FIGURE 3:

Methionine sets up a hierarchical metabolic response leading to anabolism. (A) Grouping of the methionine-induced genes, focusing on amino acid and nucleotide metabolism. The schematic shows the methionine-responsive genes in various amino acid and nucleotide biosynthesis pathways, along with their fold changes in gene expression (indicated by the color bar). The substrates/cofactors produced by the PPP-GDH-PLP node (see Figure 2) for the individual steps in these pathways is also mapped on to the schematic. Note that all gene products induced by methionine in these pathways use PPP intermediates, NADPH, PLP and/or glutamine/glutamate (indicated within gray ovals) in their biochemical reactions. (B) A bird’s-eye view description of the amino acid biosynthesis steps regulated by methionine, with metabolically expensive or inexpensive steps indicated. Each bead (or filled circle) represents a step in the pathway (prepared according to the individual amino acid pathways shown at https://pathway.yeastgenome.org/; details in Supplemental Figures 4 and 5). A step is considered expensive (red) when it is either the entry point or the exit point or if it involves ATP utilization or reduction. All the rest of the steps are considered inexpensive (gray). Methionine-induced steps are shown with a yellow fill at the centre of the circle for the given step. p = 7.4e^-5 (Fisher’s exact test) for methionine-dependent induction of genes encoding the critical, rate-limiting, or costly steps in amino acid biosynthesis (not significant for the inexpensive steps). (C) A proposed hierarchical organization of the methionine-mediated anabolic remodeling. Methionine induces expression of genes in the PPP-GDH-PLP node, which provides precursors for the key steps in the biosynthesis of all other amino acids and nucleotides, and these steps are also directly induced by methionine.