The 2-oxoglutarate supply exerts significant control on the lysine synthesis flux inSaccharomyces cerevisiae

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To determine the extent to which the supply of the precursor 2-oxoglutarate (2-OG) controls the synthesis of lysine in Saccharomyces cerevisiae growing exponentially in high glucose, top-down elasticity analysis was used. Three groups of reactions linked by 2-OG were defined. The 2-OG supply group comprised all metabolic steps leading to its formation, and the two 2-OG consumer groups comprised the enzymes and transporters involved in 2-OG transformation into lysine and glutamate and their further utilization for protein synthesis and storage. Various 2-OG steady-state concentrations that produced different fluxes to lysine and glutamate were attained using yeast mutants with increasing activities of Krebs cycle enzymes and decreased activities of Lys synthesis enzymes. The elasticity coefficients of the three enzyme groups were determined from the dependence of the amino acid fluxes on the 2-OG concentration. The respective degrees of control on the flux towards lysine (flux control coefficients) were determined from their elasticities, and were 1.1, 0.41 and −0.52 for the 2-OG producer group and the Lys and Glu branches, respectively. Thus, the predominant control exerted by the 2-OG supply on the rate of lysine synthesis suggests that over-expression of 2-OG producer enzymes may be a highly effective strategy to enhance Lys production.The elasticity analysis approach of metabolic control analysis was applied to determine what controls the flux of lysine synthesis in Saccharomyces cerevisiae. The flux control coefficients for the 2-oxoglutarate supplier group of reactions, and the lysine and glutamate syntheses pathways, were 1.1, 0.41 and −0.52, respectively. This indicated that lysine synthesis was mainly controlled by the supply of the precursor 2-oxoglutarate.

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