Creating the right chemistry in Pathways

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Creating the right chemistry in Pathways

• M.A. Ott (CMBI)

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Contents
M.A. Ott
Creating the right chemistry in Pathways

• Enzymes and Metabolites
• Metabolic Pathways and Reactions
• Representing Chemistry
• BioMeta Database

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Ongoing progess in omics
M.A. Ott
Creating the right chemistry in Pathways

• Genomics going strong
• Transcriptomics good progress
• Proteomics some progress
• Metabolomics less progress
• Systems biology not in ten years

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Pathways which?
M.A. Ott
Creating the right chemistry in Pathways
Signalling pathways
Metabolic pathways
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Metabolite and pathway databases
M.A. Ott
Creating the right chemistry in Pathways
http//www.genome.ad.jp/kegg/ http//www.brenda.un
i-koeln.de/ http//www.expasy.org/tools/pathways/
http//www.empproject.com/ http//metacyc.org/ htt
p//ecocyc.org/ http//www.ncgr.org/pathdb/ http/
/medicago.vbi.vt.edu/B-Net/ http//www.mol-net.de/
biopath/ http//www.ergo-light.com/ERGO/ http//ww
w.reactome.org/ http//www.chem.qmul.ac.uk/iubmb/e
nzyme/
Kyoto Encyclopedia of Genes and Genomes BRENDA
enzyme database ExPASy biochemical pathway EMP
enzymology and metabolism data MetaCyc metabolic
pathways EcoCyc E. coli genome and
metabolism PathDB biological pathways and
networks B-NET - Biochemical Network BioPath
C_at_ROL database ERGO comprehensive genome
analysis Reactome biological processes IUBMB
enzymes
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Metabolism and friends
M.A. Ott
Creating the right chemistry in Pathways

• Metabolism The reactions in organisms
• Anabolism Synthesis of larger biomolecules
  from smaller ones Usually requires
  energy input
• Catabolism Break down of larger molecules
  into smaller ones Usually releases energy

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Enzymes
M.A. Ott
Creating the right chemistry in Pathways

• Virtually all metabolic reactions require
  enzymatic catalysis
• Rate enhancement factor can be up to 1015
• Enzymes are highly reaction-specific,
  catalyzing only one conversion
• Enzymes are substrate-specific, limiting their
  action to only one compound or to related
  compounds

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The Metabolic Network
M.A. Ott
Creating the right chemistry in Pathways
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Some metabolites
M.A. Ott
Creating the right chemistry in Pathways

• Common metabolitesWater, NADH, ATP,
  Phosphate,
• End products of pathwaysVitamin B12, Urea,
  Penicillin, Ecdysone,
• Intermediates in pathwaysGlucose-6-P,
  Lanosterol, Precorrins, Shikimate,

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Common metabolites ATP / ADP
M.A. Ott
Creating the right chemistry in Pathways
Full structures
Shorthand
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Common metabolites NADH / NAD
M.A. Ott
Creating the right chemistry in Pathways
Full structures
Shorthand
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Common metabolites and chemical distance
M.A. Ott
Creating the right chemistry in Pathways
What is the chemical distance between B and D?
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Common metabolites
M.A. Ott
Creating the right chemistry in Pathways
Water Ammonia Phosphate ATP, ADP NADH,
NAD NADPH, NADP FAD, FADH2 FMN, FMNH2 SAM,
SAH Coenzyme A Glutamate/2-Oxoglutarate
Phosphorylation Reduction/oxidation Reductio
n/oxidation Reduction/oxidation Reduction/oxidati
on Methyl group transfer Acyl group
transfer Amino/ketone group exchange
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Cholesterol biosynthesis outline
M.A. Ott
Pathways and Molecules
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Cholesterol biosynthesis from squalene
M.A. Ott
Pathways and Molecules
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Metabolic disorders
M.A. Ott
Pathways and Molecules

• Inability to synthesize compoundsAbsence of
  important compounds
• Inability to degrade compoundsAccumulation of
  undesired waste productsE.g., in phenylketonuria

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Phenylketonuria (error in phenylalanine
catabolism)
M.A. Ott
Pathways and Molecules
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The BioMeta Database
M.A. Ott
Creating the right chemistry in Pathways
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BioMeta database structure
M.A. Ott
Creating the right chemistry in Pathways
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BioMeta database structure
M.A. Ott
Creating the right chemistry in Pathways
Reaction 1 Mol_1 Mol_2 lt-gt Mol_3
Mol_4 Reaction 2 Mol_2 Mol_3 --gt Mol_5
Mol_6 Reaction 3 2 Mol_6 --gt
Mol_7
R-M Links
Molecules
Reactions
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Sample database query
M.A. Ott
Creating the right chemistry in Pathways

• ec_nr enzyme_name rxn_id rev role
  stoich name
• ---------------------------------------------
  ------------------
• 1.2.3.4 oxalate oxidase MR000247 ir s
  1 Oxalic acid
• ,, ,, ,, ,, s
  1 O2
• ,, ,, ,, ,, p
  1 H2O2
• ,, ,, ,, ,, p
  2 CO2

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Molecular structure identification
M.A. Ott
Creating the right chemistry in Pathways

• Mesomerism (resonance forms)
• Tautomerism (variable positions of hydrogens)
• Other chemical flexibility
• Protonation state

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Molecular structures and reactions
M.A. Ott
Creating the right chemistry in Pathways

• Reactions balancing atoms charges
• adding direction/reversibility
• Molecules adding stereochemical configurations
• canonicalizing tautomeric form

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And now whats really going on
M.A. Ott
Creating the right chemistry in Pathways

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Accuracy required!
M.A. Ott
Creating the right chemistry in Pathways

• Without accurate chemical structures and
  balancedreaction descriptions, a biochemical
  pathways database is unsuitable for chemical
  computation

• Graph-theoretical considerations for creating a
  network
• Idem for describing fluxes
• Docking applications need correct stereochemistry

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Some unresolved issues
M.A. Ott
Creating the right chemistry in Pathways

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BioMeta database
M.A. Ott
Creating the right chemistry in Pathways

• Based on freely available data (KEGG Ligand
  database)
• Augmentation, completion and correction of
  small-molecule information - Adding missing
  stereochemistry to structures - Balancing atoms
  and charges in reactions - Establishing the
  reversibility and direction of reactions
• Search for alternative pathways between
  metabolites
• Search for missing enzymes

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Alternative pathways
M.A. Ott
Creating the right chemistry in Pathways
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BioMeta things being done
M.A. Ott
Creating the right chemistry in Pathways

• Enhancing compound/reaction structures
• Establishing directionality/reversibility of
  reactions
• Distinguishing cofactors/current/external/
  common metabolites from real metabolites
• Adding more compound data, e.g. pKa (curve)
• Increasing functionality of WWW interface

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BioMeta things to do
M.A. Ott
Creating the right chemistry in Pathways

• Atom-to-atom correspondence (reaction mapping)
• Tautomer handling
• Pathway search generation
• Cellular localization
• Enzyme species relations

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Acknowledgements
M.A. Ott
Creating the right chemistry in Pathways

• Felix van Diggelen
• Gert Vriend
• CMBI