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Introduction to biochemical networks

Graph-based analysis of biochemical networks. Introduction to biochemical networks. H 2 O. L-Methionine. L-Phenylalanine. ATP. Small molecules. Chemical Reaction. Macromolecules. Protein. DNA. Protein-DNA interaction. Organelles. Mitochondrion. Chloroplast. Cell nucleus. Ribosome.

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Introduction to biochemical networks

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  1. Graph-based analysis of biochemical networks Introduction to biochemical networks Jacques van HeldenJacques.van.Helden@ulb.ac.be

  2. H2O L-Methionine L-Phenylalanine ATP Small molecules

  3. Chemical Reaction

  4. Macromolecules Protein DNA

  5. Protein-DNA interaction

  6. Organelles Mitochondrion Chloroplast Cell nucleus Ribosome source: http://tidepool.st.usm.edu/capstone/

  7. Cells Eukaryote Prokaryote source: http://tidepool.st.usm.edu/capstone/

  8. Organs Lung Brain Heart Source: http://sig.biostr.washington.edu/projects/da/

  9. Bacteria Yeast Animal Plant Fungus Organisms Monocellular Multicellular

  10. glutamate gamma-glutamyl kinase proB proB ATP ATP 2.7.2.11 2.7.2.11 catalyzes catalyzes expression codes for ADP ADP gamma-glutamyl phosphate gamma-glutamylphosphate reductase proA proA NADPH; H+ NADPH; H+ 1.2.1.41 1.2.1.41 catalyzes catalyzes codes for expression NADP; Pi NADP; Pi glutamate gamma-semialdehyde spontaneous spontaneous H2O H2O 1-pyrroline-carboxylate 1-pyrroline-5-carboxylate reductase proC proC NADPH NADPH 1.5.1.2 1.5.1.2 catalyzes catalyzes codes for expression NADP NADP proline proline inhibits inhibits Metabolic Pathway: Proline Biosynthesis in E.coli

  11. r4 reaction 2.7.2.4 catalysis expr expression repr repression up-reg up-regulation Aspartate biosynthesis L-Aspartate inhib inhibition aspartate kinase II/homoserine dehydrogenase II ATP act activation metL 2.7.2.4 expr r1 ADP repr L-aspartyl-4-P Aspartate semialdehyde deshydrogenase NADPH asd 1.2.1.11 expr r2 NADP+; Pi Lysine biosynthesis L-aspartic semialdehyde metJ NADPH 1.1.1.3 r3 NADP+ repr expr Threonine biosynthesis L-Homoserine repr SuccinylSCoA Homoserine O-succinyltransferase Methioninerepressor metA 2.3.1.46 expr r4 HSCoA inhib Alpha-succinyl-L-Homoserine Cysteine biosynthesis repr L-Cysteine Cystathionine-gamma-synthase metB 4.2.99.9 expr r5 repr Succinate Cystathionine metR repr H2O Cystathionine-beta-lyase metC 4.4.1.8 expr r6 expr Pyruvate; NH4+ Homocysteine Cobalamin-independent-homocysteine transmethylase metR metE 2.1.1.14 expr up-reg 5-MethylTHF r7 THF Cobalamin-dependent-homocysteine transmethylase metH 2.1.1.13 expr up-reg L-Methionine ATP; H2O S-adenosylmethionine synthetase metK 2.5.1.6 expr r8 Pi; PPi S-Adenosyl-L-Methionine act Methionine Biosynthesis in E.coli

  12. Aspartate biosynthesis L-Aspartate ATP Aspartate kinase HOM3 2.7.2.4 ADP L-aspartyl-4-P NADPH Aspartate semialdehyde deshydrogenase HOM2 1.2.1.11 NADP+; Pi L-aspartic semialdehyde NADPH Homoserine deshydrogenase HOM6 1.1.1.3 NADP+ Threonine biosynthesis MET31 MET32 Met31pmet32p L-Homoserine AcetlyCoA Homoserine O-acetyltransferase MET2 2.3.1.31 CoA O-acetyl-homoserine Sulfur assimilation Sulfide O-acetylhomoserine (thiol)-lyase MET17 4.2.99.10 MET28 Homocysteine Cbf1p/Met4p/Met28p complex CBF1 Cysteine biosynthesis MET4 5-methyltetrahydropteroyltri-L-glutamate Methionine synthase (vit B12-independent) GCN4 Gcn4p MET6 2.1.1.14 5-tetrahydropteroyltri-L-glutamate L-Methionine MET30 Met30p S-adenosyl-methionine synthetase I SAM1 H20; ATP 2.5.1.6 S-adenosyl-methionine synthetase II Pi, PPi SAM2 S-Adenosyl-L-Methionine Methionine Biosynthesis in S.cerevisiae

  13. Sulfur Assimilation in yeast Sulfate (extracellular) Sulfate transporter SUL1 Sulfate transport Sulfate transporter SUL2 Sulfate (intracellular) ATP Sulfate adenylyltransferase MET3 2.7.7.4 PPi MET31MET32 Met31p Met32p Adenylyl sulfate (APS) ATP Adenylyl sulfatekinase MET14 2.7.1.25 ADP 3'-phosphoadenylylsulfate (PAPS) NADPH 3'-phosphoadenylylsulfatereductase MET16 1.8.99.4 MET28 NADP+; AMP; H+; 3'-phosphate (PAP) CBF1 Cbf1p/Met4p/Met28p complex sulfite MET4 Putative Sulfite reductase MET5 3 NADPH; 5H+ 1.8.1.2 GCN4 Gcn4p 3 NADP+; 3 H2O Sulfite reductase (NADPH) MET10 sulfide Methionine biosynthesis MET30 Met31p

  14. L-Aspartate 2.7.2.4 S.cerevisiae E.coli L-aspartyl-4-P 1.2.1.11 L-aspartic semialdehyde 1.1.1.3 L-Homoserine 2.3.1.31 2.3.1.46 Alpha-succinyl-L-Homoserine O-acetyl-homoserine 4.2.99.9 Cystathionine 4.2.99.10 4.4.1.8 Homocysteine 2.1.1.14 L-Methionine 2.5.1.6 S-Adenosyl-L-Methionine Alternative methionine pathways

  15. KEGG "consensus pathway" for Methionine metabolism

  16. Aspartate biosynthesis L-Aspartate ATP aspartate kinase III metL 2.7.2.4 ADP L-aspartyl-4-P NADPH; H+ aspartate semialdehyde deshydrogenase asd Methionine biosynthesis 1.2.1.11 NADP+; Pi L-aspartic semialdehyde Threnonine biosynthesis pyruvate dihydrodipicolinate synthase dapA 4.2.1.52 2 H2O dihydropicolinic acid NADPH or NADH; H+ dihydrodipicolinate reductase dapB 1.3.1.26 NADP+ or NAD+ tetrahydrodipicolinate succinyl CoA tetrahydrodipicolinae N-succinyltransferase dapD 2.3.1.117 CoA N-succinyl-epsilon-keto-L-alpha-aminopimelic acid glutamate succinyl diaminopimelateaminotransferase dapC 2.6.1.17 alpha-ketoglutarate succinyl diaminopimelate H2O N-succinyldiaminopimelatedesuccinylase dapE 3.5.1.18 succinate LL-diaminopimelic acid diaminopimelateepimerase dapF 5.1.1.7 meso-diaminopimelic acid diaminopimelatedecarboxylase lysRprotein lysR lysA 3.5.1.18 CO2 L-lysine Lysine biosynthesis in Escherichia coli

  17. LYS5 LYS2 Lysine biosynthesis in Saccharomyces cerevisiae 2-Oxoglutarate Acetyl-CoA homocitrate synthase LYS20 4.1.3.21 CoA 1,2,4-Tricarboxylate homocitrate dehydratase LYS7 But-1-ene-1,2,4-tricarboxylate H2O homoaconitate hydratase LYS4 4.2.1.36 Homoisocitrate NAD+ 1.1.1.87 H+; NADH Oxaloglutarate Homoisocitrate dehydrogenase 1.1.1.87 CO2 2-Oxoadipate L-Glutamate aminoadipate aminotransferase 2.6.1.39 2-Oxoglutarate L-2-Aminoadipate H+ ; NADH (or NADPH) amlnoadipate semialdehyde dehydrogenase 1.2.1.31 NAD+( or NADP+); H2O L-2-Aminoadipate 6-semialdehyde L-Glutamate ; NADPH (or NADH); H+ saccharopine dehydrogenase (glutamate forming) LYS9 1.5.1.10 NADP+ (OR NAD+); H2O N6-(L-1,3-Dicarboxypropyl)-L-lysine NADP+ (OR NAD+) ; H2O saccharopine dehydrogenase (lysine forming) LYS1 1.5.1.7 2-Oxoglutarate ; NADPH (OR NADH) ; H+ L-lysine

  18. Lysine biosynthesis in KEGG (yeast enzymes in green)

  19. Threonine biosynthesis in Escherichia coli L-Aspartate ATP inhibition Aspartate kinase Ihomoserine dehydrogenase I 2.7.2.4 translation catalysis ADP L-Aspartyl-4-P NADPH Aspartate semialdehyde deshydrogenase asd 1.2.1.11 catalysis expression NADP+; Pi L-Aspartic semialdehyde NADPH inhibition 1.1.1.3 catalysis NADP+ L-Homoserine ATP inhibition Cystathionine-gamma-synthase 2.7.1.39 translation catalysis ADP L-Homoserine phosphate H2O Cystathionine-beta-lyase 4.4.1.8 translation catalysis Pi L-Threonine thrABC mRNA thrABC operon transcription Attenuation

  20. Aspartate-derivative amino acids aspartate common fork for aspartate derivatives inhibition inhibition inhibition L-aspartic semialdehyde Homoserine biosynthesis Lysine biosynthesis inhibition inhibition inhibition L-Cysteine L-Homoserine L-Lysine Methionine biosynthesis Threonine biosynthesis inhibition inhibition inhibition L-Threonine L-Methionine Isoleucine biosynthesis inhibition L-Isoleucine

  21. Proline utilization in Escherichia coli Proline proline transporter transport catalysis translocation putP expression repression Proline H2O; FAD proline dehydrogenase/pyrroline-5-carboxylate dehydrogenase putA expression catalysis 1.2.1.11 FADH2 1-pyrroline-5-carboxylate NAD; H2O 1.2.1.11 catalysis NADH cytoplasm glutamate membrane extracellular space

  22. Extracellular space Extracellular space TNFalpha TNFalpha activates activates TNFR1 TNFR1 Cell membrane Cell membrane Cytoplasm Cytoplasm TRADD TRADD binds binds binds binds binds binds TRAFF2 TRAFF2 activates activates cIAP1 cIAP1 apoptosis apoptosis IKK complex IKK complex gamma subunit gamma subunit NIK NIK activates activates IKKbeta IKKbeta S26 S26 IKKalpha IKKalpha IKAP IKAP activates activates catalyzes catalyzes P-IkappaB P-IkappaB Ubiq-P-IkappaB Ubiq-P-IkappaB P-IkappaB P-IkappaB IkappaB IkappaB degradation degradation ubiquitination ubiquitination phosphorylation phosphorylation dissociates dissociates NFkappaB NFkappaB NFkappaB NFkappaB NFkappaB NFkappaB NFkB/P-IkB complex NFkB/P-IkB complex NFkB/IkB complex NFkB/IkB complex Nuclear membrane Nuclear membrane translocates translocates Nucleus Nucleus regulates transcription regulates transcription NFkappaB NFkappaB Signal transduction: TNF pathway

  23. PHO2 PHO2 PHO3 PHO3 acid phosphatase acid phosphatase acid phosphatase acid phosphatase expression codes for up-regulates is secreted secretion expression codes for Up-regulates expression up-regulates PHO5, 11,12 PHO5, 11,12 catalyzes catalyzes up-regulates Pho2p Pho2p Pi transporter Pi transporter up-regulates expression codes for orthophosphoric monoester orthophosphoric monoester PHO84, 86,87,88,89 PHO84, 86,87,88,89 alkaline phosphatase alkaline phosphatase H2O H2O up-regulates Pho4p Pho4p expression codes for orthophosphoric monoester orthophosphoric monoester PHO8 PHO8 H2O H2O 3.1.3.1 3.1.3.1 PHO4 PHO4 3.1.3.2 3.1.3.2 catalyzes catalyzes up-regulates (nucleus) PHO81 PHO81 transports facilitates up-regulates alcohol alcohol Pi Pi alcohol alcohol is tranferred translocates expression codes for expression codes for is tranferred transport Pho4p-Phosphate Pho4p-Phosphate Pi Pi 2.7.1.- 2.7.1.- Pho4p Pho4p inhibits inhibits catalyzes catalyzes Pho81p Pho81p inhibits inhibits Pho85p Pho85p Pho80p Pho80p extracellular space (cytoplasm) Pho85-Pho80 complex Pho85-Pho80 complex Phosphate utilization in yeast

  24. nucleus Mevalonate biosynthesis cytosol cytosol glycolysis acetyl-CoA acetyl-CoA beta oxidation of fatty acids beta oxidation of fatty acids beta-ketothiolyase beta-ketothiolyase 2 2 ACAT1 ACAT1 2.3.1.9 2.3.1.9 catalyzes catalyzes expression codes for HSCoA HSCoA acetoactetyl-CoA acetoactetyl-CoA HMG-CoA synthase HMG-CoA synthase HMGCS1 HMGCS1 acetyl-CoA; H2O acetyl-CoA; H2O 4.1.3.5 4.1.3.5 catalyzes catalyzes expression codes for HSCoA HSCoA inhibits inhibits SREPB SREPB LDL LDL up-regulates up-regulates HMG-CoA HMG-CoA inhibits inhibits ER membrane ER membrane up-regulates up-regulates protein kinase protein kinase inhibits inhibits HMG-CoA reductase HMG-CoA reductase 2 NADPH; 2H+ 2 NADPH; 2H+ is transcribed transcription is translated translation 1.1.1.34 1.1.1.34 catalyzes catalyzes HMGCR mRNA HMGCR mRNA 2 NADP+; HSCoA 2 NADP+; HSCoA HMGCR HMGCR inhibits inhibits inhibits inhibits SREBP pathway SREBP pathway mevalonate mevalonate non sterol metabolites degrades degrades inhibits inhibits sterol biosynthesis sterol biosynthesis

  25. Legend gene gene ER membrane ER membrane inhibits inhibits sterols sterols compound compound ER lumen ER lumen protein protein activates activates SCAP SCAP link from/ to other map link from/ to other map compartment compartment SREBP precursor SREBP precursor cleavage cleavage catalyzes catalyzes Site 1 protease Site 1 protease codes for codes for site 1 cleaved site 1 cleaved SREBP precursor SREBP precursor cleavage cleavage catalyzes catalyzes Site 2 protease Site 2 protease cytosol cytosol SREBP SREBP translocation translocation nucleus nucleus sterol biosynthesis sterol biosynthesis SREBP SREBP sterol uptake sterol uptake fatty acid biosynth. fatty acid biosynth. SREBP transcription factor SREBP protein SREBP pathway

  26. Glycolysis : feed-forward activation Glucose Fructose 2,6-biphosphate Hexokinase Glucose 6-phosphate Fructose biphosphatase 2 Fructose 6-phosphate activates Phosphofructokinase Fructose 1,6-biphosphate Dihydroxyacetone phosphate Glyceraldehyde3-phosphate Phosphoenolpyruvate activates Pyruvate kinase Pyuvate

  27. Glycolysis : feed-back inhibition Glucose Hexokinase Glucose 6-phosphate Fructose 6-phosphate Phosphofructokinase Fructose 1,6-biphosphate inhibits Dihydroxyacetone phosphate Glyceraldehyde3-phosphate inhibits inhibits Phosphoenolpyruvate Pyruvate kinase inhibits inhibits Pyuvate Alanine Citrate Krebbs cycle Respiratory chain H+ ATP

  28. Gluconeogenesis Glucose Pi Glucose6-phosphatase H2O Glucose 6-phosphate De novo synthesis of glucose, in conditions of glucose starvation It is not the reverse of glycolysis Gluconeogenesis costs 6 phosphate bonds/glucose, whereas glycolysis brings 2 phosphate bonds/glucose Fructose 6-phosphate Pi Fructose 1,6-biphosphatase H2O Fructose 1,6-biphosphate Dihydroxyacetone phosphate Glyceraldehyde3-phosphate Glycerol Phosphoenolpyruvate GDP Phosphoenolpyruvatecarboxylase GTP Oxaloacetate ADP Pyruvatecarboxylase ATP Pyuvate

  29. Regulation of gluconeogenesis Glucose Glucose6-phosphatase Fructose 2,6-biphosphate H2O Glucose 6-phosphate Phosphofructokinase 2 Fructose 6-phosphate inhibits AMP activates inhibits ADP Fructose 1,6-biphosphatase activates ATP Fructose 1,6-biphosphate Dihydroxyacetone phosphate Glyceraldehyde3-phosphate Glycerol Phosphoenolpyruvate Phosphoenolpyruvatecarboxylase Oxaloacetate Pyruvatecarboxylase Pyuvate

  30. nucleus Mevalonate biosynthesis cytosol cytosol glycolysis acetyl-CoA acetyl-CoA beta oxidation of fatty acids beta oxidation of fatty acids beta-ketothiolyase beta-ketothiolyase 2 2 ACAT1 ACAT1 2.3.1.9 2.3.1.9 catalyzes catalyzes expression codes for HSCoA HSCoA acetoactetyl-CoA acetoactetyl-CoA HMG-CoA synthase HMG-CoA synthase HMGCS1 HMGCS1 acetyl-CoA; H2O acetyl-CoA; H2O 4.1.3.5 4.1.3.5 catalyzes catalyzes expression codes for HSCoA HSCoA inhibits inhibits SREPB SREPB LDL LDL up-regulates up-regulates HMG-CoA HMG-CoA inhibits inhibits ER membrane ER membrane up-regulates up-regulates protein kinase protein kinase inhibits inhibits HMG-CoA reductase HMG-CoA reductase 2 NADPH; 2H+ 2 NADPH; 2H+ is transcribed transcription is translated translation 1.1.1.34 1.1.1.34 catalyzes catalyzes HMGCR mRNA HMGCR mRNA 2 NADP+; HSCoA 2 NADP+; HSCoA HMGCR HMGCR inhibits inhibits inhibits inhibits SREBP pathway SREBP pathway mevalonate mevalonate non sterol metabolites degrades degrades inhibits inhibits sterol biosynthesis sterol biosynthesis

  31. Summary - biochemical networks • Biochemical networks combine different types of molecular interactions (reaction, catalysis, activation, transport, ...) • Context-dependence • The activity of a protein is context-dependent (environment, cell-type, subcellular location, ...). • Regulation • Multiple mechanisms: transcriptional, RNA maturation, translational, location, protein degradation, ... • Enzymes involved in a common pathway are generally co-regulated. • Isofunctional proteins • An organism can contain several proteins able to carry out the same function. • Isofunctional proteins are usually regulated differentially : each copy will be active under specific conditions. • Multifunctional proteins • A single protein can carry several functions.

  32. Summary - biochemical networks • Enzyme sequence/structure is relatively well conserved between organisms. • The transcriptional regulation mechanism (transcription factor, binding sites) is much less conserved than enzyme sequence/structure. • Each organism has a specific set of enzymes in its genome. • Some organisms have many enzymes and are able to live in a wide variety of conditions. • Some organisms have a restricted number of enzyme, and rely on external input for the other compounds. • Different organisms can use alternative pathways to synthesise the same molecule.

  33. Metabolic pathways Pathway evolution • Different organisms use different pathways for the biosynthesis/utilization of the same compound. • Our current knowledge is based on a restricted number of model organisms. • Even in these organisms, many pathways still need to be characterized (e.g. amino acid degradation is still not well known in yeast). • Reactions that could be part of totally novel pathways • Many reactions without known catalyst • Many catalysed reactions from LIGAND not part of any KEGG pathway Metabolic regulation • Metabolic pathways are generally regulated • Multiple levels of regulation • Transcriptional regulation often affects most enzymes of a pathway

  34. Path finding in biochemical neworks • 2-ends path finding • Find all pathways from compound A to compound B • 1-end path finding • Find all genes regulated by a membrane receptor via a signal transduction pathway • 1-end path finding, reverse • Find all proteins and compounds exerting a director indirect action on the level of expression of a given gene • Circuit finding • Find all feed-back loops

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