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SRI International Bioinformatics1
A BRG Biofuels Metabolic Engineering Project
Bioinformatics Research Group
SRI International
Ron CaspiMario Latendresse
Peter Karp
October 2010 Pathway Tools Workshop
SRI International Bioinformatics2
Two Main Parts
This project will be conducted in the BRG group. Funded by the Department of Energy (DOE) under the direction of Peter Karp, PI
Soon to be started The project has two main parts:
1. Curating MetaCyc for biofuel pathways under the supervision of Ron Caspi, co-PI;
2. A computational tool to infer new pathways, co-PI, Mario Latendresse. (Not biofuels specific)
SRI International Bioinformatics3
Computational Tool
Basic statement of the problem:
Given a source and target metabolites, what are the possible metabolic pathways from the source to the target in a given organism?
And rank these pathways based on their qualityAnd constrained these pathways: number of
carbon atoms from the source to the target, length of pathway, number of genes to delete or add, and so on
SRI International Bioinformatics4
Computational Tool Approach
Use a searching algorithm (A*) that can use expert knowledge as well as precise evaluation algorithms of the quality of pathways found
Based on 1. Tracing of carbon atoms in pathways. From the source to
target, the number of carbon atoms can be evaluated.2. Gibbs free energy of reactions will help the evaluation of
the feasibility of existing and new pathways. A prototype A*, based on compound similarity,
has been written to find the shortest pathway between two compounds
SRI International Bioinformatics5
The A* algorithm
A general searching algorithm in a tree-like search space
Uses two evaluating functions g(path) and h(rest-path)
Function g evaluates the path (length, Gibbs energy, cost of enzymes, and so on) seen so far
Function h evaluates the potential of current path (based on heuristics) to the target metabolite
Next node to search is based on the value of h: go in the best direction
Function h can use expert knowledge as well as precise calculations
SRI International Bioinformatics6
A* Searching
SRI International Bioinformatics7
A* Prototype Results
Found all the pathways described in the paper by McShan, Rao, Shah on Pathminer, Bioinformatics, Vol. 19, no 13, 2003.
For example, from citrate to L-histidine (E. coli)In less than a second or a few seconds for a
seven step pathwaysProof of concept since the feasibility of such
pathways is not proven: not enough constrained applied so far
SRI International Bioinformatics8
Gibbs Free Energy Computation by the Group Contribution MethodPrototype implementation of Jankowski’s methodStill needs a full evaluation
SRI International Bioinformatics9
Curation of Biofuel Pathways in MetaCyc
1. Identify lignocellulose degrading enzymes and curate them into MetaCyc
2. Expand the coverage of hydrogenases in MetaCyc to include representatives of all known classes and subtypes
3. Expand MetaCyc coverage of fatty acids and lipids biosynthetic enzymes to reflect currently known metabolic and genetic information about oil production in algae and cyanobacteria
4. We will identify biochemically verified pathways involved in processes relevant to biofuel production
SRI International Bioinformatics10
Graphical Extension of Pathway Tools
Show complex polymers degradation processes that involve multiple enzymes attacking simultaneously a complex molecule at different sites
SRI International Bioinformatics11
Validating the Computational Tool
The new biofuel pathways will be used to evaluate the capability of the computational tool.
SRI International Bioinformatics12
A BRG Biofuels Metabolic Engineering Project
Questions?