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Lee metbolic eng synthetic bio BME 162 GuestLecture Apr2_2012

Lee metbolic eng synthetic bio BME 162 GuestLecture Apr2_2012

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Metabolic Engineering Ra0onal redesign of cells to meet commercial objec0ves by the modifica0on of exis0ng – or the introduc0on of en0rely new – metabolic pathways Typically uses gene$c engineering to modify or introduce metabolic pathways Emerging methods: synthe0c biology (chemical or nonna0ve sources of genes and gene products) To date, primarily applied to microbial cells such as bacteria and yeast Interfaces with systems biology Biological molecules interact with one another Produc0on of a molecule is the property of the en0re pathway Cellular phenotype is a property of the en0re cell Emergent proper0es 4/2/12 1 BME 162 Guest Lecture
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Basic Principles Emphasis on systems of reac0ons, i.e. pathways and networks , rather than individual enzymes A defini0on of a pathway : a sequence of feasible and observable biochemical reac0on steps connec0ng a specified set of input and output biochemical molecules The myriad func0ons of cellular metabolism is accomplished by the concerted ac0ons of a highly interconnected network of pathways Network ac0vity needs to be quan0ta0vely characterized at physiological (opera0onal) states In vitro enzyma0c ac0vity ≠ metabolic rates in vivo Flux distribu$on : rela0ve degrees of engagement of the various pathways in the intact cell 4/2/12 2 BME 162 Guest Lecture
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Applica0ons Add new catabolic ac0vity Degrada0on of toxic chemicals (e.g. aroma0cs, chlorinated organic acids, heavy metals) Modify (‘improve’) cell property Tolerate stressful (e.g. hypoxic, high ethanol) culture condi0ons Over-­૒produce metabolites or biosynthe0c products Bulk (e.g. 1,3-­૒propanediol) and specialty chemicals (e.g. amino acids, bio-­૒polymers) Biomass derived carbon fuels Produce chemicals new to the host organism Drug discovery (e.g. ‘natural products’ as precursors for an0bio0cs, an0oxidants, and cancer therapeu0cs) Biomedical applica0ons Elucida0on of disease mechanisms Iden0fica0on of targets for metabolic diseases, e.g. cancer 4/2/12 3 BME 162 Guest Lecture
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Prospects for Biofuels 2000 - 2007 Projections for 2030 4/2/12 4 BME 162 Guest Lecture
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Tradi0onal route for alcohol fuels is fermenta0on sugars PYR Acetolactate lactate + pyruvate - CO 2 Acetoin 2,3-butanediol - CO 2 + 2H OAA malate succinate propionate + CO 2 ATP ADP + 2H + 2H - H 2 O - CO 2 formate acetyl-CoA + CoA CO 2 H 2 acetoacetyl-CoA butyryl-CoA acetone isopropanol butyric acid butanol CO 2 H 2 ethanol + acetyl-CoA, - CoA - CoA - CoA + 4H acetic acid + 2H - CO 2 - CoA-SH + 2H - CoA - CoA + 4H + 4H Note: Not all of these pathway will be present in a single organism Thl/PhaA: acetyl-CoA acetyltransferase CtfAB/AtoAD: acetoacetyl-CoA transferase Adc: acetoacetate decarboxylase Adh: alcohol dehydrogenase Hbd: 3-hydroxybutyryl-CoA dehydrogenase Crt: crotonase Bcd-EtfAB/Ter: butyryl-CoA dehydrogenase AdhE2: aldehyde/alcohol dehydrogenase Fermentation in Clostridium* acetobutylicum 4/2/12 5 BME 162 Guest Lecture
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Direct synthesis from amino acids is also possible Atsumi et al. Nature. 2008;451(7174):86-9.
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