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S-adenosylmethionine metabolism buffering is regulated by a decrease in glycine N-methyltransferase via the nuclear

Soshiro Kashio1,2, Masayuki Miura1,3

  • 1Department of Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Proceedings of the National Academy of Sciences of the United States of America
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Maintaining stable S-adenosylmethionine (SAM) levels is vital. This study reveals that reducing glycine N-methyltransferase (Gnmt) via the nuclear ubiquitin-proteasome system (UPS) helps conserve SAM during starvation.

Keywords:
DrosophilaS-adenosylmethioninefat bodymetabolismubiquitin–proteasome system

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Area of Science:

  • Metabolic regulation
  • Cellular homeostasis
  • Biochemistry

Background:

  • Metabolic homeostasis relies on balanced metabolite production and consumption.
  • Mechanisms controlling metabolite consumption, particularly S-adenosylmethionine (SAM), are under-investigated.
  • SAM metabolism is crucial for methylation, polyamine biosynthesis, and transsulfuration.

Purpose of the Study:

  • To investigate the regulation of SAM consumption in *Drosophila* fat body (FB) under SAM-limiting conditions.
  • To elucidate the role of glycine N-methyltransferase (Gnmt) in maintaining SAM stability.
  • To understand the involvement of the nuclear ubiquitin-proteasome system (UPS) in SAM homeostasis.

Main Methods:

  • Analysis of SAM levels in *Drosophila* FB during nutrient deprivation.
  • Investigating the degradation pathway of Gnmt using the nuclear UPS.
  • Employing genetic manipulation to suppress nuclear UPS function and observe effects on starvation tolerance.

Main Results:

  • Gnmt, a key SAM-consuming enzyme in the FB, is degraded via the nuclear UPS during starvation.
  • Inhibition of SAM synthesis and starvation conditions lead to decreased Gnmt levels.
  • Suppression of nuclear UPS-mediated Gnmt reduction enhances starvation tolerance.

Conclusions:

  • Nuclear UPS-mediated degradation of Gnmt is a mechanism to maintain SAM levels under conditions of SAM shortage.
  • This regulatory pathway plays a significant role in metabolic adaptation to starvation.
  • Targeting Gnmt regulation via the nuclear UPS could be a strategy for enhancing stress tolerance.