Abstract
The biological methyl donor S-adenosyl-l-methionine (AdoMet) is spontaneously degraded by inversion of its sulfonium center to form the R,S diastereomer. Unlike its precursor, (S,S)-AdoMet, (R,S)-AdoMet has no known cellular function and may have some toxicity. Although the rate of (R,S)-AdoMet formation under physiological conditions is significant, it has not been detected at substantial levels in vivo in a wide range of organisms. These observations imply that there are mechanisms that either dispose of (R,S)-AdoMet or convert it back to (S,S)-AdoMet. Previously, we identified two homocysteine methyltransferases (Mht1 and Sam4) in yeast capable of recognizing and metabolizing (R,S)-AdoMet. We found similar activities in worms, plants, and flies. However, it was not established whether these activities could prevent R,S accumulation. In this work, we show that both the Mht1 and Sam4 enzymes are capable of preventing R,S accumulation in Saccharomyces cerevisiae grown to stationary phase; deletion of both genes results in significant (R,S)-AdoMet accumulation. To our knowledge, this is the first time that such an accumulation of (R,S)-AdoMet has been reported in any organism. We show that yeast cells can take up (R,S)-AdoMet from the medium using the same transporter (Sam3) used to import (S,S)-AdoMet. Our results suggest that yeast cells have evolved efficient mechanisms not only for dealing with the spontaneous intracellular generation of the (R,S)-AdoMet degradation product but for utilizing environmental sources as a nutrient.
Highlights
We previously found that two homocysteine methyltransferases in the yeast Saccharomyces cerevisiae, Mht1 and Sam4, are capable of using (R,S)-AdoMet as the methyl donor, metabolizing this molecule [15]
Homologs for Mht1 and Sam4, as well as (R,S)-AdoMet dependent homocysteine methyltransferase activities, were found in worms, plants, and flies [15]. We demonstrate that these enzymes are capable of limiting the accumulation of (R,S)-AdoMet in intact yeast cells
We found that the accumulation of (R,S)-AdoMet in yeast cells and in chemical solution was similar
Summary
At least one radical AdoMet enzyme, the HemN coproporphyrin III oxidase in Escherichia coli, has been found to bind both (R,S)- and (S,S)-AdoMet [25]. It is unclear whether the R,S form is converted to methionine and the deoxyadenosyl radical. Another depletion pathway involves homocysteine methyltransferase activity that transfers methyl groups from a methyl donor to homocysteine to create methionine. We previously found that two homocysteine methyltransferases in the yeast Saccharomyces cerevisiae, Mht and Sam, are capable of using (R,S)-AdoMet as the methyl donor, metabolizing this molecule [15]. We show that yeast cells are capable of transporting (R,S)-AdoMet from the external environment, suggesting that yeast can metabolize both endogenously formed and environmental (R,S)-AdoMet
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