uwe reyle institute of computational linguistics university of stuttgart

Processing Natural Language Comments in Biological

Databases: Molecular Assemblies and Their Catalitic Functions.

A Case Study

Uwe Reyle

Institute of Computational Linguistics

University of Stuttgart

EMLEuropean Media Laboratory

Heidelberg

INRIAInstitute National de Recherche en

Informatique et AutomatiqueGrenoble

Biological Databases

Proteins

EnzymesCompounds

Pathways

flat files – no relational/deductive databasesmade for Biologists – not for Machines

Biological Databases

Proteins

EnzymesCompounds

Pathways

Data-ModelOntology

Efficient Querying

Overview

• Genes, Proteins and Enzymes• Swissprot Protein Database• Two Examples

– Semantic Processing – Parsing Protein Names

• Merits for – Coreference Resolution– Extraction/Detaction of Molecular Assemblies

gene polypeptide

Chromosome

biochemical reactions

compounds (e.g. sugar...)molecularassembly

EC

EC

EC enzyme

TranslationTranscription

PosttranslationalModifications

Molecular Assembly

Catalitic Activity

Pathways

gene polypeptide

Chromosome

biochemical reactions

compounds (e.g. sugar...)molecularassembly

EC

EC

EC enzyme

CATALITIC ACTIVITY

PATHWAY

SUBUNIT

DE POS

DE INCLUDES CONTAINS

FUNCTION

Swissprot Entries

Reference Database

Proteins

EnzymesCompounds

Pathways

Swissprot

Swissprot vs. Medline

Papers

Medline Abstracts

Swissprot

• fact + organism + experimental context• enormous vocabulary• coreference = intra-document coreference + coreference to database

IE• fact• much smaller vocabulary• coreference = intra-document coreference

RECOMMENDED NAME dipeptidyl-peptidase IV

SYNONYMS peptidase, dipeptidyl, IVPep X leukocyte antigen CD26 glycylprolyl dipeptidylaminopeptidaseglycylproline-dipeptidyl-aminopeptidaseglycylproline aminopeptidaseXaa-Pro-dipeptidyl-aminopeptidasedipeptidyl-peptide hydrolaselymphocyte, antigen CD26postproline dipeptidyl aminopeptidase IVglycylprolyl aminopeptidasedipeptidyl-aminopeptidase IVGly-Pro-naphthylamidaseDPP IV/CD26 glycoprotein GP110amino acyl-prolyl dipeptidyl aminopeptidasedipeptidyl aminopeptidase IVT cell triggering molecule Tp103 dipeptidyl-peptidase IV (CD26) X-prolyl dipeptidyl aminopeptidaseX-PDAP aminopeptidase, glycylproline

Coreference to DE-line of database entry

Structure of Swissprot Entries

3. The different line types 3.1 The ID line 3.2 The AC line 3.3 The DT line 3.4 The DE line 3.5 The GN line 3.6 The OS line 3.7 The OG line 3.8 The OC line 3.9 The OX line 3.10 The reference (RN, RP, RC, RX, RA, RT, RL) lines 3.11 The CC line 3.12 The DR line 3.13 The KW line 3.14 The FT line 3.15 The SQ line 3.16 The sequence data line 3.17 The // line

Quality of information by marking: experiment, similarity, ...

Each entry refers to a polypeptide in one single organism

An Example

ID ACCD_ECOLI STANDARD; PRT; 304 AA.AC P08193; P78251; P76937;DE ACETYL-COENZYME A CARBOXYLASE CARBOXYL TRANSFERASE SUBUNIT BETA

(EC 6.4.1.2) (ACCASE BETA CHAIN).CC -!- FUNCTION: THIS PROTEIN IS A COMPONENT OF THE ACETYL COENZYME A

CARBOXYLASE COMPLEX; FIRST, BIOTIN CARBOXYLASE CATALYZES THE CARBOXYLATION OF THE CARRIER PROTEIN AND THEN THE TRANSCARBOXYLASE TRANSFERS THE CARBOXYL GROUP TO FORM

MALONYL-COA. CC -!- SUBUNIT: ACETYL-COA CARBOXYLASE IS AN HETEROHEXAMER OF

BIOTIN CARBOXYL CARRIER PROTEIN, BIOTIN CARBOXYLASE AND THE TWO SUBUNITS OF CARBOXYL TRANSFERASE IN A 2:2 COMPLEX.

-!- CATALITIC ACTIVITY, PATHWAY, SIMILARITY, FEATURES, ...

Variety of SUBUNIT-lines

• HETERODIMER...

• PP2 CONSISTS OF A COMMON HETERODIMERIC CORE ENZYME, COMPOSED OF A 36 KDA CATALITIC SUBUNIT (SUBUNIT C) AND A 65 KDA CONSTANT REGULATORY SUBUNIT (PR65 OR SUBUNIT A), THAT ASSOCIATES WITH A VARIETY OF REGULATORY SUBUNITS. PROTEINS THAT ASSOCIATE WITH THE CORE DIMER INCLUDE THREE FAMILIES OF ...

Subunit-lines of type NP

<DE> A-kinase anchor protein 5<SUBUNIT> BINDING PROTEIN FOR DIMER OF PKA

AND ALSO FOR PKC AND PP2B. EACH ENZYME IS INHIBITED WHEN BOUND TO THE ANCHOR PROTEIN.

<DE> Potassium-transporting ATPase alpha chain<SUBUNIT> HETERODIMER COMPOSED OF TWO

SUBUNITS, ALPHA AND BETA.


<DE> A-kinase anchor protein 5<SUBUNIT> BINDING PROTEIN FOR DIMER OF PKA AND

ALSO FOR PKC AND PP2B. EACH ENZYME IS INHIBITED WHEN BOUND TO THE ANCHOR PROTEIN.

(AKAP5 : (PKA:PKA)), where PKA is inhibited PKC AKAP5 and PP2B AKAP5

where PKC and PP2B are inhibited

<DE> Potassium-transporting ATPase alpha chain<SUBUNIT> HETERODIMER COMPOSED OF TWO

SUBUNITS, ALPHA AND BETA.




<DE> Potassium-transporting ATPase alpha chain<SUBUNIT> HETERODIMER COMPOSED OF TWO SUBUNITS,

ALPHA AND BETA. Potassium-transporting ATPase (alpha : beta) Potassium-transporting ATPase alpha chain (alpha : beta)




<DE> Potassium-transporting ATPase alpha chain<SUBUNIT> HETERODIMER COMPOSED OF TWO SUBUNITS,

ALPHA AND BETA. Potassium-transporting ATPase (alpha : beta) Potassium-transporting ATPase alpha chain (alpha : beta)

Task: parse recommended name

Structure of Polypeptide Names that Refer to Subunits of Proteines

AssemblyName SubunitRef

Protein NameEnzyme Name

{beta 1, ASHI, lacH, ...} subunit30 kda subunit{small, major, second largest,...} subunittype B catalitic subunit subunit {alpha 3, 2 type B, ...}iron-sulfur subunit alpha-2{alpha, light, catalitic,...} chain cytochrome B-558

homologprecursor; phrase(s)

vacuolarsoluableanaerobic

Problems

• We cannot assume a dictionary of assembly names

• AssemblyName very often end with a highly ambiguous symbol that may also be used to start the SubunitRef expression

- F, A1, I, II, i, ..., geneName, ...• Nomenclature of subunits does not exist• Contextual knowledge is needed to disambiguate,

e.g., XYase A1 large chain

Assembly Names• Mitogen-activated protein kinase kinase kinase kinase acting on a kinase that acts on a protein kinase one of these kinases is mitogen-activated, not the protein, however

• „kinase“ has 1 semantic argument, namely the molecule X that it phosphorylates

Acceptor/Donor

Group phosphoryl Function transfer

Acceptor/Donor ...Group phosphorylFunction transfer

CoA Carboxylase Carboxyl Transferase Acceptor/Donor CoA Carboxylase Group carboxyl Function transfer

Acceptor/Donor X Group carboxyl Function transfer

ADJ-Rel CoA Carboxylase

With ADJ-Rel {,is_expressed_by, ...}

Assembly Names

Semantic Relations projected from the Lexicon

• carboxyl transferase transcarboxylase (IUPAC)• transcarboxylation carboxylation • transcarboxylate carboxylate

• phosphorylate, biotinylate, adenylylate, ... • transphosphorylate, ... • crossphosphorylate, ...

Coreference (local)






Coreference (local)






PP-attachment: semantics of Heterohexamer

Coreference (non-local)

ID ACCD_ECOLI STANDARD; PRT; 304 AA.AC P08193; P78251; P76937;DE ACETYL-COENZYME A CARBOXYLASE CARBOXYL TRANSFERASE SUBUNIT BETA (EC

6.4.1.2) (ACCASE BETA CHAIN).CC -!- FUNCTION: THIS PROTEIN IS A COMPONENT OF THE ACETYL COENZYME A




ACETYL-COENZYME A CARBOXYLASE CARBOXYL TRANSFERASE SUBUNIT XYZXYZ SUBUNIT OF ACETYL-COENZYME A CARBOXYLASE CARBOXYL TRANSFERASE

...


ID ACCA_ECOLI STANDARD; PRT; 318 AA.AC P30867;DE ACETYL-COENZYME A CARBOXYLASE CARBOXYL TRANSFERASE SUBUNIT ALPHA

(EC 6.4.1.2).CC -!- FUNCTION: THIS PROTEIN IS A COMPONENT OF THE ACETYL COENZYME

A CARBOXYLASE COMPLEX; FIRST, BIOTIN CARBOXYLASE CATALYZES THE CARBOXYLATION OF THE CARRIER PROTEIN AND THEN THE

TRANSCARBOXYLASE TRANSFERS THE CARBOXYL GROUP TO FORM MALONYL- COA.

CC -!- CATALYTIC ACTIVITY: CARBOXYBIOTIN CARBOXYL CARRIER PROTEIN + ACETYL-COA = BIOTIN CARBOXYL CARRIER PROTEIN + MALONYL-COA.

CC -!- PATHWAY: FIRST STEP IN LONG-CHAIN FATTY ACID SYNTHESIS.CC -!- SUBUNIT: ACETYL-COA CARBOXYLASE IS AN HETEROHEXAMER OF BIOTIN

CARBOXYL CARRIER PROTEIN, BIOTIN CARBOXYLASE AND THE TWO SUBUNITS OF CARBOXYL TRANSFERASE IN A 2:2 COMPLEX.CC -!- SIMILARITY: TO THE C-TERMINUS OF MAMMALIAN PROPIONYL-COA

CARBOXYLASE BETA CHAIN.


ID BCCP_ECOLI STANDARD; PRT; 156 AA.AC P02905;DE BIOTIN CARBOXYL CARRIER PROTEIN OF ACETYL-COA CARBOXYLASE

(BCCP).CC -!- FUNCTION: THIS PROTEIN IS A COMPONENT OF THE ACETYL

COENZYME A CARBOXYLASE COMPLEX; FIRST, BIOTIN CARBOXYLASE CATALYZES THE CARBOXYLATION OF THE CARRIER PROTEIN AND THEN THE TRANSCARBOXYLASE TRANSFERS THE CARBOXYL GROUP TO FORM MALONYL-COA.

CC -!- PATHWAY: FIRST STEP IN LONG-CHAIN FATTY ACID SYNTHESIS.CC -!- SUBUNIT: HOMODIMER.


ID ACCC_ECOLI STANDARD; PRT; 449 AA.AC P24182;DE BIOTIN CARBOXYLASE (EC 6.3.4.14) (A SUBUNIT OF ACETYL-COA CARBOXYLASE) (EC 6.4.1.2) (ACC).CC -!- FUNCTION: THIS PROTEIN IS A COMPONENT OF THE ACETYL COENZYME A CARBOXYLASE COMPLEX; FIRST, BIOTIN CARBOXYLASE CATALYZES THE CARBOXYLATION OF THE CARRIER PROTEIN AND THEN

THE TRANSCARBOXYLASE TRANSFERS THE CARBOXYL GROUP TO FORM MALONYL-COA.CC -!- CATALYTIC ACTIVITY: ATP + BIOTIN-CARBOXYL-CARRIER PROTEIN + CO(2) = ADP + ORTHOPHOSPHATE + CARBOXYBIOTIN-CARBOXYL-CARRIER PROTEIN.CC -!- PATHWAY: FIRST STEP IN LONG-CHAIN FATTY ACID SYNTHESIS.CC -!- SUBUNIT: ACETYL-COA CARBOXYLASE IS AN HETEROHEXAMER OF BIOTIN CARBOXYL CARRIER PROTEIN, BIOTIN CARBOXYLASE AND THE TWO SUBUNITS OF CARBOXYL TRANSFERASE IN A 2:2 COMPLEX.CC -!- SIMILARITY: TO OTHER BIOTIN-DEPENDENT ENZYMES AND CARBAMOYL- PHOSPHATE SYNTHETASES.

ExtractionID ACCD_ECOLI STANDARD; PRT; 304 AA.AC P08193; P78251; P76937;DE ACETYL-COENZYME A CARBOXYLASE CARBOXYL TRANSFERASE SUBUNIT BETA



MALONYL-COA.CC -!- SUBUNIT: ACETYL-COA CARBOXYLASE IS AN HETEROHEXAMER OF


CC -!- SIMILARITY: BELONGS TO THE ACCD / PCCB FAMILY.

Complex consisting of 6 subunits

ExtractionID ACCD_ECOLI STANDARD; PRT; 304 AA.AC P08193; P78251; P76937;DE ACETYL-COENZYME A CARBOXYLASE CARBOXYL TRANSFERASE SUBUNIT BETA



MALONYL-COA.CC -!- SUBUNIT: ACETYL-COA CARBOXYLASE IS AN HETEROHEXAMER OF


CC -!- SIMILARITY: BELONGS TO THE ACCD / PCCB FAMILY.

Acetyl-CoA Carboxylase

Carrier Protein Biotin Carboxylase

Alpha Alpha Beta Beta

Carboxyl Transferase

Completing the Picture

ID BIRA_ECOLI STANDARD; PRT; 321 AA.AC P06709;CC -!- FUNCTION: BIRA ACTS BOTH AS A BIOTIN-OPERON REPRESSOR

AND AS THE ENZYME THAT SYNTHESIZES THE COREPRESSOR,ACETYL COA:CARBON-DIOXIDE LIGASE. THIS PROTEIN ALSO

ACTIVATES BIOTIN TO FORM BIOTINYL-5'-ADENYLATE AND TRANSFERS THE BIOTIN MOIETY TO BIOTIN-ACCEPTING PROTEINS.

CC -!- CATALYTIC ACTIVITY: ATP + BIOTIN + APO-[ACETYL-COA:CARBON-DIOXIDE LIGASE (ADP FORMING)]

= AMP + PYROPHOSPHATE + [ACETYL-COA:CARBON-DIOXIDE LIGASE (ADP FORMING)].CC -!- SUBUNIT: MONOMER.CC -!- SIMILARITY: WITH OTHER BACTERIAL BIRA AND WITH

EUKARYOTIC BIOTIN APO-PROTEIN LIGASE.

= Acetyl CoA Carboxylase

Conclusion• Sophisticated IE must incorporate

– Domain Ontology (EML, INRIA,IMS)

– Lexical Semantics (IMS)

– Morphological Analysis + Compositional Semantics (IMS)

– Discourse Semantics (IMS)

• Work on the Lexicon of Cell-Biology– Organic Chemical Compounds

„Was bedeutet UREYLEN“ (C. Gerstenberger, IMS)

– Semantic/ontological classification of 100 chemical Verbs (Phillip Cimiano Lavin, IMS)

– Enzyme- and Protein Names (work in progres)

uwe reyle institute of computational linguistics university of stuttgart

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