Abstract
The dipeptide L-carnosine (β-alanyl-L-histidine) has been described as enigmatic: it inhibits growth of cancer cells but delays senescence in cultured human fibroblasts and extends the lifespan of male fruit flies. In an attempt to understand these observations, the effects of L-carnosine on the model eukaryote, Saccharomyces cerevisiae, were examined on account of its unique metabolic properties; S. cerevisiae can respire aerobically, but like some tumor cells, it can also exhibit a metabolism in which aerobic respiration is down regulated. L-Carnosine exhibited both inhibitory and stimulatory effects on yeast cells, dependent upon the carbon source in the growth medium. When yeast cells were not reliant on oxidative phosphorylation for energy generation (e.g. when grown on a fermentable carbon source such as 2% glucose), 10–30 mM L-carnosine slowed growth rates in a dose-dependent manner and increased cell death by up to 17%. In contrast, in media containing a non-fermentable carbon source in which yeast are dependent on aerobic respiration (e.g. 2% glycerol), L-carnosine did not provoke cell death. This latter observation was confirmed in the respiratory yeast, Pichia pastoris. Moreover, when deletion strains in the yeast nutrient-sensing pathway were treated with L-carnosine, the cells showed resistance to its inhibitory effects. These findings suggest that L-carnosine affects cells in a metabolism-dependent manner and provide a rationale for its effects on different cell types.
Highlights
The dipeptide L-carnosine (b-alanyl-L-histidine) was characterized more than a century ago and occurs naturally in tissues such as brain, kidney and skeletal muscle at concentrations up to 20 mmol kg21 dry muscle mass [1]
L-Carnosine causes an increase in the lifespan of human fibroblasts [3] and E. coli cells [26]
Our experiments to determine the effect of L-carnosine on yeast revealed a profound effect on the viability of glucose-grown cells (Table 1; Figure 2), consistent with earlier findings by Holliday and McFarland, who showed that Lcarnosine inhibits the growth of cancer cells [7]
Summary
The dipeptide L-carnosine (b-alanyl-L-histidine) was characterized more than a century ago and occurs naturally in tissues such as brain, kidney and skeletal muscle at concentrations up to 20 mmol kg dry muscle mass [1] While related dipeptides such as anserine and homocarnosine are found in the muscle tissues of mammals, birds and fish [2], they do not seem to exhibit the range of properties shown by L-carnosine [3], which may be a consequence of insufficient study (but see reference [7] for a comparison with L-carnosine). The Crabtree effect [14], the inhibition of respiration in the presence of glucose, is a key metabolic feature of tumors, rapidly-proliferating normal cells and the respiro-fermentative yeast species, Saccharomyces cerevisiae: when grown on a fermentable carbon source, such as 2% glucose, aerobic respiration is actively down-regulated in this yeast [15,16] Both tumor cells and fermenting yeast derive the majority of their ATP production from glycolysis. S. cerevisiae can grow on non-fermentable carbon sources, such as 2% glycerol, by employing oxidative phosphorylation for ATP generation
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