Open chemical dictionaries and ontologies for biosciences

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Open chemical dictionaries and ontologies for
biosciences
Kirill Degtyarenko, EMBL-EBI
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The team

• Rafael Alcántara
• Michael Ashburner
• Volker Ast
• Sergio Contrino
• Michael Darsow
• Paula de Matos
• Marcus Ennis
• Janna Hastings
• Alan McNaught
• Martin Zbinden

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Thanks

• EU funding
• Tamara Kulikova photo

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What is EBI ?
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EMBL-EBIThe European Bioinformatics Institute

• We develop and provide
• EMBL Nucleotide Sequence Database
• UniProt (Swiss-Prot/TrEMBL/PIR)
• InterPro
• Macromolecular Structure Database
• ENSEMBL
• ArrayExpress

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EMBL-EBIThe European Bioinformatics Institute

• Is also home to
• Gene Ontology editorial office http//www.geneonto
  logy.org/

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What is an ontology?
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What is an ontology?
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Ontology definitions

• Ontology the theory or study of being as such
  i.e., of the basic characteristics of all reality
  (Encyclopædia Britannica)
• Ontology or the science of something and of
  nothing, of being and not-being, of the thing and
  the mode of the thing, of substance and accident
  (Gottfried Wilhelm Leibniz)
• Ontology A formal definition of concepts
  (entities, relationships) of a given area of
  knowledge, described in a standardized form
  (Carugo Pongor, 2002)
• An ontology is a specification of a
  conceptualization (Tom Gruber)
• More cracking definitions from http//www.formalon
  tology.it/ !

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Working definition
Ontology an explicit specification of some
topic which includes a vocabulary of terms
(names) with defined logical relationships to
each other. Jane Lomax, EBI
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NCBI Taxonomy
Eukaryota Metazoa Chordata Craniata
Vertebrata Euteleostomi Archosauria
Aves Neognathae
Passeriformes Hirundinidae
Hirundo Hirundo rustica
Phylum ? Subphylum ?
Class ? Order ?
Family ? Genus ? Species ?
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Enzyme Taxonomy
EC 2 Transferases EC 2.8 Transferring
sulfur-containing groups EC 2.8.2
Sulfotransferases EC 2.8.2.25 Flavonol
3-sulfotransferase
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OBO
Open Biomedical Ontologies is an umbrella web
address for well-structured controlled
vocabularies for shared use across different
biological and medical domains http//obo.source
forge.net/
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ChEBI What is it?
Chemical Entities of Biological Interest an
EBI database/dictionary of biochemical compounds
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What are the biochemical compounds?
Can be defined as consisting of molecules not
directly encoded by the genome ... that are
either the products of nature or are synthetic
products used ... to intervene in the processes
of living organisms Michael Ashburner
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Molecular entity
Any constitutionally or isotopically distinct
atom, molecule, ion, ion pair, radical, radical
ion, complex, conformer etc., identifiable as a
separately distinguishable entity IUPAC Gold
Book
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In fact, ChEBI contains

• Molecular entities
• trans-vaccenic acid
• Groups
• trans-vaccenoyl group
• Classes
• fatty acids

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Small molecules?

• Yes, but big molecules as well!
• alumina
• amylose
• metaborate
• poly(vinyl alcohol)

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1-D ChEBI

• Numeric ID
• Carefully checked terminology
• Unambiguous ChEBI name
• IUPAC names
• Cross-references to free resources

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Unambiguous ChEBI name

• CHEBI28918
• L-adrenaline
• not just adrenaline

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IUPAC name

• 4-(1R)-1-hydroxy-2-(methylamino)ethylbenzene-1,
  2-diol

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The Unpronounceables
CHEBI32902 gibberellin A4
IUPAC name (1R,2R,5R,8R,9S,10R,11S,12S)-12-hydr
oxy-11-methyl-6-methylidene-16-oxo-15-oxapentacycl
o9.3.2.15,8.01,10.02,8heptadecane-9-carboxylic
acid
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Need for 2-D

• Better to see the face than to hear the name
  (Zen proverb)
• Structures and identifiers based on structures
  offer new ways of crosslinking to other databases
• Our users desperately want it!

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Connection table
ChEBI 9 10 0 0 0 0 999 V2000
11.8219 -7.2713 0.0000 C 0 0 0 0 0 0
0 0 0 0 0 0 11.8219 -8.0922 0.0000 C
0 0 0 0 0 0 0 0 0 0 0 0 12.6074
-7.0165 0.0000 N 0 0 0 0 0 0 0 0 0
0 0 0 11.1072 -6.8574 0.0000 C 0 0
0 0 0 0 0 0 0 0 0 0 12.6039 -8.3505
0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0
11.1072 -8.5027 0.0000 N 0 0 0 0 0
0 0 0 0 0 0 0 13.0886 -7.6818
0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0
10.3923 -7.2713 0.0000 N 0 0 0 0 0 0
0 0 0 0 0 0 10.3888 -8.0922 0.0000 C
0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 0
0 0 0 1 3 1 0 0 0 0 1 4 1 0 0 0
0 2 5 1 0 0 0 0 2 6 1 0 0 0 0
3 7 1 0 0 0 0 4 8 2 0 0 0 0 6 9
2 0 0 0 0 5 7 2 0 0 0 0 8 9 1 0
0 0 0 M END
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2-D ChEBI

• One or more 2-D (or 3-D) connection tables
• One is default
• Autogenerated images (PNG)
• Default diagrams should be unambiguous

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Art of chemical drawing
(R)-camphor
ambiguous
unambiguous
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From 2-D back to 1-D

• SMILES
• InChI

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SMILES (1)

• Simplified Molecular Input Line Entry
  Specification
• Developed by David Weininger in 1988
• Extended by others (e.g. Daylight)
• String of standard ASCII characters
• A number of valid SMILES can be produced for the
  same molecule

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SMILES (2)

• N1CNC2C1CNCN2
• c1ncc2ncnc2n1
• C1N\CN/C\2N/CN\C1/2
• c1ncnc2/NC\Nc12
• n1cc2c(nc1)ncn2
• Hc1nc(H)c2n(H)c(H)nc2n1

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InChI (1)

• IUPAC International Chemical Identifier or InChI
• Open source
• Developed by Stein, Heller, Tchekhovskoi and
  McNaught
• Used by NIST, PubChem, CML and ChEBI

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InChI (2)
InChI1/C5H4N4/c1-4-5(8-2-6-1)9-3-7-4/h1-3H,(H,6,7
,8,9)
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Limitations (1)

• Stereochemistry other than sp3 tetrahedral and
  sp2 trigonal planar
• Polymers
• Conformers
• Radicals/different spin state
• Topological isomers
• Mixtures
• Markush structures

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Limitations (2)
cisplatin
transplatin
InChI1/2ClH.2H3N.Pt/h21H21H3/q2/p-2
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3-D ChEBI
cisplatin
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ChEBI ontology

• Molecular structure ontology
• Subatomic particle ontology
• Biological role ontology
• Application ontology

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L-adrenaline

• Molecular structure ontology
• catecholamines
• Biological role ontology
• hormone
• Application ontology
• antiglaucoma
• bronchodilator
• cardiostimulant

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The family relations
L-cystein-S-yl
L-cysteine()
L-cysteine zwitterion
cysteine
D-cysteine
L-cysteino
L-cysteine
L-cysteinium
L-cysteinyl
L-cysteinate(1)
L-cysteine residue
L-cysteinate(2)
L-cysteinate residue
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Relationships in ChEBI
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Is A relationship
?
L-cysteine
cysteine
is a
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Is Enantiomer Of
?
L-cysteine
D-cysteine
is enantiomer of
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Is Tautomer Of
L-cysteine
L-cysteine zwitterion
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Is Conjugate Acid Of
L-cysteinium
L-cysteinate(2)
L-cysteine
L-cysteinate(1)
is conjugate acid of
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Is Conjugate Base Of
L-cysteinium
L-cysteinate(2)
L-cysteine
L-cysteinate(1)
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Acid/base relationships
L-cysteinium
L-cysteinate(2)
?
?
L-cysteine
L-cysteinate(1)
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Is Part Of
?
L-cysteinium
L-cysteine hydrochloride
is part of
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Is Substituent Group From
L-cysteine


L-cysteinyl
L-cysteino


L-cysteine residue
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Has Parent Hydride
is parent hydride of
H
benzene
1,2,3-trichlorobenzene
has parent hydride
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Has Functional Parent
is functional parent of
F
L-cysteine
S-(4-bromophenyl)-L-cysteine
has functional parent
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The family relations
L-cysteine()
L-cysteinium
L-cystein-S-yl
cysteine
L-cysteine zwitterion
L-cysteine
D-cysteine
L-cysteino
L-cysteinyl
L-cysteinate(1)
L-cysteine residue
L-cysteinate(2)
L-cysteinate residue
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Ontology of L-cysteine
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Ontology of L-cysteine (1)
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Ontology of L-cysteine (2)
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Current status (25.04.07)
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Users of ChEBI

• ArrayExpress
• BIND
• BioModels
• ChemIDplus
• Human Metabolite Database
• KEGG COMPOUND
• Reactome
• Industry (Chenomx, Lion, etc.)

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http//www.ebi.ac.uk/come/

• Italian word come (how)
• English word come (not GO)
• Classification Of Metalloproteins
• COfactors and Metals
• COMplex proteins, etc.
• Co-Ordination of Metals in proteins
• Contrino and me

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COMe version 5.1

• Controlled vocabulary
• 1376 protein classes (PRX)
• 524 bioinorganic motifs (BIM)
• 179 small molecules (MOL)
• organised as
• XML version (master)
• Oracle version

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COMe top of hierarchy
Complex proteins belong to at least one of three
groups

• Metalloprotein
• Organic prosthetic group protein
• Modified amino acid protein

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COMe entry PRX000552
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Path to PRX000552
   complex protein  PRX000001 includes  
?  metalloprotein  PRX000002 includes     ?
 iron protein  PRX000004 includes       ?
 iron-sulphur protein  PRX000007
includes         ?  Fe(34)S4 protein  PRX000054
includes           ?  Fe4S4Cys4
protein  PRX000088 includes             ?
 Fe4S4/DMSO reductase-like  PRX000546
includes               ?  formate dehydrogenase
catalytic subunit  PRX000557 includes            
     ?  molybdenum formate dehydrogenase
catalytic subunit  PRX000733 includes            
       ?  formate dehydrogenase N, catalytic
subunit  PRX000552 includes
Instance ?  formate dehydrogenase,
nitrate-inducible, major subunit Escherichia
coli UniProtP24183
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Molecule (MOL)

• Controlled vocabulary of small molecular
  entities bound to complex proteins
• Cross-references to (bio)chemical resources
  chemPDB , NIST Chemistry Webbook, LIGAND, RESID
• In future ChEBI

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COMe entry MOL000015
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Bioinorganic motif (BIM)

• A common structural feature of a class of
  functionally related, but not necessarily
  homologous, proteins, that includes the metal
  atom(s) and first coordination shell ligands
• Degtyarenko (2000) Bioinformatics 16, 851864

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Example BIM000027
T-4
Fe(SG.Cys)4
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Example BIM000056
(Fe2S2)(ND.His)2(SG.Cys)2
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Example BIM000061
Fe4(µ3-S)4(OD.Asp)(SG.Cys)3
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Fe4S4sirohaem centre (1)
MOL000131 Fe4S4
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Fe4S4sirohaem centre (2)
BIM000008 Fe4(µ3-S)4(SG.Cys)4
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Fe4S4sirohaem centre (3)
BIM000026 (Fe4S4)(SG.Cys)3Fe(por)µ-(SG.Cys)

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Relationships in COMe

• IsA inherits all attributes
• PRX to PRX
• cytochrome c IsA cytochrome
• Is_Part_Of no inheritance
• BIM to BIM MOL to MOL MOL to BIM BIM to
  PRX
• Fe(por)(NE.His)2 Is_Part_Of cytochrome b5
• Is_Bound_To no inheritance
• MOL to PRX
• haem b Is_Bound_To cytochrome c

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Paths to PRX000552
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Physico-chemical ontology ???

• Physico-chemical property
• Physico-chemical method
• Available at OBO web site (http//obo.sourceforge.
  net/)

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Molecular entity has

• Mass (molecular weight)
• Size
• Shape
• Charge
• Structure
• One can derive many properties from known
  complete structure
• Spectra

• ?

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Relationships in FIX

• IsA
• Raman spectroscopy IsA vibrational spectroscopy
• Is_Part_Of
• phasing method Is_Part_Of crystallography
• Can_Be_Determined_By
• molecular structure Can_Be_Determined_By
  crystallography

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Molecular Property vs Method
Heat capacity Mass Net charge Shape Size Structur
e Geometry Connectivity Topography
Calorimetry Centrifugation Crystallography Electro
phoresis Isotope method Mass spectrometry Microsco
py Spectroscopy
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A snapshot of FIX (1)
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A snapshot of FIX (2)
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A snapshot of FIX (3)
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Physico-chemical process (REX)

• IUPAC definitions (if available)
• Macroscopic and microscopic processes
• Available at OBO web site

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Biochemical reactions (1)

• Enzymatic reactions
• Non-enzymatic reactions

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Biochemical reactions (2)

• Catalytic Catalyst
• Enzymatic protein
• Abzymatic antibody
• Deoxyribozymatic DNA
• Ribozymatic RNA
• Heterogeneous surface (e.g. metal)
• Homogeneous solute (e.g. metal)
• Non-catalytic
• Photoinduced
• Spontaneous

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Biochemical reactions (3)

• Biotransformation
• A B ? C D (A, B, C, D small molecules)
• Binding
• A M ? AM (M macromolecule)
• Molecular transport
• A(compartment X) ? A(compartment Y)
• Electron and exciton transfer reactions
• Conformation change (e.g. folding)

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Relationships in REX

• IsA
• redox reaction IsA chemical reaction
• Is_Part_Of
• photoexcitation Is_Part_Of photoabsorption
• Is_Reverse_Of
• associative desorption Is_Reverse_Of
  dissociative adsorption
• Not DAG!

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A snapshot of REX (1)
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A snapshot of REX (2)
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A snapshot of REX (3)
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Users

• ChEBI, FIX, REX
• Oscar3 (University of Cambridge)
• ProjectProspect (Royal Society of Chemistry)
• Gene Ontology
• ChEBI REX
• Coming soon IntEnz
• COMe
• InterPro

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Summary

• Ontologies provide controlled vocabulary
  organised as a directed graph
• ChEBI standard terminology and structure of
  (bio)chemical compounds
• COMe ontology for bioinorganic proteins
• FIX controlled vocabulary for physico-chemical
  properties and methods
• REX controlled vocabulary for physico-chemical
  processes

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Links to remember
http//www.ebi.ac.uk/chebi/ http//www.ebi.ac.uk/c
ome/ http//www.ebi.ac.uk/kirill/FIX/ http//www
.ebi.ac.uk/kirill/REX/
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GrazieThank you???????
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Future plans

• Diversity of biochemical reactions and
  mechanistic aspects of enzymatic catalysis
• Development of database for quantitative
  properties of functional centres in
  metalloproteins and other complex proteins
• Further development of ontology of complex
  proteins based on the concept of bioinorganic
  motif

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Diversity of biochemical reactions

• Unambiguous chemical representation of reactions
• Further development of REX
• Collaboration with IntEnz, MACiE

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Quantitative properties of functional centres

• From qualitative to quantitative annotation
• Proteins utilise and modulate properties of
  non-peptide groups
• Redox potentials
• Absorption maxima (better, spectra)
• Dissociation constants
• Collaboration with experimentalists (here?)

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Metalloproteins

• Further development of COMe
• Annotation and prediction of metal-binding sites
• Selectivity and specificity of metalloprotein
  cofactors
• Collaborations (University of Edinburgh, Academia
  Sinica)

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Metal-binding sites in proteins

• Position-specific annotation of experimentally
  determined and inferrable metal-binding sites in
  the UniProt and closely connected resources (e.g.
  InterPro)
• Automation of major annotation steps to ensure
  the sustainability of this feature with minimum
  maintenance/curation in the future
• Development of prediction methodology for protein
  metal binding sites from multiple sequence
  alignments

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Selectivity and specificity of metalloprotein
cofactors

• Two separate problems binding selectivity and
  catalytic efficiency
• The database of experimentally defined
  qualitative and quantitative data for
  protein-metal interactions (coordination
  geometry, binding constants, redox potentials)
• Density functional theory (DFT)
• Continuum dielectric methods (CDM)

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Computational metallomics

• Metallomics comprehensive analysis of the
  entirety of metal and metalloid species within a
  cell or tissue type
• A branch of metabolomics
• Enzymatic reactions, transport phenomena, metal
  targeting (metallochaperones) and non-catalytic
  reactions
• The database of metal metabolism and transport
  pathways