Pathways & Molecules

M.A. Ott (CMBI) Pathways & Molecules

M.A. Ott Pathways and Molecules Contents • Enzymes and Metabolites • Metabolic Pathways: Cholesterol Biosynthesis • Metabolic Disorders • BioMeta Database

M.A. Ott Pathways and Molecules Metabolite and Pathway Databases 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@ROL database ERGO comprehensive genome analysis Reactome biological processes IUBMB enzymes http://www.genome.ad.jp/kegg/ http://www.brenda.uni-koeln.de/ http://www.expasy.org/tools/pathways/ http://www.empproject.com/ http://metacyc.org/ http://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://www.reactome.org/ http://www.chem.qmul.ac.uk/iubmb/enzyme/

M.A. Ott Pathways and Molecules Metabolism and Friends • 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

M.A. Ott Pathways and Molecules Enzymes • 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

M.A. Ott Pathways and Molecules The Metabolic Network

M.A. Ott Pathways and Molecules Some Metabolites • “Common” metabolites:Water, NADH, ATP, Phosphate, … • End products of pathways:Vitamin B12, Urea, Penicillin, Ecdysone, … • Intermediates in pathways:Glucose-6-P, Lanosterol, Precorrins, Shikimate, …

M.A. Ott Pathways and Molecules Common Metabolites: ATP / ADP Full structures: Shorthand:

M.A. Ott Pathways and Molecules Common Metabolites: NADH / NAD+ Full structures: Shorthand:

M.A. Ott Pathways and Molecules Common Metabolites Water Ammonia Phosphate ATP, ADP NADH, NAD+ NADPH, NADP+ FAD, FADH2 FMN, FMNH2 SAM, SAH Coenzyme A Glutamate/2-Oxoglutarate Phosphorylation Reduction/oxidation Reduction/oxidation Reduction/oxidation Reduction/oxidation Methyl group transfer Acyl group transfer Amino/ketone group exchange

M.A. Ott Pathways and Molecules Cholesterol Biosynthesis: Outline

M.A. Ott Pathways and Molecules Cholesterol Biosynthesis from Squalene

M.A. Ott Pathways and Molecules Metabolic Disorders • Inability to synthesize compounds:Absence of important compounds • Inability to degrade compounds:Accumulation of undesired waste productsE.g., in phenylketonuria

M.A. Ott Pathways and Molecules Phenylketonuria (Error in Phenylalanine Catabolism)

M.A. Ott Pathways and Molecules The BioMeta Database

M.A. Ott Pathways and Molecules BioMeta Database Structure

M.A. Ott Pathways and Molecules BioMeta Database Structure Reaction 1: Mol_1 + Mol_2 <-> Mol_3 + Mol_4 Reaction 2: Mol_2 + Mol_3 --> Mol_5 + Mol_6 Reaction 3: 2 Mol_6 --> Mol_7 R-M Links Molecules Reactions

M.A. Ott Pathways and Molecules Sample Database Query ec_nr | enzyme_name | rxn_id |rev| role |stoich| name --------+-----------------+----------+---+------+------+------------ 1.2.3.4 | oxalate oxidase | MR000247 | i | s | 1 | Oxalic acid 1.2.3.4 | oxalate oxidase | MR000247 | i | s | 1 | O2 1.2.3.4 | oxalate oxidase | MR000247 | i | p | 1 | H2O2 1.2.3.4 | oxalate oxidase | MR000247 | i | p | 2 | CO2

M.A. Ott Pathways and Molecules Molecular Structures and Reactions Reactions: balancing atoms & charges adding direction/reversibility Molecules: adding stereochemical configurations “canonicalizing” tautomeric form

M.A. Ott Pathways and Molecules Alternative Pathways

M.A. Ott Pathways and Molecules BioMeta Database • 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

M.A. Ott Pathways and Molecules BioMeta: Things Being Done • 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) • Building WWW interface

M.A. Ott Pathways and Molecules BioMeta: Things To Do • Atom-to-atom correspondence (reaction mapping) • Pathway search & generation • Cellular localization • Enzyme – species relations

M.A. Ott Pathways and Molecules Acknowledgements Felix van Diggelen Gert Vriend CMBI

Pathways & Molecules