Abstract
In mammals, methionine adenosyltransferase (MAT), the enzyme responsible for S-adenosylmethionine (AdoMet) synthesis, is encoded by two genes, MAT1A and MAT2A. In liver, MAT1A expression is associated with high AdoMet levels and a differentiated phenotype, whereas MAT2A expression is associated with lower AdoMet levels and a dedifferentiated phenotype. In the current study, we examined regulation of MAT2A gene expression by l-methionine availability using HepG2 cells. In l-methionine-deficient cells, MAT2A gene expression is rapidly induced, and methionine adenosyltransferase activity is increased. Restoration of l-methionine rapidly down-regulates MAT2A mRNA levels; for this effect, l-methionine needs to be converted into AdoMet. This novel action of AdoMet is not mediated through a methyl transfer reaction. MAT2A gene expression was also regulated by 5'-methylthioadenosine, but this was dependent on 5'-methylthioadenosine conversion to methionine through the salvage pathway. The transcription rate of the MAT2A gene remained unchanged during l-methionine starvation; however, its mRNA half-life was significantly increased (from 100 min to more than 3 h). The effect of l-methionine withdrawal on MAT2A mRNA stabilization requires both gene transcription and protein synthesis. We conclude that MAT2A gene expression is modulated as an adaptive response of the cell to l-methionine availability through its conversion to AdoMet.
Highlights
In mammals, methionine adenosyltransferase (MAT), the enzyme responsible for S-adenosylmethionine (AdoMet) synthesis, is encoded by two genes, MAT1A and MAT2A
L-Methionine Restriction Induces MAT2A mRNA Levels and MAT Activity in HepG2 Cells—To evaluate the effect of Lmethionine levels on MAT2A gene expression, HepG2 cells were cultured for different periods of time in L-methioninedeficient MEM with 5% fetal calf serum, and MAT2A expression was assessed by Northern blotting
The magnitude of MAT2A mRNA accumulation was dependent on the levels of L-methionine in the culture medium, as observed when HepG2 cells were cultured for 24 h in MEM supplemented with increasing concentrations of this amino acid (Fig. 1B)
Summary
Methionine adenosyltransferase (MAT), the enzyme responsible for S-adenosylmethionine (AdoMet) synthesis, is encoded by two genes, MAT1A and MAT2A. The magnitude of MAT2A mRNA accumulation was dependent on the levels of L-methionine in the culture medium, as observed when HepG2 cells were cultured for 24 h in MEM supplemented with increasing concentrations of this amino acid (Fig. 1B).
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