Methionine coordinates a hierarchically organized anabolic program enabling proliferation

Mol Biol Cell. 2018 Dec 15;29(26):3183-3200. doi: 10.1091/mbc.E18-08-0515. Epub 2018 Oct 24.


Methionine availability during overall amino acid limitation metabolically reprograms cells to support proliferation, the underlying basis for which remains unclear. Here we construct the organization of this methionine-mediated anabolic program using yeast. Combining comparative transcriptome analysis and biochemical and metabolic flux-based approaches, we discover that methionine rewires overall metabolic outputs by increasing the activity of a key regulatory node. This comprises the pentose phosphate pathway (PPP) coupled with reductive biosynthesis, the glutamate dehydrogenase (GDH)-dependent synthesis of glutamate/glutamine, and pyridoxal-5-phosphate (PLP)-dependent transamination capacity. This PPP-GDH-PLP node provides the required cofactors and/or substrates for subsequent rate-limiting reactions in the synthesis of amino acids and therefore nucleotides. These rate-limiting steps in amino acid biosynthesis are also induced in a methionine-dependent manner. This thereby results in a biochemical cascade establishing a hierarchically organized anabolic program. For this methionine-mediated anabolic program to be sustained, cells co-opt a "starvation stress response" regulator, Gcn4p. Collectively, our data suggest a hierarchical metabolic framework explaining how methionine mediates an anabolic switch.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Cell Proliferation
  • Gene Expression Regulation, Fungal*
  • Glutamate Dehydrogenase / genetics
  • Glutamate Dehydrogenase / metabolism
  • Glutamic Acid / biosynthesis
  • Glutamine / biosynthesis
  • Metabolism / drug effects
  • Metabolism / genetics*
  • Methionine / metabolism*
  • Methionine / pharmacology
  • Nucleotides / biosynthesis
  • Pentose Phosphate Pathway / drug effects
  • Pentose Phosphate Pathway / genetics*
  • Pyridoxal Phosphate / metabolism*
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism


  • Basic-Leucine Zipper Transcription Factors
  • GCN4 protein, S cerevisiae
  • Nucleotides
  • Saccharomyces cerevisiae Proteins
  • Glutamine
  • Glutamic Acid
  • Pyridoxal Phosphate
  • Methionine
  • Glutamate Dehydrogenase