo performs thefollowing functions: Integration of the files in the ISIS/Base version of MACiE Identification of reactant, product and spectator molecules Splitting of groups of molecules Automatic mapping of atoms within the reaction Checking for mass and charge conservation throughout the reac-tion (stoichiometry) Integration and checking of MACiE Dictionary entries.Once the conversion process has been completed, a further tool inthe Jumbo Toolkit, called CMLSnap (Holliday et al., 2004), canbe used to create an animation of the reaction. This animationincludes all of the atoms and bonds involved as well as the electronmovements, which are calculated automatically. It is expected thatCML will become our primary method of data entry and storage.CURATIONThe annotation process involves input and validation steps. Termshave been rigorously defined either from the IUPAC Gold Book(McNaught et al., 1997), such as chemical terms like hydrolysis, orfrom primary literature, such as mechanism, which is defined usingIngold’s terminology (Ingold, 1969), originally put forward in the1930s. All of the technical and scientific terms used in MACiE arecontained in the MACiE dictionary, which is available at the URLhttp://www-mitchell.ch.cam.ac.uk/macie/glossary.html and is alsoavailable as a raw XML file.The entries online are accessed via an HTML look-up table andinclude all of the information available in the database. The originalISIS/Base format file and the raw CML files can be supplied.FUTURE WORKFuture work includes expanding the dataset to include a representat-ive set of EC numbers (at the sub-subclass level), creating a searchinterface for MACiE and developing authoring tools for MACiEin CML. Ongoing research focuses on the evolution of enzymecatalysis and the classification of enzyme reaction mechanisms.ACKNOWLEDGEMENTSG.J.B. would like to thank Dr Jonathan Goodman for his invaluablehelp with organic chemistry queries. We would also like tothank the EPSRC (G.L.H. and J.B.O.M.), the BBSRC (G.J.B. andJ.M.T.—CASE studentship in association with Roche ProductsLtd; N.M.O.B. and J.B.O.M.—grant BB/C51320X/1), the ChileanGovernment’s Ministerio de Planificación y Cooperación andCambridge Overseas Trust (D.E.A.) for funding and Unilever forsupporting the Centre for Molecular Science Informatics.Conflict of Interest: none declared.REFERENCESBartlett,G.J. et al. (2002) Analysis of catalytic residues in enzyme active sites.J. Mol. Biol., 324, 105–121.Berman,H.M. et al. (2000) The Protein Data Bank. Nucleic Acids Res., 28, 235–242.Holliday,G.L. et al. (2004) CMLSnap: animated reaction mechanisms. InternetJ. Chem., 7, Article 4.Ingold,C.K. (1969) Structure and Mechanism in Organic Chemistry. 2nd edn, CornellUniversity Press, Ithaca, NY, Chapters 5–15.Kanehisa,M. et al. (2004) The KEGG resource for deciphering the genome. NucleicAcids Res., 32, D277–D280.McNaught,A.D. and Wilkinson,A. (1997) International Union of Pure and AppliedChemistry Compendium of Chemical Terminology (‘‘The Gold Book’’). 2nd edn,ISBN 0-8-654-26848.Nagano,N. (2005) EzCatDB: the Enzyme Catalytic-mechanism Database. NucleicAcids Res., 33, D407–D412.Orengo,C.A. et al. (1997) CATH—a hierarchic classification of protein domainstructures. Structure, 5, 1093–1108.Pegg,S.C-H. et al. (2005) Representing structure-function relationships in mechanis-tically diverse enzyme superfamilies. Pac. Symp. Biocomput., 358–369.Porter,C.T. et al. (2004) The Catalytic Site Atlas: a resource of catalytic sites andresidues identified in enzymes using structural data. Nucleic Acids Res., 32,D129–D133.Schomburg,I. et al. (2004) BRENDA, the enzyme database: updates and major newdevelopments. Nucleic Acids Res., 32, D431–D433.Wakelin,J. et al. (2005) CML tools and information flow in atomic scale simulations.Mol. Simul., 31, 315–322.OHHNOR R'R''NO OHHR''R R'+Fig. 1. The overall reaction for a b-lactamase.G.L.Holliday et al.4316

Analysis of catalytic residues in enzyme active sites.

BRENDA, the enzyme database: updates and major new developments.

CATH—a hierarchic classiﬁcation of protein domain structures.

CML tools and information ﬂow in atomic scale simulations.

CMLSnap: animated reaction mechanisms.

EzCatDB: the Enzyme Catalytic-mechanism Database.

Representing structure-function relationships in mechanistically diverse enzyme superfamilies.

Structure and Mechanism in Organic Chemistry. 2nd edn,

The Catalytic Site Atlas: a resource of catalytic sites and residues identiﬁed in enzymes using structural data.

The KEGG resource for deciphering the genome.

The Protein Data Bank.

MACiE: a database of enzyme reaction mechanisms.

http://dx.doi.org/10.1093/bioinformatics/bti693

MACiE: a database of enzyme reaction mechanisms.

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