Lee metbolic eng synthetic bio BME 162 GuestLecture Apr2_2012

V1 v2 v1 a b v2 a c v3 c b db dt v1 v3 b2 1 0 1 0 0 1

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Unformatted text preview: 0 0 0 0 1 -1 0 0 0 0 0 -1 0 0 0 SUC 0 0 0 0 0 0 0 0 1 -1 0 1 0 0 0 0 0 0 MAL 0 0 0 0 0 0 0 0 0 1 -1 0 1 0 0 0 0 0 GOX 0 0 0 0 0 0 0 0 0 0 0 1 -1 0 0 0 0 0 OOA 0 0 0 0 1 -1 0 0 0 0 1 0 0 0 0 0 0 0 CO2 0 0 0 1 -1 0 0 1 1 0 0 0 0 0 0 -1 0 0 4/2/12 BME 162 Guest Lecture 16 Metabolic Flux Analysis b1 Reaction Network Mass Balances: dA dt = b1 − v1 − v2 v1: A B v2: A C v3: C B dB dt = v1 + v3 − b2 −1 0 1 0 0 1 0 −1 1 −1 0 0 Ⱥ v1 Ⱥ Ⱥv Ⱥ 0 Ⱥ Ⱥ 2 Ⱥ Ⱥ v Ⱥ 0 Ⱥ ⋅ Ⱥ 3 Ⱥ Ⱥ b − 1Ⱥ Ⱥ 1 Ⱥ Ⱥ Ⱥb Ⱥ Ⱥ 2 Ⱥ Ⱥb3 Ⱥ Ⱥ Ⱥ B Bex v3 C b3 Cex Aex Pseudo Steady State (PSS) dX = S ⋅v = 0 dt b2 A v2 dC dt = v2 − v3 − b3 Matrix Form: Ⱥ dA Ⱥ Ⱥ− 1 dt Ⱥ Ⱥ Ⱥ dB Ⱥ = Ⱥ 1 dt Ⱥ Ⱥ Ⱥ ȺdC dt Ⱥ Ⱥ 0 Ⱥ Ⱥ Ⱥ Aex v1 A B Bex C v: flux distribution Cex 4/2/12 BME 162 Guest Lecture 17 Flux Map Model organism: Bacillus subtilis Fischer and Sauer (2005) , Nature Genetics 37, 636 - 640 4/2/12 BME 162 Guest Lecture 18 Flux Es0ma0on Using Isotopic Labeling Experiments A C v2 v2 v2 B v1 v1 v1 D F E Metabolite balances cannot resolve split between v1 and v2 Enzymes catalyze atom transitions B C 1 2 3 4/2/12 FM+0/FM+1=f(v1,v2) 1 2 3 4 BME 162 Guest Lecture v1/v2=g(FM+0,FM+1) 19 Elementary Flux Mode (EFM) •  Need for systema0c defini0on and enumera0on of pathways –  Excep0ons (that are the rules) to textbook defini0ons of pathway •  “Series of consecu0ve enzyma0c reac0ons that produce specific products” •  “Set of oriented reac0ons interac0ng under given condi0ons via simple intermediates, where the concentra0on of a simple intermediate is determined by a single pair of produc0on/consump0on reac0ons” –  EFM: a minimal set of enzymes that could operate at steady state, with the enzymes weighted by their rela0ve fluxes •  Non ­decomposable •  Any steady state flux pa=ern can be expressed as a non ­nega$ve linear combina$on...
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