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Evolution & organisation of metabolic pathways Bas Kooijman Dynamic Energy Budget theory for metabolic organisation adult Dept of Theoretical Biology Vrije Universiteit, Amsterdam http://www.bio.vu.nl/thb/deb/ Amsterdam, 2004/03/31 the dynamic structure of life Central Metabolism source polymers monomers waste/source Modules of central metabolism • Pentose Phosphate (PP) cycle glucose-6-P ribulose-6-P, NADP NADPH • Glycolysis glucose-6-P pyruvate ADP + P ATP • TriCarboxcyl Acid (TCA) cycle pyruvate CO2 NADP NADPH • Respiratory chain NADPH + O2 NADP + H2O ADP + P ATP Evolution of central metabolism in prokaryotes (= bacteria) 3.8 Ga 2.7 Ga i = inverse ACS = acetyl-CoA Synthase pathwayRC = Respiratory Chain Kooijman, Hengeveld 2003 The symbiontic nature of PP = Pentose Phosphate cycle Gly = Glycolysis metabolic evolution TCA = TriCarboxylic Acid cycle Acta Biotheoretica (to appear) Prokaryotic metabolic evolution Heterotrophy: • pentose phosph cycle • glycolysis • respiration chain Phototrophy: • el. transport chain • PS I & PS II • Calvin cycle Chemolithotrophy • acetyl-CoA pathway • inverse TCA cycle • inverse glycolysis Early ATP generation FeS2 FeS H2 S0 H2S 2eS0 H2S 2H2O 2OH- 2H+ ADP Pi FeS + S0 FeS2 ADP + Pi ATP • ATPase • hydrogenase • S-reductase ATP 2H+ Madigan et al 1997 Substrate processing Fractions of SU ·· unbound A· SU-A complex ·B SU-B complex AB SU-A,B complex Synthesizing Units: generalized enzymes process arriving fluxes of substrate reversed flux is small mixtures of processing schemes are possible Kooijman, 2001 Biomass: reserve(s) + structure(s) Reserve(s), structure(s): generalized compounds, mixtures of proteins, lipids, carbohydrates: fixed composition Reserve(s) do complicate model & implications & testing Reasons to delineate reserve, distinct from structure • metabolic memory • biomass composition depends on growth rate • explanation of respiration patterns (freshly laid eggs don’t respire) method of indirect calorimetry fluxes are linear sums of assimilation, dissipation and growth inter-species body size scaling relationships • fate of metabolites (e.g. conversion into energy vs buiding blocks) Reserve vs structure Reserve does not mean: “set apart for later use” compounds in reserve can have active functions Life span of compounds in • reserve: limited due to turnover of reserve all reserve compounds have the same mean life span • structure: controlled by somatic maintenance structure compounds can differ in mean life span Important difference between reserve and structure: no maintenance costs for reserve Empirical evidence: freshly laid eggs consist of reserve and do not respire Homeostasis Homeostasis: constant body composition in varying environments Strong homeostasis generalized compounds applies to reserve(s) and structure(s) separately Weak homeostasis: ratio reserve/structure becomes and remains constant if food or substrate is constant (while the individual is growing) applies to juvenile and adult stages, not to embryos Implication: stoichiometric constraints on growth Methanotrophs CO2 reserve NH3 CH4 O2 Macro-chemical reaction at fixed growth rate CH 4 YCX CO2 YNX NH 3 (1 YCX ) CH nHW OnOW N nNW YHX H 2O DEB decomposition into • assimilation (substrate reserve) catabolic & anabolic aspect • maintenance (reserve products) • growth (reserve structure) catabolic & anabolic aspect yield coefficients vary with growth reserve, structure differ in composition composition of biomass varies with growth Kooijman, Andersen & Kooi 2004 Anammox Macro-chemical reaction at r = 0.0014 h-1 1 NH 4 1.32 NO2 0.068 HCO3 0.128 H 1.025 N 2 0.260 NO3 0.068 CH 2O0.5 N 0.15 2.030 H 2O DEB decomposition into • assimilation (substrate reserve) catabolic & anabolic aspect • maintenance (reserve products) • growth (reserve structure) catabolic & anabolic aspect yield coefficients vary with growth reserve, structure differ in composition composition of biomass varies with growth rm = 0.003 h-1; kE = 0.0127 h-1; kM = 0.0008 h-1 ySE = 8.8; yVE = 0.8 nHE = 2; nOE = 0.46; nNE = 0.25 nHV = 2; nOV = 0.51; nNV = 0.125 Brandt, 2002 Nitrogen cycle Brocadia anammoxidans some cyanobacteria, Azotobacter, Azospirillum, Azorhizobium, Klebsiella, Rhizobium,some others Nitrosomonas Some crucial conversions depend on few species Nitrobacter many CHON= biomass Syntrophy Coupling hydrogen & methane production energy generation aspect at aerobic/anaerobic interface ethanol acetate 3 dihydrogen 2 C2 H 6O 2 H 2O O2 2 C2 H 3O 2 H 4 H 2 dihydrogen bicarbonate 3 methane 4 H 2 CHO H CH 4 3 H 2O Total: 2 C2 H 6O CO2 O2 CH 4 2 C2 H 3O3 2 H methane hydrates >300 m deep, < 8C linked with nutrient supply Product Formation According to Dynamic Energy Budget theory: pyruvate, mg/l Product formation rate = wA . Assimilation rate + wM . Maintenance rate + wG . Growth rate For pyruvate: wG<0 Applies to all products, heat & non-limiting substrates Indirect calorimetry (Lavoisier, 1780): heat = wO JO + wC JC + wN JN No reserve: 2-dim basis for product formation throughput rate, h-1 Glucose-limited growth of Saccharomyces Data from Schatzmann, 1975 Symbiosis substrate product Symbiosis substrate substrate Steps in symbiogenesis Free-living, homogeneous Structures merge Free-living, clustering Internalization Reserves merge biomass density Chemostat Steady States Free living Products substitutable Free living Products complementary Exchange on flux-basis Structures merged throughput rate symbiont host Endosymbiosis Exchange on conc-basis Reserves merged Host uses 2 substrates Symbiogenesis • symbioses: fundamental organization of life based on syntrophy ranges from weak to strong interactions; basis of biodiversity • symbiogenesis: evolution of eukaryotes (mitochondria, plastids) • DEB model is closed under symbiogenesis: it is possible to model symbiogenesis of two initially independently living populations that follow the DEB rules by incremental changes of parameter values such that a single population emerges that again follows the DEB rules • essential property for models that apply to all organisms Kooijman, Auger, Poggiale, Kooi 2003 Quantitative steps in symbiogenesis and the evolution of homeostasis Biological Reviews 78: 435 - 463 Symbiogenesis 1.5-2 Ga 1.2 Ga Eukaryote metabolic evolution First eukaryotes: heterotrophs by symbiogenesis compartmental cellular organisation Acquisition of phototrophy frequently did not result in loss of heterotrophy Acquisition of membrane transport between internalization of mitochondria and plastids No phagocytosis in fungi & plants; loss? pinocytosis in animals = phagocytosis in e.g. amoeba? Direct link between phagocytosis and membrane transport? Membrane traffic The golgi apparatus serves as a central clearing house and channel between the endo- and exoplasmic domains 1 ER-Golgi shuttle 2 secretory shuttle between Golgi and plasma membrane 2’ crinophagic diversion 3 Golgi-lysosome shuttle 3’ alternative route from Golgi to lyosomes via the plasma membrane and an endosome 4 endocytic shuttle between the plasma membrane and an endosome 4’ alternative endocytic pathway bypassing an endosome 5 plasma membrane retrieval 6 endosome-lysosome pathway 7 autophagic segregation From: Duve, C. de 1984 A guided tour of the living cell, Sci. Am. Lib., New York Clathrin unknown in prokaryotes Chloroplast dynamics Coordinated movement of chloroplasts through cells Sizes of blobs do not reflect number of species Survey of organisms Myxomycota Protostelida Bikont DHFR-TS gene fusion loss phagoc.Apusozoa membr. dyn unikont mainly celllose gap junctions tissues (nervous) mitochondria bicentriolar primary mainly chitin chloroplast EF1 insertion secondary Plasmodiophoromycota Chlorarachnida Cercozoa Cercomonada chloroplast Amoebozoa Archamoeba tertiary chloroplast photo symbionts Bacteria Bacteria Rhizopoda Sporozoa Percolozoa Excavates Euglenozoa Loukozoa AlveoDinozoa lates Ciliophora chloroplasts Chytridiomycota cortical alveoli Actinopoda (brown algae) Phaeophyceae Xanthophyceae Raphidophyceae Chrysophyceae Synurophyceae Eustigmatophyceae Labyrinthulomycota Dictyochophyceae Bicosoecia Pedinellophyceae Pelagophyceae Bigyromonada Bacillariophyceae Pseudofungi (diatoms) Bolidophyceae Opalinata Prymnesiophyceae Metamonada Cryptophyceae triple roots Granuloreticulata forams Xenophyophora Basidiomycota Ascomycota fungi Glomeromycota Zygomycota Microsporidia animals animals Choanozoa Composed by Bas Kooijman (plants) Cormophyta (green algae) Chlorophyceae Plantae (red algae) Rhodophyceae Glaucophyceae Cells, individuals, colonies vague boundaries • plasmodesmata connect cytoplasm; cells form a symplast: plants • pits and large pores connect cytoplasm: fungi, rhodophytes • multinucleated cells occur; individuals can be unicellular: fungi, Eumycetozoa, Myxozoa, ciliates, Xenophyophores, Actinophryids, Biomyxa, diplomonads, Gymnosphaerida, haplosporids, Microsporidia, nephridiophagids, Nucleariidae, plasmodiophorids, Pseudospora, Xanthophyta (e.g. Vaucheria), most classes of Chlorophyta (Chlorophyceae, Ulvoph Charophyceae (in mature cells) and all Cladophoryceae, Bryopsidophyceae and Dasycladophycea • cells inside cells: Paramyxea • uni- and multicellular stages: multicellular spores in unicellular myxozoa, gametes • individuals can remain connected after vegetative propagation: plants, corals, b • individuals in colonies can strongly interact and specialize for particular tasks: syphonophorans, insects, mole rats Kooijman, Hengeveld 2003 The symbiontic nature of metabolic evolution Acta Biotheoretica (to appear) Heterocephalus glaber rotifer Conochilus hippocrepis (Endo)symbiosis Frequent association between photo- and heterotroph photo hetero: carbohydrates (energy supply) photo hetero: nutrients (frequently NH3 or NO3-) most (perhaps all) plants have myccorrhizas, the symbiosis combines photolithotrophy and organochemotrophy Also frequent: association between phototroph and N2-fixer where N2-fixer plays role of heterotroph Symbiosis: living together in interaction (basic form of life) Mutualism: “benefit” for both partners symbioses need not be mutualistic “benefit” frequently difficult to judge and anthropocentric Syntrophy: one lives of products of another (e.g. faeces) can be bilateral; frequent basis of symbiosis Chlorochromatium (Chlorobibacteria, Sphingobacteria) (= Chlorochromatium) From: Margulis, L & Schwartz, K.V. 1998 Five kingdoms.Freeman, NY (Endo)symbiosis Paramecium bursaria ciliate with green algae Cladonia diversa ascomycete with green algae Ophrydium versatile ciliate with green algae Peltigera ascomycete with green algae (Endo)symbiosis Chlorophyte symbionts visible through microscope Grazed by reindeer in winter Rangifer tarandus Lichen Cladonia portentosa Mitochondria TriCarboxylic Acid cycle (= Krebs cycle) Enzymes pass metabolites directly to other enzymes enzymes catalizing transformations 5 & 7: bound to inner membrane (and FAD/FADH2) Net transformation: Acetyl-CoA + 3 NAD+ + FAD + GDP 3- + Pi2- + 2 H2O = 2 CO2 + 3 NADH + FADH2 + GTP 4- + 2 H+ + HS-CoA Dual function of intermediary metabolites building blocks energy substrate Transformations: 1 Oxaloacetate + Acetyl CoA + H2O = Citrate + HSCoA 2 Citrate = cis-Aconitrate + H2O 3 cis-Aconitrate + H2O = Isocitrate 4 Isocitrate + NAD+ = α-Ketoglutarate + CO2 + NADH + H+ 5 α-Ketoglutarate + NAD+ + HSCoA = Succinyl CoA + CO2 + NADH + H+ 6 Succinyl CoA + GDP 3- + Pi 2- + H+ = Succinate + GTP 4- + HSCoA 7 Succinate + FAD = Fumarate + FADH2 8 Fumarate + H2O = Malate 9 Malate + NAD+ = Oxaloacetate + NADH + H+ all eukaryotes once possessed mitochondria, most still do enzymes are located in metabolon; channeling of metabolites Pathways & allocation structure structure maintenance reserve maintenance reserve structure maintenance reserve Mixture of products & intermediary metabolites that is allocated to maintenance (or growth) has constant composition Kooijman & Segel, 2004 Numerical matching for n=4 0 3 4 4 3 2 Unbound fraction Product flux 1 2 1 Spec growth rate Rejected flux 0 1 2 3 Spec growth rate = 0.73, 0.67, 0.001, 0.27 handshaking = 0.67, 0.91, 0.96, 0.97 binding prob k = 0.12, 0.19, 0.54, 0.19 dissociation nSE = 0.032,0.032,0.032,0.032 # in reserve nSV = 0.045,0.045,0.045,0.045 # in structure yEV = 1.2 res/struct kE = 0.4 res turnover jEM = 0.02 maint flux n0E = 0.05 sub in res Matching pathway whole cell No exact match possible between production of products and intermediary metabolites by pathway and requirements by the cell But very close approximation is possible by tuning abundance parameters nSi E , nSiV and/or binding and handshaking parameters ρi , αi Good approximation requires all four tuning parameters per node growth-dependent reserve abundance plays a key role in tuning Kooijman, S. A. L. M. and Segel, L. A. (2004) How growth affects the fate of cellular substrates. Bull. Math. Biol. (to appear)