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ntologiesin biologicalchemistry
Kirill Degtyarenko Sergio Contrino @ EBI
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• COMe
http://www.ebi.ac.uk/~kirill/come/
• IntEnz
http://www.ebi.ac.uk/intenz/
• This talk and more info
http://www.ebi.ac.uk/~kirill/biometal/
Links
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• Structure
• Physico-chemical properties
• Biological function
• 2-D, 2.5-D or 3-D structure
• Not deduced from the structure
• Biochemical reactions, mostly
• Structural
Ontologies for “biochemical” compounds
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hysico-chemical roperties
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Physico-chemical property
• Molecular property
• Supramolecular property
• System property
• Reaction property
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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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Molecular property
Heat capacity
Mass
Net charge
Shape
Size
StructureGeometry
Connectivity
Topography
Method
Calorimetry
Centrifugation
Crystallography
Electrophoresis
Isotope method
Mass spectrometry
Microscopy
Spectroscopy
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Raman spectroscopy
Chandrasekhara Venkata Raman
Raman effect
1928
Raman spectrum
IS BASED ON
vibrational spectroscopy
YIELDS
ISA
DISCOVERED BY
DISCOVERED IN
protein secondary structure
protein conformation
ISA
Amide bands
FEATURES
AFFECTS
IS USED TO INVESTIGATE
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Physico-chemical ontology
• Physico-chemical property
• Physico-chemical method
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tructure
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Chemical data
• 0-D: ENZYME, ChemicalOntology
• 2-D: COMPOUND, GSK, NIST
• 3-D: MSDhttp://www.ebi.ac.uk/msd-srv/chempdb/
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%observable universe (cf. "Lenin's definition of matter")
<energy (has *no rest mass*)
%electromagnetic radiation
<photon
%(other forms of energy, can elaborate later)
<matter (has *rest mass*)
%free elementary particles having non-zero rest mass (*molar!*)
<elementary particle
%electron
%proton
%neutron
%molecular matter (here the chemical ontology starts)
%grouped_by_composition
%compound ; synonym:chemical substance
<formula unit
<molecular entity
%atom
<electron
<nucleus
<proton
<neutron
%element
%atomic ion
%atomic radical
%molecule
<group
%molecular ion
%molecular radical
%noncovalent crystal molecule
%ionic crystal molecule
%metallic crystal molecule
%covalent molecule
%discrete covalent molecule
%giant covalent molecule
%coordination molecule
(continued)
%ion
%atomic ion
%molecular ion
%radical
%atomic radical
%molecular radical
%mixture
<compound
%heterogeneous mixture
%colloidal suspension
%liquid aerosol
%solid aerosol
%foam
%emulsion
%sol
%solid foam
%gel
%solid sol
%homogeneous mixture
%solution
<solute
<solvent
%solid solution
...
%grouped_by_state_of_matter
%plasma
%gas
%liquid
%solid
%heterogeneous mixture
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Molecular ontology
• noncovalent crystal• ionic crystal• metallic crystal
• covalent• giant covalent• discrete covalent
•coordination
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• Metalloproteins
• Organic prosthetic group proteins
• Modified amino acid proteins
Complex proteins
• Proteins consisting of more than one polypeptide chain
• Combinations of all groups
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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 K.N. (2000) Bioinformatics 16, 851–864]
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Dimensionality of BIM
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Fe0
D
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Fe1
P-D-x(2)-H-[DE]-[LI]-[LIVMF]-G-H-[LIVMC]-P-x(n)-E
D
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N
N
O
O
H2O
H2OFe
N
N 2
D
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N
N
O
O
H2O
H2OFe
N
N 2.5
D
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3
D
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http://www.ebi.ac.uk/~kirill/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
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COMe version 2.11
• Controlled vocabulary• No definitions• 1079 protein classes (PRX)• 351 bioinorganic motifs (BIM)• 132 small molecules (MOL)
organised as:• XML version (master)• Oracle version
monthyear
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Relationships in COMe
• isKindOf : inherits all attributes PRX to PRX ; BIM to BIM ; MOL to MOL
• isPartOf : no inheritanceBIM to BIM ; MOL to MOL ; MOL to BIM ; BIM to PRX
• isBoundTo : no inheritanceMOL to PRX
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- <term value="rusticyanin" id="PRX000193" dbxref="InterPro:IPR001243">
</term>
<bim coordination="T-4">Cu(ND.His)2(SD.Met)(SG.Cys)</bim>
N
N
Cu
S Cys
S
N
N
- <substructure id="BIM000085">
</substructure>
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- <substructure id="BIM000245">
</substructure>
<bim>heme(OD.Asp)(OE.Glu)(SD.Met)</bim>
<term value="hemediol-L-aspartyl ester-L-glutamyl ester-L-methionine sulfonium" dbxref="RESID:AA0280" />
<term value="heme m" />
- <substructure id="BIM000246">
<bim>(CBB.heme)(SD.Met)</bim>
</substructure>
- <substructure id="BIM000247">
<bim>(CMD.heme)(OD.Asp)</bim>
</substructure>
- <substructure id="BIM000248">
<bim>(CMB.heme)(OE.Glu)</bim>
</substructure>
Asp
O
ON
N
N
N
Fe
OO
OO
S+Met
O
GluO
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- <substructure id="BIM000281">
</substructure>
<bim>MIO</bim>
<!-- originates from cyclization and dehydration of internal Ala-Ser-Gly -->
<term value="3,5-dihydro-5-methylidene-4H-imidazol-4-one" lref=" MEDLINE:21462607" />
<term value="4-methylidene-imidazole-5-one" dbxref="PDB:1B8F" />
N
N
CH2
O
O
NHNH
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Verdict on structure representation in COMe
• Metal-containing BIMIntuitively understandable
• Organic prosthetic groupSometimes not
• Modified amino acid(s)Not really… but we can link to RESID @ http://srs.ebi.ac.uk/
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COMe: future work
• More PRX, BIM, MOL
• Building blocks for BIMs
• Representation of inheritance
• 2.5-D representation of BIM / MOL (?)
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iological function
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Biochemical reactions (I)
• Enzymatic reactions
• Non-enzymatic reactions
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Biochemical reactions (II)• Binding
A + M A—M (A = “small molecule”)
• Biotransformation A + B C + D (A, B, C, D = small molecules)
• Molecular transport A(compartment X) A(compartment Y)
• Electron and exciton transfer reactions
• Conformation change (e.g. folding)
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Biotransformation reactions
• Catalytic Catalyst Enzymatic protein Ribozymatic RNA Heterogeneous surface (e.g. metal) Homogeneous solute (e.g. metal)
• Non-catalytic Photoinduced — “Spontaneous” —
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Aromatic amino acid hydroxylasesEC 1.14.16.1
L-Phe + H4B + O2 = L-Tyr + H2B + H2O
EC 1.14.16.2
L-Tyr + H4B + O2 = 3,4-dihydroxy-L-Phe + H2B + H2O
EC 1.14.16.4
L-Trp + H4B + O2 = 5-hydroxy-L-Trp + H2B + H2O
I. RH + tetrahydrobiopterin + O2 =
ROH + 4a-hydroxytetrahydrobiopterin
II. 4a-hydroxytetrahydrobiopterin = 6,7-dihydrobiopterin + H2O
III. 6,7-dihydrobiopterin = 7,8-dihydrobiopterin
In fact...
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ABC of enzyme use
• Alcohol (~2500 BC)
• Bread (~2600 BC)
• Cheese (~1000 BC)
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Enzyme Nomenclature• Enzyme Commission: established 1956 by
IUB• Now: NC-IUBMB• Assigns EC numbers which were supposed to
serve as unique identifiers of enzymatic reactions
• Classification by overall reaction catalysed (not by the reaction mechanism nor any other specific property of an enzyme)
• EC numbers form a strict hierarchy of ISA relationships
• http://www.ebi.ac.uk/intenz/
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Overall transformations in “enzymatic reactions”
EC1 Oxidoreductases
EC2 Transferases
EC3 Hydrolases
EC4 Lyases
EC5 Isomerases
EC6 Ligases
Aox + Dred Ared + Dox
A-X + B-H A-H + B-X
A–B + HOH A–H + B–OH
X–Y–Z X=Y + Z
A B
A + B + XTP A–B + XDP + Pi
A + B + XTP A–B + XMP + PPi
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Overall transformations in organic chemistry
• Addition
• Elimination
• Substitution
• Rearrangement
A + B A–B
A–B A + B
A–X + B–Y A–Y + B–X
A B
(after R.B. Grossman, 1999)
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Reaction mechanisms in organic chemistry
• Polar Polar acidic Polar basic
• Free-radical
• Pericyclic
• Metal-mediated and -catalysed
(after R.B. Grossman, 1999)
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Mechanism of biochemical reaction
• Mechanism of reaction irrespectively of
catalyst
• e.g. homolytic vs heterolytic bond scission
• Mechanism of reaction according to
catalyst nature
• e.g. Cu-containing vs FAD-containing
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EC 1.2.3.4
Anatomy of an EC number
oxalate + O2 = 2 CO2 + H2O2
EC 1.2.3.4
• EC 1 Oxidoreductase
EC 1.2.3.4
• EC 1.2 Acting on the aldehyde or oxo group of donors
EC 1.2.3.4
• EC 1.2.3 With oxygen as acceptor
EC 1.2.3.4
• EC 1.2.3.4 Oxalate oxidase
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Redundancy and deficiency
• Overall transformations in “enzymatic reactions”
are mostly based on those of organic chemistry
• EC3 (Hydrolases), many EC1 (Oxidoreductases)
and some EC4 (Lyases) can be considered kind of
EC2 (Transferases)
• One part of EC6 (Ligases) reactions can be
considered kind of EC3 (Hydrolases)
• No classification for some fundamental reaction
types, e.g. addition not to double bonds
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• EC 4.99.1.1 ferrochelataseprotoporphyrin + Fe2+ = protoheme + 2 H+
creates metal–N bond
EC 4.99 Other Lyases
• EC 4.99.1.2 alkylmercury lyaseRHg+ + H+ = RH + Hg2+
breaks metal–C bond
• Both these enzymes should not be classified as lyases
(example thanks to Keith Tipton)
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Other problems
• No explicit difference between enzymatic
reactions and enzymes is made, therefore
• Some enzymes were given different EC numbers
on the basis of different cofactor or origin (!)
• The reactions are always written as if they were
reversible, therefore
• Enzymes catalysing the opposite reactions are
given the same EC number
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In fact...These may be different enzymes!
EC 1.18.1.2
• Ferredoxin:NADP+ reductase
[Fe2S2]+ferredoxin + NADP+ [Fe2S2]2+
ferredoxin + NADPH
• Adrenodoxin reductase
[Fe2S2]2+adrenodoxin + NADPH [Fe2S2]+
adrenodoxin + NADP+
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Sub-subclasses in EC1.1–1.10
• EC 1.x.1 With NAD or NADP as acceptor• EC 1.x.2 With a heme protein as acceptor• EC 1.x.3 With oxygen as acceptor• EC 1.x.4 With a disulfide as acceptor• EC 1.x.5 With a quinone as acceptor• EC 1.x.7 With an iron–sulfur protein as acceptor• EC 1.x.6 With a nitrogenous group as acceptor• EC 1.x.8 With a flavin as acceptor• EC 1.x.99 With other acceptors
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ISA EC 1.1.1.2 alcohol dehydrogenase (NADP) ISA EC 1.1.1.91 aryl-alcohol dehydrogenase (NADP) ISA EC 1.1.1.97 3-hydroxybenzyl-alcohol dehydrogenase
Current classification
EC 1.1.1 With NAD or NADP as acceptor
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ISA EC 1.1.1.2 alcohol dehydrogenase (NADP) ISA EC 1.1.1.91 aryl-alcohol dehydrogenase (NADP)
ISA EC 1.1.1.97 3-hydroxybenzyl-alcohol dehydrogenase
Alternative classification
EC 1.1.1 With NAD or NADP as acceptor
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Other relationships between enzyme entities
• Structural and functional
relationships
• Historical relationships
• Dodgy relationships
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Structural and functional relationships
• (reaction) EC A is KindOf (reaction) EC B
• (enzyme) EC A is PartOf (enzyme) EC B
• EC A is involved in metabolic process Z
• product of EC A is a substrate of EC B
• EC A activates (enzyme) EC B
• EC A inactivates (enzyme) EC B
• EC A phosphorylates (enzyme) EC B
• EC A dephosphorylates (enzyme) EC B
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Historical relationships
Entry transfer:
• EC A is transferred to EC B
Entry merger:
• EC A is incorporated in EC B
Entry split:
• EC A is part transferred to EC B1
• EC A is part transferred to EC B2
Entry reinstatement:
• (deleted) EC A reinstated as EC B
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Dodgy relationships
• EC A is not identical to EC B (never should)
• EC A may be identical to EC B (if proven, one of the entries should be deleted as “identical to”)
• EC A is probably identical to EC B (same)
• EC A is related to EC B (how?)
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Acknowledgements
IntEnz team:• Michael Darsow• Astrid Fleischmann• Wolfgang Fleischmann
• John Garavelli (RESID)• Rolf Apweiler