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SUMMARY:Metabolic regulation of the stress response and the cancer cell's 
 Warburg effect - Markus Ralser (University of Cambridge\, Dept of Biochemi
 stry)
DTSTART:20130218T160000Z
DTEND:20130218T170000Z
UID:TALK42046@talks.cam.ac.uk
CONTACT:Florian Markowetz
DESCRIPTION:Stability of the metabolic network is a premise for life. This
  stability requires a modular substructure of the metabolic network\, whic
 h allows that biochemical modules operate and are controlled semi-independ
 ently. We use artificial metabolic deficiencies in yeast to study how the 
 network reconfigures after a perturbation. We find\, that a surprisingly l
 ow number of phenotype variation is represented in quantitative metabolome
  data\, indicating that metabolic network mainly maintains its stability b
 y acting on transcriptome and proteome. To identify metabolic regulators\,
  we recently completed a prototrophic yeast gene deletion collection which
  is used for systematic metabolic profiling.\n\nIn the second part of the 
 talk\, I'll present data about the regulatory function of a metabolic enzy
 me\, pyruvate kinase (PYK)\, which coordinates the interplay of at least t
 hree important parts of metabolism. We found that altered PYK levels regul
 ates respiration. Surprisingly\, levels of reactive oxygen species (ROS) d
 o not correlate\, and we find that reduced activity of PK enzyme induced r
 esistance to oxidants. This adaptation is attributable to accumulation of 
 the PYK substrate phosphoenolpyruvate (PEP). PEP acts as feedback inhibito
 r of the glycolytic enzyme triosephosphate isomerase (TPI). TPI inhibition
  stimulates the pentose phosphate pathway\, increased anti-oxidative metab
 olism\, and prevented ROS accumulation. Thus\, a metabolic feedback loop\,
  initiated by PYK\, mediated by its substrate and acting on TPI\, synchron
 ises energy- and redox metabolism when cells respire. Originating from a s
 ingle catalytic step\, this autonomous re-configuration of central carbon 
 metabolism prevents oxidative stress upon shifts between fermentation and 
 respiration. 
LOCATION:Cancer Research UK Cambridge Institute\, Lecture Theatre
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