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Biological P athways

Biological P athways. Janick Mathys. Biological P athways. Definition Biochemical compounds Biological interactions Energy Control interactions Levels of abstraction Types of biological pathways Integration of pathways Inference Issues. Biological Pathways. Definition:

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Biological P athways

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  1. BiologicalPathways Janick Mathys

  2. BiologicalPathways Definition Biochemical compounds Biological interactions Energy Control interactions Levels of abstraction Types of biological pathways Integration of pathways Inference Issues

  3. Biological Pathways Definition: A biological pathway is a sequence of interactions between biochemical compounds aimed at the maintenance and control of the flow of information, energy and biochemical compounds in the cell and the ability of the cell to change its behaviour in response to stimuli.

  4. Biological Pathways Definition: A biological pathway is a sequence of interactions between biochemical compounds aimed at the maintenance and control of the flow of information, energy and biochemical compounds in the cell. Main types of compounds in the context of pathways: - proteins and protein complexes - (part of) genes - metabolites

  5. Biochemical compounds • (part of) genes • proteins and protein complexes • metabolites • Amino acids and peptides : A, C, F, G, H, S… • Carbohydrates (sugars) • Cell-structure components • Cofactors, prosthetic groups and electron carriers: vitamins • Fatty acids and lipids • Nucleotides and nucleic acids: A, C, T, G • Monocarbon compounds: CO, CH4, CH3OH • Essential elements: S, P, O2, Fe, radicals • Aromatic compounds: compounds with special stability and properties due to a closed loop of electrons (ring structure) • …

  6. Biochemical compounds genes - Fundamental physical and functional units of heredity - Ordered sequences of nucleotides located in a particular position on a particular chromosome that encodes a specific functional product (i.e. protein or RNA molecule) regulatory DNA sequences - Small conserved sequences that interact with special types of proteins (TF) thereby activating or repressing the expression of target genes - Located in the promotor region in front of the target gene Regulatory sequences RBS gene Promoter

  7. Biochemical compounds Protein: 3D-chain of amino acids that is represented as a linear sequence of amino acid letter codes and performs a molecular function proteins and protein complexes Ras protein Transcription initiation complex in eukaryotes

  8. Biochemical compounds metabolites Any product of metabolism such as an intermediate or an end product that is excreted Examples: - amino acids e.g. cysteine - carbohydrates e.g. glucose - …

  9. Biological Pathways Definition: A biological pathway is a sequence of interactions between biochemical compounds aimed at the maintenance and control of the flow of information, energy and biochemical compounds in the cell. Biological Interactions: Substrates Products Interaction Energy

  10. Biological Interactions Substrates Products Interaction Main types of interactions in the context of pathways: - Expression - Assembly/Disassembly - Transport - Chemical reactions Energy

  11. Biological Interactions I. Expression: The process by which a gene's information is converted into a protein Expressed genes are transcribed into mRNA and translated into protein or transcribed into RNA but not translated (transfer and ribosomal RNAs). II. Assembly: The formation of a complex of proteins, RNA and/or DNA with a molecular function that cannot be performed by the individual compounds Gene Protein Expression Protein A Complex Assembly Protein B

  12. Biological Interactions Fus1 Cell fusion protein 1 fus1 Expression - Expression: mRNA fus1 DNA Nucleus DNA fus1 mRNA Fus1 protein AA1 AA2 AA3 Yeast

  13. Biological Interactions • Assembly of complexes: Ribosomes: - complexes of RNA and proteins - translate genetic information into protein Prokaryotes Eukaryotes

  14. Biological Interactions Detail: Assembly of the small ribosomal subunit in prokaryotes Prokaryotes

  15. 16S rRNA 21 proteins Biological Interactions ribosome 23S rRNA 5S rRNA 31 proteins Prokaryotes

  16. Biological Interactions III. Transport: Change of location of compounds IV. Chemical reaction: Compound A at location 1 Compound A at location 2 Transport Compound A Compound B Reaction

  17. Biological Interactions - Transport: a. Transport of nascent proteins through plasma membrane of the ER: b. Transport of glucose from the lumen of the intestine into the blood: Ribosome - nascent protein complex in cytoplasm Nascent protein in lumen of ER Transport Glucose in intestine Glucose in epithelial cell Glucose in blood Transport Transport

  18. Biological Interactions Plasma membrane of the ER a. Transport of nascent proteins into the lumen of the endoplasmic reticulum in eukaryotes ER : organelle of eukaryotic cells consisting of a ±continuous system of membrane-bound cavities throughout the cytoplasm of a cell. Its function is the transport of proteins that have to be secreted to the membrane of the cell. Eukaryotes

  19. Biological Interactions Plasma membrane of the ER b.Glucose transport from the lumen of the intestine into the blood stream Higher Eukaryotes

  20. Biological Interactions - Chemical reactions: 1. Redox reactions: Oxidation - Reduction (Photosynthesis): transfer of e- from electron donors to electron acceptors 2. Phosphorylation - Dephosphorylation (Signal transduction): addition/removal of phosphate groups 3. Hydrolysis: breakdown of bonds in compounds through the addition of water 4. Splitting or forming of a C-C bond 5. Isomerisation: Change of geometry or structure of a compound 6. Polymerisation 7. …

  21. Chemical Reactions 1. Oxidation – Reduction of NADH – NAD+: H+ + 2e- +

  22. Chemical Reactions 2. Phosphorylation: Phosphorylation cascade involved in the uptake of glucose into the cell 1. Non ionic glucose is pumped through the cell membrane, which is negatively charged 2. A cascade of phosphorylations and dephos- phorylations takes place resulting in the phosphorylation of glucose as it enters the cell 3. The ionic nature of Glucose-6-P prevents it from escaping back through the membrane -OH Prokaryotes ATP ADP

  23. Chemical Reactions 3. Hydrolysis: hydrolysis of lactose into galactose and glucose by beta-galactosidase 1. Lactose is pumped through the cell membrane 2. Hydrolysis of lactose into galactose and glucose immediately as it enters the cell => Extra step (energy cost) as compared with the metabolism of glucose Prokaryotes

  24. Chemical Reactions 4. Splitting C-C bonds: Cleavage of fructose-1,6-PP to dihydroxyacetone-P + glyceraldehyde-3-P P has the size of fructose core => 2 negative P in close proximity => stress 5. Isomerisation: Rearrangment of Glucose-6-P into Fructose-6-P, a more compact and lower entropy (more unstable thus more willing to react) molecule Fructose-1,6-PP aldolase Fructose-1,6-PP DHAP + GA-3-P Phosphohexose isomerase Glucose-6-P Fructose-6-P

  25. Biological Interactions Substrate Product Interaction • Energy is always required to form chemical bonds • Energy is sometimes released by the breaking of chemical bonds • For biological interactions the cell uses 3 energy sources: - ATP: Adenosine TriPhosphate - GTP: Guanine TriPhosphate - Creatine phosphate • ATP is generated by electron transfer in mitochondria: - Electron carriers pick up H+ and e- released by the breakdown of nutrients (e.g. glucose) - Electron carriers transfer H+ and e- to electron carriers in the mitochondrial membrane - Transfer of e- through the mitochondrial membrane down to O2 releases energy - This energy is used to transport the H+ across the mitochondrial membrane - Rush of H+ releases energy used for phosphorylation of ADP to generate ATP Energy

  26. Energy sources • ATP: Adenosine TriPhosphate • Primary energy source of cells • Building block for DNA • High energy bonds between phosphates • Dephosphorylation of outer phosphate to form ADP releases 7.3 kcal/mol • GTP: Guanine TriPhosphate • Secondary energy source of cells • Building block for DNA • Bound by G-proteins for signal transduction • High energy bonds between phosphates • Dephosphorylation of outer phosphate to form GDP releases 7.5 kcal/mol • (Cleaving the phosphate-ribose bond would release only 5 kcal/mol) • Creatine phosphate • Extra energy source for muscle cells • Dephosphorylation releases 10.3 kcal/mol ! all nucleotides are full of energy e.g. transcription: energy comes from dNTPs themselves

  27. 16S rRNA 21 proteins Energy GTP provides energy for the assembly of the large subunit and the 30S complex ribosome 23S rRNA 5S rRNA 31 proteins Prokaryotes

  28. Energy Plasma membrane of the ER Transport of nascent proteins into the lumen of the ER in eukaryotes GTP provides energy for binding of ribosome to ribophorin and for insertion of peptide in the membrane Eukaryotes

  29. Na+ Na+ Na+ Energy Plasma membrane of the ER Glucose transport from the lumen of the intestine into the blood stream ATP provides energy for transport of Na+/K+ out/in cell (against concentration gradient) ! Transport of glucose down concentration gradient: no ATP required Higher Eukaryotes

  30. Electron carriers • NADH: Nicotinamide Adenine Dinucleotide • Oxidation to NAD+ releases 52.6 kcal/mol • Due to some inefficiency this only allows 3 ATPs to be formed • FADH2: Flavine Adenine Dinucleotide • Oxidation to FAD releases 43.4 kcal/mol • Due to some inefficiency this only allows 2 ATPs to be formed

  31. Electron carriers 1. Oxidation – Reduction of NADH – NAD+: H+ + 2e- +

  32. Biological Interactions Control Interactions: Enhance or repress other interactions Main types of control interactions: - transport facilitation - enzymatic catalysis - inhibition - activation of gene expression - repression of gene expression + -

  33. Control Interactions I. Transport Facilitation: Compound A at location 1 Compound A at location 2 Transport + Facilitation Transporter protein

  34. Control Interactions Plasma membrane of the ER - Transport Facilitation: a. Facilitation of the transport of nascent proteins into the lumen of the endoplasmic reticulum by ribophorin Eukaryotes

  35. Control Interactions Plasma membrane of the ER Transport Facilitation: b.Glucose transport from the intestine into the blood stream is facilitated by - Na+-glucose cotransporter pore complex - glucose transporter protein http://bio.winona.msus.edu/berg/ANIMTNS/FacDiff.htm Removal of Na+ in epithelial cells is facilitated by Na+/K+ pump Higher Eukaryotes

  36. Control Interactions c. Facilitation of the transport of glucose and lactose into the cell by EIICB and lactose permease Prokaryotes

  37. Control Interactions II. Catalysis of chemical reactions by enzymes: Enzymes: Proteins (RNAs) that act as biological catalysts, speeding up reaction rate by reducing the amount of required energy * by concentrating different substrates * by inducing conformational changes in substrates through binding Enzymes DO NOT participate in the reaction or alter its direction/nature Compound A Compound B Reaction + Catalysis Enzyme

  38. Control Interactions - Catalytic Enzymes : 1. Redox reactions: oxidase, dehydrogenase transfer of e- from electron donors to electron acceptors 2. Phosphorylation - Dephosphorylation: kinase, phosphatase addition - removal of phosphate groups 3. Hydrolysis: hydrolase breakdown of bonds through the addition (- removal) of water 4. Transfer of a side group: transferases 5. Splitting or forming a C-C bond: desmolase, aldolase 6. Changing geometry or structure of a compound: isomerase, gyrase 7. Joining two compounds through hydrolysis of ATP: ligase 8. Polymerisation: polymerase

  39. Control Interactions III. Inhibition: Compound A Compound B Interaction - Inhibition Compound Control interactions form a means of using compounds to introduce feedback !

  40. Control Interactions Inhibition of the transport of lactose into the cell in prokaryotes by a component (EIIAGlc) of the glucose transporter complex => Catabolite repression - Inhibition Lactose extracellular Lactose intracellular 1. Glucose is pumped through the cell membrane 2. A cascade of phosphorylations and dephos- phorylations takes place resulting in - the phosphorylation of glucose - the dephosphorylation of EIIAGlc-P into EIIAGlc 3. EIIAGlc shuts down the lactose permease, pre- venting lactose from entering the cell Conclusion: Catabolite repression: This system ensures that bacteria give preference to the most energetic nutrient Transport + - Facilitation Inhibition EIIAGlc Lactose permease

  41. Control Interactions Gene Protein IV. Activation of gene expression: V. Repression of gene expression: Expression + Activation Transcription factor Gene Protein Expression - repression Transcription factor

  42. Control Interactions Activation of gene expression:

  43. Control Interactions Activation of gene expression: - DNA is packaged into nucleosomes and higher-order chromatin structures -Transcription factor bindsspecific regulatory element - Transcription factor recruits chromatin remodeling and modifying complexes - Transcription factor recruits components of the transcription initiation complex - Transcription factor stimulates activity of assembled transcription complex

  44. Control Interactions Transcription factor (complexes): • Proteins that bind to specific regulatory sequences in the DNA • Regulate the level of expression of target gene(s) by controlling whether and how vigorously the gene is transcribed into RNA • The on/off switches and rheostats of a (group of) target gene(s) Regulatory DNA sequences • Every gene has its own cis-acting regulatory sequences • Vary greatly in complexity among genes and organisms When active transcription factors associate with the regulatory sequences of their target genes, they can function to repress (down-regulate) or induce (up-regulate) transcription of the corresponding RNA

  45. Cysteine Amino Acids Protein (Molecular Function) Pathway (Biological process)

  46. Biological Pathways • Metabolic pathways • Developmental pathways • Signal-transduction pathways • Genetic regulatory circuits = genetic networks • Pathways interact • Pathways overlap => Biochemical compounds are involved in different pathways

  47. Metabolic Pathways • Metabolism: The sum of all chemical reactions that take place within a cell providing energy for vital processes and for synthesizing new organic material • EcoCyc/HinCyc/MetaCyc: Encyclopedia of Escherichia coli Genes and Metabolism Encyclopedia of Haemophilus influenzae Genes and Metabolism • EMP: Enzymes and Metabolic Pathways database • KEGG: Kyoto Encyclopedia of Genes and Genomes • …

  48. Metabolic Pathways • Biosynthesis = Anabolism: Sequences of enzyme-catalyzed chemical reactions by which complex molecules are formed in living cells from building blocks with simple structures • Degradation = Catabolism: Sequences of enzyme-catalyzed chemical reactions by which large molecules in living cells are broken down or degraded into building blocks • Transport: Sequences of transport (facilitation) interactions by which compounds are transported from one location to another. • Energy Metabolism: Sequences of enzyme-catalyzed chemical reactions by which chemical energy obtained from the environment by degradation of nutrients or by capturing solar energy (plants) is transformed into energy-rich compounds that are required for metabolic processes

  49. Metabolic Pathways • Metabolism of: • Amino acids, peptides, proteins and derivatives • Carbohydrates (sugars) • Cell-structure components • Cofactors, prosthetic groups and electron carriers • Fatty acids and lipids • Nucleotides and nucleic acids • Monocarbon compounds • Essential elements • Aromatic compounds

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