Lee metbolic eng synthetic bio BME 162 GuestLecture Apr2_2012

G acetate propionate malonate and methylmalonate 4212

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Unformatted text preview: Common to many organisms, especially mycelial (filamentous) bacteria, e.g. actinomycetes •  Also found in fungi and plants –  Great structural variety –  Rich source of bioactive molecules •  •  •  •  Antibiotics (e.g. and erythromycin) Anticancer agents (daunomycin) Immunosuppressants (rapamycin) Veterinary products (monensin) •  Shared mechanism of biosynthesis –  Sequential condensation of short chain length fatty acids, e.g. acetate, propionate, malonate, and methylmalonate 4/2/12 BME 162 Guest Lecture 9 Taxol Semisynthesis in S. Cerevisiae 4/2/12 BME 162 Guest Lecture 10 Artemisinin Precursor Synthesis in S. Cerevisiae Ro et al. (2006) Nature. 440(13):940-3. Direct up-regulation Indirect up-regulation Repression From Artemisia annua L 4/2/12 BME 162 Guest Lecture 11 Engineering Challenge: Increasing Yield IPP: common monomer for natural products Precursor metabolites for biosynthesis derived from central carbon metabolism 4/2/12 BME 162 Guest Lecture 12 Increasing yield is ocen difficult due to compe00on with na0ve metabolic pathways General scheme Monomer synthesis 4/2/12 BME 162 Guest Lecture 13 Metabolic Engineering Strategies •  Pathway engineering –  Op0mize na0ve metabolism –  Iden0fy new routes of synthesis •  Control engineering –  Balance cell growth and product synthesis •  Modular engineering –  Flexible sub ­systems for synthesis and control 4/2/12 BME 162 Guest Lecture 14 Modeling Metabolism: Schema0c Representa0on Glucose v1 CO2 v16 G6P CO2 !! G6P v3 PYR CxHyOz v2 !! ! !! ! !! ! !! ! ! ! ! !! ! ! AcCoA !! ! !! ! !!" ! !!" ! ! Pyruvate v4 AcCoA OXA v6 CIT v14 v7 v13 GOX v12 ICIT v8 v10 SUC v9 CO2 4/2/12 CIT 2KG v15 v18 ICIT CO2 !! ! !! ! !!" ! ! SUC !! ! !!" ! !!" ! ! MAL v17 !! ! !! ! !!" ! !!" ! ! 2KG Lipid CIT v11 MAL ICIT CO2 !! ! !! ! !!" ! ! !!" ! !!! ! !!" ! ! GOX !!" ! !!" ! ! OXA CO2 v5 !! ! !!! ! !! ! ! CO2 !! ! !! ! !! ! !! ! !!" ! ! Protein N H3 BME 162 Guest Lecture 15 Stoichiometric Matrix S V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 V16 V17 v18 G6P 1 -0.5 -1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 PYR 0 1 0 -1 -1 0 0 0 0 0 0 0 0 0 0 0 0 0 ACC 0 0 0 1 0 -1 0 0 0 0 0 0 -1 -1 0 0 0 0 CIT 0 0 0 0 0 1 -1 0 0 0 0 0 0 0 0 0 -1 0 ICT 0 0 0 0 0 0 1 -1 0 0 0 -1 0 0 0 0 0 -1 OGT 0 0 0...
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This document was uploaded on 02/11/2014.

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