EC-BLAST: A Novel Tool for Finding Chemically Similar

Reactions

Dr. Syed Asad Rahman

asad@ebi.ac.uk

Thornton Group

Computational Tools for Chemical Biology

Nov-2013

Seq. to Structure

Structure to

Function

Sequence to

Function

Systems

knowledgeTranslation

Interaction

Evolution

How to classify and compare enzymes?• Find similar enzymes which can perform similar

task (Superfamily)

• Design de-novo enzymes and small molecule pathway analysis

• Optimise enzymes of commercial importance

• Drug and mode of action/ cross reactivity

• Assignment/Clustering of EC numbers based on the quantitative measure

Ontology based Classification Method• IUBMB Enzyme Commission

• 6 Primary classes with 4 levels of sub-classification• EC 1(Oxidoreductases), EC 2 (Transferases), EC 3 (Hydrolases), EC

4 (Lyases), EC 5 (Isomerases), EC 6 (Ligases)

• 6.1.1.1 (ligase)

• EC 6.1 Forming Carbon-Oxygen Bonds

• EC 6.1.1 Ligases Forming Aminoacyl-tRNA and Related Compounds

• EC 6.1.1.1 tyrosine—tRNA ligase

EC-BLAST

http://www.ebi.ac.uk/thornton-srv/software/rbl/

S. A. Rahman et. al., EC-BLAST: A Tool to Automatically Search and Compare Enzyme Reactions, Nature Methods (accepted)

Algorithm

EC Clusters: Bond and Reaction Centre Similarity

Enzyme Similarity in the Metabolic Pathways • Teichmann SA et. al.

(2001, PubMed ID: 11518524), • Rison RC et. al. (2002, PubMed ID: 12054833).

Phosphatidylinositol (PI) phosphodiesterase

(CATH: 3.20.20.190)

Linking Sequence Domains and Chemical Attributes

• Find all the sequence domains using Pfam/CATH

• Find all the chemical attributes interacting with those domains from EC-BLAST DB

• Report the chemical features and common substructure

Chemical Domains SequenceEC: 6.2.1.* Pfam: PF00501-AMP-binding UniProt: Q6FLU2

Core Fragment

Future

• Integrated database with Rhea and BRENDA reactions

• ~ 15,000 Reactions linked to UniProt, Pfam etc

• Link Chemistry to Sequence

• Toxicity

• Web service

• Collaborations

Acknowledgements

• Gemma L. Holliday

• Gilleain Torrence

• Franz Fenninger

• Lorenzo Baldacci

• Nicholas Furnham

• Sergio Martinez Cuesta

• Nimish Gopal, Sophie Williams and Saket Choudhary

• Funded by

Dame Prof. Janet M. Thornton

http://www.ebi.ac.uk/thornton-srv/software/rbl

Dr. Syed Asad Rahman

asad@ebi.ac.uk

Computational Tools for Chemical Biology Workshop

Warm up exercise

• Reaction similarity search using EC 6.1.1.1

• Look at the similarity scores and the top 10 hits.

• EC number and linked information (Pfam, PDB etc) by clicking on them

• Search for “penicillin G” using molecule search option in the EC-BLAST

Exercise 1

SUBMIT

TYPE

Exercise 1- Step 1

• Find Reactions with “penicillin G”

SELECT

SUBMIT

1. Select the top hit and return to the main screen

2. Then perform EC-BLAST using one of the reaction similarity measures.

Exercise 2 in 3 Steps

Step 1- Select the top hit

SUBMIT

SELECT

Step 2- Perform EC-BLAST

SUBMIT

SELECT

Step 3- Top 10 Hits

QUERY INFORMATION

ENZYME INFO.

BOND CHANGES

Exercise 3: Top 3 hits using Reaction Structure Similarity (KEGG ID R04868)