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

Li Na Zhao1, Mikael Björklund2,3,4, Matias J Caldez5

  • 1Department of Clinical Sciences, Lund University, Malmö, Sweden. lina.zhao@med.lu.se.

Oncogene
|March 5, 2021
PubMed

Insights

Identifying new cancer drug targets within the folate-mediated one-carbon (1C) metabolism pathway is crucial. MTHFD2 is a promising target for hematopoietic cancers, while SHMT2 is a complementary target for developing novel cancer therapies with fewer side effects.

Area of Science:

  • Biochemistry and Molecular Biology
  • Cancer Biology
  • Pharmacology

Background:

  • Current cancer drugs have significant side effects, necessitating the development of more targeted therapies.
  • The folate-mediated one-carbon (1C) metabolism pathway is frequently hyperactivated in cancer cells.
  • Inhibiting the 1C pathway shows potential for developing anticancer treatments with improved safety profiles.

Purpose of the Study:

  • To systematically review enzymes within the 1C metabolism pathway and their subcellular localization (mitochondria and cytosol).
  • To identify and evaluate novel drug targets for cancer treatment based on pathway insights.
  • To assess the therapeutic potential of specific enzymes, including MTHFD2, SHMT2, MTHFD1L, MTHFD2L, and ALDH1L2.

Main Methods:

  • Systematic review of individual enzymes in the 1C metabolic pathway.
  • Analysis of enzyme compartmentalization in mitochondria and cytosol.
  • Evaluation of enzymes as potential drug targets based on structural, biochemical, and inhibitor development data.

Main Results:

  • MTHFD2 is identified as a highly promising drug target, particularly for hematopoietic malignancies like CLL, AML, and T-cell lymphoma.
  • SHMT2 and MTHFD1L are recognized as potential therapeutic targets within the 1C pathway.
  • MTHFD2L and ALDH1L2 are deemed unsuitable as drug targets based on current understanding.

Conclusions:

  • MTHFD2 represents an excellent therapeutic target for specific cancers, supported by inhibitor development.
  • SHMT2 serves as a valuable complementary target, enhancing the potential of 1C pathway-based cancer therapies.
  • Targeting specific enzymes in the 1C pathway offers a promising strategy for developing novel anticancer drugs with reduced side effects.

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