2. Academic Validation
  3. Serine hydroxymethyltransferase as a potential target of antibacterial agents acting synergistically with one-carbon metabolism-related inhibitors

Serine hydroxymethyltransferase as a potential target of antibacterial agents acting synergistically with one-carbon metabolism-related inhibitors

  • Commun Biol. 2022 Jun 23;5(1):619. doi: 10.1038/s42003-022-03555-x.
Yuko Makino 1,  Chihiro Oe 1,  Kazuya Iwama 1,  Satoshi Suzuki 1,  Akie Nishiyama 1,  Kazuya Hasegawa 2,  Haruka Okuda 3,  Kazushige Hirata 1 4,  Mariko Ueno 1,  Kumi Kawaji 3,  Mina Sasano 3,  Emiko Usui 3,  Toshiaki Hosaka 5,  Yukako Yabuki 5,  Mikako Shirouzu 5,  Makoto Katsumi 4,  Kazutaka Murayama 5 6,  Hironori Hayashi 7 8,  Eiichi N Kodama 1 3 9 10
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
  • 2 Structural Biology Division, Japan Synchrotron Radiation Research Institute, 1-1, Sayo-chou, Hyogo, Japan.
  • 3 Division of Infectious Diseases, International Research Institute of Disaster Science, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
  • 4 Division of Clinical Laboratory, Department of Clinical Laboratory Medicine, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
  • 5 Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Suehiro 1-7-22, Tsurumi, Yokohama, Japan.
  • 6 Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan.
  • 7 Division of Infectious Diseases, International Research Institute of Disaster Science, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. hhayashi@med.tohoku.ac.jp.
  • 8 Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. hhayashi@med.tohoku.ac.jp.
  • 9 Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
  • 10 Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
PMID: 35739195 DOI: 10.1038/s42003-022-03555-x
Abstract

Serine hydroxymethyltransferase (SHMT) produces 5,10-methylenetetrahydrofolate (CH2-THF) from tetrahydrofolate with serine to glycine conversion. SHMT is a potential drug target in parasites, viruses and Cancer. (+)-SHIN-1 was developed as a human SHMT Inhibitor for Cancer therapy. However, the potential of SHMT as an Antibacterial target is unknown. Here, we show that (+)-SHIN-1 bacteriostatically inhibits the growth of Enterococcus faecium at a 50% effective concentration of 10-11 M and synergistically enhances the Antibacterial activities of several nucleoside analogues. Our results, including crystal structure analysis, indicate that (+)-SHIN-1 binds tightly to E. faecium SHMT (efmSHMT). Two variable loops in SHMT are crucial for inhibitor binding, and serine binding to efmSHMT enhances the affinity of (+)-SHIN-1 by stabilising the loop structure of efmSHMT. The findings highlight the potency of SHMT as an Antibacterial target and the possibility of developing SHMT inhibitors for treating Bacterial, viral and parasitic infections and Cancer.

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