Therapeutic Targeting of Mitochondrial One-Carbon Metabolism in Cancer

Abstract

One-carbon (1C) metabolism encompasses folate-mediated 1C transfer reactions and related processes, including nucleotide and amino acid biosynthesis, antioxidant regeneration, and epigenetic regulation. 1C pathways are compartmentalized in the cytosol, mitochondria, and nucleus. 1C metabolism in the cytosol has been an important therapeutic target for cancer since the inception of modern chemotherapy, and "antifolates" targeting cytosolic 1C pathways continue to be a mainstay of the chemotherapy armamentarium for cancer. Recent insights into the complexities of 1C metabolism in cancer cells, including the critical role of the mitochondrial 1C pathway as a source of 1C units, glycine, reducing equivalents, and ATP, have spurred the discovery of novel compounds that target these reactions, with particular focus on 5,10-methylene tetrahydrofolate dehydrogenase 2 and serine hydroxymethyltransferase 2. In this review, we discuss key aspects of 1C metabolism, with emphasis on the importance of mitochondrial 1C metabolism to metabolic homeostasis, its relationship with the oncogenic phenotype, and its therapeutic potential for cancer.

Figure 1.. 1C Metabolism Reactions, Intermediates, and Products.

1C metabolism is compartmentalized into the mitochondria and cytosol with a smaller pool in the nucleus. Folates are transported across the plasma membrane by the RFC (SLC19A1) and PCFT (SLC46A1). Serine is generated from glycolysis intermediates. Serine then enters the mitochondria and provides 1C units for the serine cycle (noted with bold blue arrows). Formate is exported to the cytosol where it serves as a source of 1C units for biosynthetic reactions. Nuclear 1C metabolism generates dTMP from dUMP to eliminate uracil misincorporation in DNA. Nuclear enzymes in light blue undergo SUMOylation in the cytosol and are imported into the nucleus during S-phase. Folate uptake into the mitochondria is mediated by the MFT (SLC25A32). Abbreviations: 10-CHO-THF, 10-formyl tetrahydrofolate; 2-PG, 2-phosphoglycerate; 3-PG, 3-phosphoglycerate; 3PS, 3-phosphoserine; 5,10-CH₂-THF, 5,10-methylene tetrahydrofolate; AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide; AICARFTase, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase; ALDH1L1, aldehyde dehydrogenase 1 family member L1; ALDH1L2, aldehyde dehydrogenase 1 family member L2; DHF, dihydrofolate; DHFR, dihydrofolate reductase; DHFRL1, dihydrofolate reductase-like1; FGAR, formyl glycinamide ribonucleotide; f-Met, formyl methionione; FAICAR, 5-formamidoimidazole-4-carboxamide ribonucleotide; GAR, glycinamide ribonucleotide; GARFTase, glycinamide ribonucleotide formyltransferase; glycine cleavage system, GCS; MFT, mitochondrial folate transporter; MTFMT, methionyl tRNA formyltransferase; MTHFD1L, methylene tetrahydrofolate dehydrogenase 1-like; MTHFD2L, methylene tetrahydrofolate dehydrogenase 2-like; MTHFR, methylene tetrahydrofolate reductase; MTR, methionine synthase; PCFT, proton-coupled folate transporter; PEP, phosphoenolpyruvate; PGDH, phosphoglycerate dehydrogenase; PKM2, pyruvate kinase muscle isozyme M2; PSAT1, phosphoserine aminotransferase 1; PRPP, phosphoribosyl pyrophosphate; PSPH, phosphoserine phosphatase; RFC, reduced folate carrier; SAM, S-adenosyl methionione; S-adenosyl methionine synthetase (SAMS); SFXN1/3, sideroflexin 1/3; SHMT1, serine hydroxymethyltransferase 1; SHMT2, serine hydroxymethyltransferase 2; THF, tetrahydrofolate; TS, thymidylate synthase.

Figure 2.. MTHFD2 Inhibitors.

MTHFD2 Inhibitors include the macrolide keto-carboxylic acid carolacton produced by the myxobacterium Sorangium cellulosum (101) and the Eli Lilly compound LY345899 (102). Newer agents include the Daiichi Sankyo compounds DS44960156 (104) and DS18561882 (105).

Figure 3.. SHMT2 Inhibitors.

SHMT2 inhibitors include the early-generation pyrazolopyran compounds originally designed as inhibitors of plant SHMT2 (110) (A).The pyrazolopyran scaffold was later optimized for inhibition of Plasmodium SHMT (111) (B) and human SHMT1/2, with RZ-2994 or SHIN1 (36) (C) and SHIN2 (114)

Figure 4.. Multi-targeted Inhibitors of SHMT2 and Cytosolic 1C Metabolism.

Structures are shown for 5-subsituted pyrrolo[3,2-d]pyrimidine compounds AGF291, AGF320 and AGF347 (35).