1. 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

2. Sequence
to
Function
Evolution
Seq.
to
Structure
Structure
to
Function

3. 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

4. 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

5. ECBLAST
S. A. Rahman et. al.,
EC-BLAST: A Tool to Automatically
Search and Compare Enzyme
Reactions, Nature Methods
(accepted)
http://www.ebi.ac.uk/thornton-srv/software/rbl/

6. Algorithm

7. EC Clusters: Bond and Reaction Centre
Similarity

8. Enzyme Similarity in the Metabolic
• Teichmann SA et. al.
Pathways
(2001, PubMed ID: 11518524),
• Rison RC et. al.
(2002, PubMed ID: 12054833).
Comparison of Reaction Centre (RC)
similarity in the E-coli core metabolic pathway
1.00
Tanimoto Scores
0.75
0.50
0.25
0.00
EC-BLAST top score
Pathway Neighbours
Random Reactions
Reaction Centre Similarity

9. Phosphatidylinositol
phosphodiesterase
(CATH: 3.20.20.190)
(PI)

10. 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  Sequence
EC: 6.2.1.* Pfam: PF00501-AMP-binding UniProt:
Q6FLU2
Core
Fragment

11. Future
•
•
•
•
•
•
Integrated database with Rhea and BRENDA reactions
~ 15,000 Reactions linked to UniProt, Pfam etc
Link Chemistry to Sequence
Toxicity
Web service
Collaborations

12. Acknowledgements
•
•
•
•
•
•
Gemma L. Holliday
Gilleain Torrence
Franz Fenninger
Lorenzo Baldacci
Dame Prof. Janet M. Thornton
Nicholas Furnham
Sergio Martinez Cuesta
• Nimish Gopal, Sophie Williams and Saket Choudhary
• Funded by

13. http://www.ebi.ac.uk/thornton-srv/software/rbl
Dr. Syed Asad Rahman
asad@ebi.ac.uk
Computational Tools for Chemical Biology
Workshop

14. 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

15. Exercise 1
• Search for “penicillin G” using molecule search option in
the EC-BLAST

16. Exercise 1- Step 1
• Find Reactions with “penicillin G”

17. Exercise 2 in 3 Steps
1. Select the top hit and return to the main screen
2. Then perform EC-BLAST using one of the reaction
similarity measures.

18. Step 1- Select the top hit

19. Step 2- Perform EC-BLAST

20. Step 3- Top 10 Hits

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