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Therapeutic targeting of the mitochondrial one-carbon pathway: perspectives, pitfalls, and potential

Oncogene volume 40, pages 2339–2354 (2021)Cite this article

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Abstract

Most of the drugs currently prescribed for cancer treatment are riddled with substantial side effects. In order to develop more effective and specific strategies to treat cancer, it is of importance to understand the biology of drug targets, particularly the newly emerging ones. A comprehensive evaluation of these targets will benefit drug development with increased likelihood for success in clinical trials. The folate-mediated one-carbon (1C) metabolism pathway has drawn renewed attention as it is often hyperactivated in cancer and inhibition of this pathway displays promise in developing anticancer treatment with fewer side effects. Here, we systematically review individual enzymes in the 1C pathway and their compartmentalization to mitochondria and cytosol. Based on these insight, we conclude that (1) except the known 1C targets (DHFR, GART, and TYMS), MTHFD2 emerges as good drug target, especially for treating hematopoietic cancers such as CLL, AML, and T-cell lymphoma; (2) SHMT2 and MTHFD1L are potential drug targets; and (3) MTHFD2L and ALDH1L2 should not be considered as drug targets. We highlight MTHFD2 as an excellent therapeutic target and SHMT2 as a complementary target based on structural/biochemical considerations and up-to-date inhibitor development, which underscores the perspectives of their therapeutic potential.

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Fig. 1: Compartmentalization of the mammalian one-carbon metabolism to mitochondria and cytosol.
Fig. 2: Chemical structure of folate.
Fig. 3: Reaction scheme of key enzymes in the 1C pathway.
Fig. 4: Our computational model of MTHFD2·NAD+·Pi·Mg2+·Pi·THF system.
Fig. 5: Our computational model of MTHFD2·NAD+·P ·THF system without Mg+.

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Acknowledgements

LNZ was supported by an A*STAR International Fellowship (AIF) from Singapore. This work is supported by the IngaBritt och Arne Lundbergs Forskningsstiftelse LU2020-0013; PK is supported by the Faculty of Medicine, Lund University; the Swedish Foundation for Strategic Research Dnr IRC15-0067, and Swedish Research Council, Strategic Research Area EXODIAB, Dnr 2009–1039. LNZ would like to thank Prof. Chew Lock Yue (NTU) and Prof. Ulf Ryde (LU) for comments on the manuscript.

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Authors and Affiliations

  1. Department of Clinical Sciences, Lund University, Malmö, Sweden

    Li Na Zhao & Philipp Kaldis

  2. Zhejiang University–University of Edinburgh (ZJU-UoE) Institute, Haining, Zhejiang, PR China

    Mikael Björklund

  3. 2nd Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China

    Mikael Björklund

  4. Deanery of Biomedical Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK

    Mikael Björklund

  5. Laboratory of Host Defense, The World Premier International Research Center Initiative (WPI) Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan

    Matias J. Caldez

  6. School of Information Science and Technology, Shanghai Tech University, Shanghai, PR China

    Jie Zheng

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Zhao, L.N., Björklund, M., Caldez, M.J. et al. Therapeutic targeting of the mitochondrial one-carbon pathway: perspectives, pitfalls, and potential. Oncogene 40, 2339–2354 (2021). https://doi.org/10.1038/s41388-021-01695-8

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