The activity reaction core and plasticity of metabolic networks Almaas e. oltvai z N.& barabasi A-L 01/04/2006
The activity reaction core and plasticity of metabolic networks Almaas E., Oltvai Z.N. & Barabasi A.-L. 01/04/2006
The idea To examine the utilization and relative flux rates of each metabolic reaction in a wide range of simulated environmental conditions 30,000 randomly and uniformly chosen optimal growth conditions(randomly assigning values for metabolic-uptake reactions and all single-carbon-source minimal medium conditions sufficient for growth Using fba on in silico models H pylori ■E.cOl ■S. cerevisiae
The idea ◼ To examine the utilization and relative flux rates of each metabolic reaction in a wide range of simulated environmental conditions ◼ 30,000 randomly and uniformly chosen optimal growth conditions (randomly assigning values for metabolic-uptake reactions) ◼ and all single-carbon-source minimal medium conditions sufficient for growth ◼ Using FBA on in silico models: ◼ H. pylori ◼ E. coli ◼ S. cerevisiae
Observations ■ Flux plastici Changes in the fluxes of already active reactions when the organism is shifted from one growth condition to another a Structural plasticity Changes in the active reaction set
Observations ◼ Flux plasticity ◼ Changes in the fluxes of already active reactions when the organism is shifted from one growth condition to another ◼ Structural plasticity ◼ Changes in the active reaction set
Metabolic core Definition The set of reactions that are active under all conditions Metabolic cores in different organisms H. pylori:138of381(36.200) ■E.coi:90of758(11.900 S cerevisiae: 33 of 1172(2.8%o) a Property The reactions in the metabolic core form a single connected cluster
Metabolic core ◼ Definition ◼ The set of reactions that are active under all conditions ◼ Metabolic cores in different organisms: ◼ H. pylori: 138 of 381 (36.2%) ◼ E. coli: 90 of 758 (11.9%) ◼ S. cerevisiae: 33 of 1172 (2.8%) ◼ Property ◼ The reactions in the metabolic core form a single connected cluster
The metabolic core of e. coli 3DDAH7P T3P2 E4P UDPNAM 13DPG DHSK ALA 2PG ESP MDA 3PSME 4PPNCYSH DALA CHOR UNPTDO 4PPNTE ADCHOR DPCOA COA )Ey AHTD PNAG O6R PSP UDPGG2A ACA 2) A6RPSP THE C140ACP C120ACP C141ACP C160ACP C161ACP C181ACI A6RP6P2 UoPg23a A6RP DISAC1P PEP PGP RIBFLV KPo CMPKDO K2LIPIV CDPETN LPS GLYCOGEN ADPGLC GIP UDPG AOPHEP NAD NMN一PP1 UTP UDP METTHE OTHIO TTHE RTHIO NADPH GMP CoP DTTP一 DTDp OTMI
The metabolic core of E. coli
Essentiality of reactions in metabolic core Two types of reactions in metabolic core Reactions that are essential for growth under all conditions H. pylori: no data in the paper E. coli: 81 out of 90 n Experimental data: 747o of the enzymes that catalyze core metabolic reactions are essential, compared with a 19.6%o lethality fraction of the noncore enzymes S cerevisiae: all 33 Experimental data: 84%o of the core enzymes are essential, whereas 15.6%o of noncore enzymes are essential Reactions that are required for optimal metabolic performance a When assuming a 10%o reduction in the growth rate the size of the metabolic core becomes 83 in E. coli
Essentiality of reactions in metabolic core ◼ Two types of reactions in metabolic core ◼ Reactions that are essential for growth under all conditions ◼ H. pylori: no data in the paper ◼ E. coli: 81 out of 90 ◼ Experimental data: 74.7% of the enzymes that catalyze core metabolic reactions are essential, compared with a 19.6% lethality fraction of the noncore enzymes. ◼ S. cerevisiae: all 33 ◼ Experimental data: 84% of the core enzymes are essential, whereas 15.6% of noncore enzymes are essential. ◼ Reactions that are required for optimal metabolic performance ◼ When assuming a 10% reduction in the growth rate, the size of the metabolic core becomes 83 in E. coli
Size of the metabolic cores s Metabolic cores in different organisms H pylori: 36.2%o E. coli: 11.90o S cerevisiae: 2.8%0 ■ Explanation Little flexibility for biomass production in H pylori 61°0 of the e pylori reactions are active on average Higher metabolic flexibility in E. coli and S. cerevisiae On average, 35.3%o and 19.7%o of the reactions are required in E. coli and s cerevisiae,respectively. Alternative pathways: 20 out of the 51 biomass constituents in E coli are not produced by the core The more reactions a metabolic network possesses, the stronger is the network-induced redundancy, and the smaller is the core
Size of the metabolic cores ◼ Metabolic cores in different organisms: ◼ H. pylori: 36.2% ◼ E. coli: 11.9% ◼ S. cerevisiae: 2.8% ◼ Explanation ◼ Little flexibility for biomass production in H. pylori ◼ 61% of the H. pylori reactions are active on average. ◼ Higher metabolic flexibility in E. coli and S. cerevisiae ◼ On average, 35.3% and 19.7% of the reactions are required in E. coli and S. cerevisiae, respectively. ◼ Alternative pathways: 20 out of the 51 biomass constituents in E. coli are not produced by the core. ◼ The more reactions a metabolic network possesses, the stronger is the network-induced redundancy, and the smaller is the core
Conservation of the metabolic core The average core enzyme in E coli H. pylori has orthologs in 71.7%o of the 32 reference bacteria. While the noncore enzymes have an 55 evolutionary retention of only 47.70 This difference is not a simple 63 consequence of the high-lethality fraction of the core enzymes 18 Random selection of 90 enzymes with a 74. 7o lethality ratio has an average evolutionary retetion of E. coli s, cerevisiae Maintaining the core s integrity is a collective need of the organism
Conservation of the metabolic core ◼ The average core enzyme in E. coli has orthologs in 71.7% of the 32 reference bacteria. While the noncore enzymes have an evolutionary retention of only 47.7%. ◼ This difference is not a simple consequence of the high-lethality fraction of the core enzymes. ◼ Random selection of 90 enzymes with a 74.7% lethality ratio has an average evolutionary retetion of only 63.4% Maintaining the core’s integrity is a collective need of the organism
Regulatory control on metabolic core ■ mrna half-live Average half-life for the core enzymes: 14.0 min Average half-life for the noncore enzymes: 10.5 min Activating and repressive regulatory links Extended core: a set of 234 reactions that are active in more than 90%o of the 30,000 simulated growth conditions Core enzyme-encoding operons: 52.3%o repressive, 35. 7%o activating; and 10%o dual interactions Noncore enzyme-encoding operons: 45%o repressive; 45%o activating, and 10%o dual interactions Synchronization ■ Flux correlation mRNA expression correlation All data are of e. coli
Regulatory control on metabolic core ◼ mRNA half-lives ◼ Average half-life for the core enzymes: 14.0 min ◼ Average half-life for the noncore enzymes: 10.5 min ◼ Activating and repressive regulatory links ◼ Extended core: a set of 234 reactions that are active in more than 90% of the 30,000 simulated growth conditions ◼ Core enzyme-encoding operons: 52.3% repressive; 35.7% activating; and 10% dual interactions ◼ Noncore enzyme-encoding operons: 45% repressive; 45% activating; and 10% dual interactions ◼ Synchronization ◼ Flux correlation ◼ mRNA expression correlation All data are of E. coli
Practical implications I The core enzvmes may prove effective antibiotic targets a Currently used antibiotics Fosfomycin and cycloserine inhibit cell-wall peptidoglycan Sulfonamides and trimethoprim inhibit tetrahydrofolte biosvnthesis a Both pathways are present in H. pylori and E coli
Practical implications ◼ The core enzymes may prove effective antibiotic targets. ◼ Currently used antibiotics: ◼ Fosfomycin and cycloserine inhibit cell-wall peptidoglycan. ◼ Sulfonamides and trimethoprim inhibit tetrahydrofolte biosynthesis. ◼ Both pathways are present in H. pylori and E. coli
