Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 29, Issue 26, Pages 3183-3200Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E18-08-0515
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Funding
- Wellcome Trust-DBT IA intermediate fellowship [IA/I/14/2/501523]
- Department of Biotechnology, Government of India [BT/PR13446/COE/34/30/2015]
- Stem/DBT institutional support
- inStem
- Department of Science and Technology and Science and Engineering Research Board (DST-SERB) national postdoctoral fellowships [PDF/2015/000225, PDF/2016/000416, PDF/2016/001877]
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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 ratelimiting 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.
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