Evidence of carbon monoxide-mediated phase advancement of the yeast metabolic cycle

Prototrophic strains of budding yeast exhibit robust metabolic cycles during continuous growth under nutrient-limiting conditions. Previous studies revealed periodic fluctuations of aminole-vulinic acid, a precursor of heme, indicating that heme biosynthesis is temporally regulated during these metabolic cycles. The enzyme that catabolizes heme, heme oxygenase, was found to be expressed in a highly periodic manner at both the mRNA and protein level. Heme oxygenase generates the biological gas, carbon monoxide (CO), as a product of heme catabolism. It is shown that pulsed administration of CO induces a phase advancement into the oxidative, respiratory phase of the metabolic cycles. This CO-mediated phase advancement takes place only if the gas is administered during the temporal window when it is predicted to be generated. It is further shown that a yeast strain bearing a targeted deletion of the gene encoding heme oxygenase displays protracted metabolic cycles. These observations provide evidence that gaseous CO may function as a cellular signaling molecule that helps cue metabolic cycling.