Abstract
The methyl cycle is a universal metabolic pathway providing methyl groups for the methylation of nuclei acids and proteins, regulating all aspects of cellular physiology. We have previously shown that methyl cycle inhibition in mammals strongly affects circadian rhythms. Since the methyl cycle and circadian clocks have evolved early during evolution and operate in organisms across the tree of life, we sought to determine whether the link between the two is also conserved. Here, we show that methyl cycle inhibition affects biological rhythms in species ranging from unicellular algae to humans, separated by more than 1 billion years of evolution. In contrast, the cyanobacterial clock is resistant to methyl cycle inhibition, although we demonstrate that methylations themselves regulate circadian rhythms in this organism. Mammalian cells with a rewired bacteria-like methyl cycle are protected, like cyanobacteria, from methyl cycle inhibition, providing interesting new possibilities for the treatment of methylation deficiencies.
Highlights
The methyl cycle is a universal metabolic pathway providing methyl groups for the methylation of nuclei acids and proteins, regulating all aspects of cellular physiology
SAM is converted into adenosylhomocysteine (SAH) that is rapidly hydrolyzed into homocysteine (Hcy) and adenosine by the enzyme adenosylhomocysteinase (AHCY) to prevent competitive inhibition of methyltransferase enzymes by SAH
We show that the link between methylation and the circadian clock we uncovered in mammals has been conserved during more than 2.5 billion years of evolution, and that circadian rhythm perturbations can be used as a quantitative gauge for the physiological consequences of methylation deficiency
Summary
The methyl cycle is a universal metabolic pathway providing methyl groups for the methylation of nuclei acids and proteins, regulating all aspects of cellular physiology. Partial rewiring of the mammalian methyl cycle by ectopically expressing the E. coli SAH nucleosidase completely protected the methyl cycle from AHCY inhibition, and allowed normal circadian rhythms, even in the presence of a saturating concentration of inhibitor. These observations demonstrate the importance of methyl metabolism in the regulation of biological rhythms from cyanobacteria to humans and suggest a therapeutic application of methyl cycle reprogramming to alleviate the detrimental impact of methylation deficiencies
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