Transcript Pathway databases

Pathway databases
Goto S, Bono H, Ogata H, Fujibuchi W, Nishioka T, Sato K,
Kanehisa M. (1997) Organizing and computing metabolic
pathway data in terms of binary relations. Pac Symp
Biocomput, 175-86
P.R. Romero and P. Karp Nutrition-Related Analysis of
Pathway/Genome Databases Pacific Symposium on
Biocomputing 6:470-482 (2001).
(KEGG vs EcoCyc)
seems pretty obvious
• As compared to a sequence database
– (DNA or amino acid sequences)
– Prior organization based on sequence homologies
• Pathways as alternative approach to whole-cell model
– But similar- based on systemic understanding
– Building from the bottom up instead of top-down
– Also similarly in initial phases
• Technical details of implementation will be irritatingly vague
• Links constructed from functional interactions
– Fairly logical next step for biologists
– Moving from diagrams to graph/network structures
• So…metabolic networks and regulatory networks
Apoptosis
Citric acid cycle
Pain
the Boehringer-Mannheim wallcharts
more pain
Metabolic networks
• Each enzyme/reaction can be a path between nodes
– Each node is an enzyme substrate (product or reactant)
• Converting individual reactions to paths and nodes
– Produces directed graphs
• Classification of biochemical reactions
– EC numbering system (Enzyme Commission)
– Hierarchical numerical system i.e. 1.5.3.1
– Based on organic chemistry involved, not proteins
• How to translate from function to specific proteins?
Function to Enzyme mapping in
KEGG
• Original network based on biochemical studies
– Boehringer Mannheim and Japanese Biochemical Society
• How to assign function to enzyme? Do it by hand
– Then use FASTA sequence comparisons on each new genome
– Why does this irritate me? (feel free to shoot me down here)
• Which assignments are supported by experimental evidence?
• But anyway…
– Binary relations linking various pieces of data
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EC number to a particular enzyme
Organism to gene
Reactant to enzyme
Enzyme to product
Can produce derivative structures like reactant to product
• Lots of opportunities for relational database fun
Examples of relational links
The join function in KEGG
• Query relaxation
– Relaxing constraints on the lower two
numbers
– in the EC number system, i.e. 5.1.x.x
– Can search up hierarchy of sequences in EC
family
• Path computation
– Construction based on substrate-product
relations
KEGG example
EcoCyc (e. Coli encyclopedia)
• Takes approach based on single enzyme
reactions
– All assignments based on hand-annotations
– Integrated with complete genome data
• Allows for building of metabolic network
– You can start with known required compounds
(growth media and inside cell)
– Feed to get all required organic compounds (amino
acids, nucleic acids, etc)
– Focus on small molecules- i.e. no polymers
• Proteins (amino acid polymers)
• DNA and RNA (nucleic acid polymers)
What they did
• List of metabolites produced by network:
– Starting compound A, A -> B
– B -> C
– Therefore A-> C, repeat as necessary
• Finding precursors
– Product C not produced from above computation
• Find all reactions that produce C, i.e. A + B -> C
– Backtrack A and B to find their precursors
– Repeat as necessary until no reaction can be found
– This identifies earliest precursors with unknown origin
» outputs every possible combination of precursors
Results (sort of)
• Known inputs and outputs
– Necessary for cell survival and growth
– “bootstrapping” elements - already present in the cell
• Are required for their own synthesis
Results (2)
• Essential Elements
– DNA, RNA, amino acids
– Membrane components (phospholipids)
– Extracellular components
• Peptidoglycan- cross-linked sugar-amino acid chains
• Cell wall (surrounds bacterial cell)
Results (3)
– Identifies unknown synthesis
pathways and oddities in
simulation
– Cob(I)alamin
• Already known it can’t be synthesized
• Only used in anaerobic growth
• But it was simulated under aerobic
conditions
• Aerobic version of reaction requires 5…
– Synthesis of which is unknown
– Proteins are treated as bootstrap
compounds
– Some looped compounds
– Others have unknown synthesis
pathways