ntologies in biological chemistry kirill degtyarenko sergio contrino @ ebi

ntologiesin biologicalchemistry

Kirill Degtyarenko Sergio Contrino @ EBI

• 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/

[email protected]

Links

















mailto:[email protected]





• 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

hysico-chemical roperties

Physico-chemical property

• Molecular property

• Supramolecular property

• System property

• Reaction property

Molecular entity has…

• Mass (“molecular weight”)

• Size

• Shape

• Charge

• Structure One can derive many properties from

known complete structure

• Spectra ?

Molecular property

Heat capacity

Mass

Net charge

Shape

Size

StructureGeometry

Connectivity

Topography

Method

Calorimetry

Centrifugation

Crystallography

Electrophoresis

Isotope method

Mass spectrometry

Microscopy

Spectroscopy

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

Physico-chemical ontology

• Physico-chemical property

• Physico-chemical method

tructure

Chemical data

• 0-D: ENZYME, ChemicalOntology

• 2-D: COMPOUND, GSK, NIST

• 3-D: MSDhttp://www.ebi.ac.uk/msd-srv/chempdb/

http://www.ebi.ac.uk/msd-srv/chempdb/











%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

Molecular ontology

• noncovalent crystal• ionic crystal• metallic crystal

• covalent• giant covalent• discrete covalent

•coordination

• Metalloproteins

• Organic prosthetic group proteins

• Modified amino acid proteins

Complex proteins

• Proteins consisting of more than one polypeptide chain

• Combinations of all groups

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]

Dimensionality of BIM

Fe0

D

Fe1

P-D-x(2)-H-[DE]-[LI]-[LIVMF]-G-H-[LIVMC]-P-x(n)-E

D

N

N

O

O

H2O

H2OFe

N

N 2

D

N

N

O

O

H2O

H2OFe

N

N 2.5

D

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

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

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

- <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>


</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" />


<bim>(CBB.heme)(SD.Met)</bim>

</substructure>


<bim>(CMD.heme)(OD.Asp)</bim>

</substructure>


<bim>(CMB.heme)(OE.Glu)</bim>

</substructure>

Asp

O

ON

N

N

N

Fe

OO

OO

S+Met

O

GluO

</substructure>

<bim>MIO</bim>



<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

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/

http://srs.ebi.ac.uk/







COMe: future work

• More PRX, BIM, MOL

• Building blocks for BIMs

• Representation of inheritance

• 2.5-D representation of BIM / MOL (?)

iological function

Biochemical reactions (I)

• Enzymatic reactions

• Non-enzymatic reactions

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)

Biotransformation reactions

• Catalytic Catalyst Enzymatic protein Ribozymatic RNA Heterogeneous surface (e.g. metal) Homogeneous solute (e.g. metal)

• Non-catalytic Photoinduced — “Spontaneous” —

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...

ABC of enzyme use

• Alcohol (~2500 BC)

• Bread (~2600 BC)

• Cheese (~1000 BC)

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/








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

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)

Reaction mechanisms in organic chemistry

• Polar Polar acidic Polar basic

• Free-radical

• Pericyclic

• Metal-mediated and -catalysed

(after R.B. Grossman, 1999)

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

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

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

• 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)

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

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+

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

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

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

Other relationships between enzyme entities

• Structural and functional

relationships

• Historical relationships

• Dodgy relationships

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

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

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?)

Acknowledgements

IntEnz team:• Michael Darsow• Astrid Fleischmann• Wolfgang Fleischmann

• John Garavelli (RESID)• Rolf Apweiler

ntologies in biological chemistry kirill degtyarenko sergio contrino @ ebi

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