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Mitochondrial Methylenetetrahydrofolate Published OnlineFirst June 22, 2015; DOI: 10.1158/1541-7786.MCR-15-0117 Perspective Molecular Cancer Research Mitochondrial Methylenetetrahydrofolate Dehydrogenase (MTHFD2) Overexpression Is Associated with Tumor Cell Proliferation and Is a Novel Target for Drug Development Philip M. Tedeschi1, Alexei Vazquez2, John E. Kerrigan3, and Joseph R. Bertino4 Abstract Rapidly proliferating tumors attempt to meet the demands for sensitive to treatment with MTX. A key enzyme upregulated in nucleotide biosynthesis by upregulating folate pathways that rapidly proliferating tumors but not in normal adult cells is the provide the building blocks for pyrimidine and purine biosyn- mitochondrial enzyme methylenetetrahydrofolate dehydroge- thesis. In particular, the key role of mitochondrial folate enzymes nase (MTHFD2). This perspective outlines the rationale for spe- in providing formate for de novo purine synthesis and for provid- cific targeting of MTHFD2 and compares known and generated ing the one-carbon moiety for thymidylate synthesis has been crystal structures of MTHFD2 and closely related enzymes as a recognized in recent studies. We have shown a significant corre- molecular basis for developing therapeutic agents against lation between the upregulation of the mitochondrial folate MTHFD2. Importantly, the development of selective inhibitors enzymes, high proliferation rates, and sensitivity to the folate of mitochondrial methylenetetrahydrofolate dehydrogenase is antagonist methotrexate (MTX). Burkitt lymphoma and diffuse expected to have substantial activity, and this perspective supports large-cell lymphoma tumor specimens have the highest levels of the investigation and development of MTHFD2 inhibitors for mitochondrial folate enzyme expression and are known to be anticancer therapy. Mol Cancer Res; 13(10); 1361–6. Ó2015 AACR. Introduction this activity in embryos was shown by knocking out this gene (nmdmc) in mice. The homozygous gene knockout mice died in In 1960, Scrimgeour and Huennekens (1) reported that, in utero after day 12. Heterozygous mice were healthy, but were contrast with cytoplasmic methylenetetrahydrofolate dehydroge- smaller and had pale livers, and the only abnormality detected nase (MTHFD1), which uses NADP as the coenzyme, ascites was a reduced number of nucleated cells in the liver. However, tumors contained a NAD-dependent methylenetetrahydrofolate there were no differences in the frequencies of hematopoietic dehydrogenase, MTHFD2. This observation went unnoticed until precursors. 1985, when Mejia and McKenzie (2) found that MTHFD2 was These authors postulated that "the NAD (rather than NADP) also expressed in embryonic liver, and not in adult tissues. This dependent dehydrogenase activity" is required to promote "a enzyme had both methylenetetrahydrofolate dehydrogenase and more thermodynamically favorable pathway to balance the pools cyclohydrolase activity and was different from the cytoplasmic of 10-formyl-THF during development" (5). The generation of enzyme (MTHFDl), which requires NADP as a cofactor and is one-carbon units by mitochondria in embryonic mammalian trifunctional, also containing cyclohydrolase and formyltetrahy- fibroblasts lacking MTHFD2 was completely blocked, and impor- drofolate synthetase activity (Fig. 1A; ref. 3). Patel and colleagues tantly, the cytoplasmic folate enzymes could not synthesize (4) then showed that this MTHFD2 was located in the mitochon- sufficient purines to allow cell growth. These MTHFD2-deficient dria and, unlike MTHFD1, was highly expressed in embryos and fibroblasts were found to be glycine auxotrophs, suggested to be a decreased in activity as the embryos matured. The importance of consequence of the accumulation of the MTHFD2 substrate 5, 10- methylenetetrahydrofolate. The accumulation of methylenetetra- hydrofolate inhibits serine hydroxymethyltransferase (SHMT2) 1Department of Pharmacology, Rutgers Cancer Institute of New Jer- sey, Robert Wood Johnson Medical School, Rutgers University, New and therefore blocks glycine generation. Thus, both glycine gen- Brunswick, New Jersey. 2Cancer Research UK Beatson Institute, Glas- eration and an inability to regenerate THF would be common 3 gow, United Kingdom. Department of Bioinformatics, Rutgers Can- properties of cells with MTHFD2 deficiency (4). cer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey. 4Departments of MTHFD2, shown to be overexpressed in rapidly proliferating Medicine and Pharmacology, Rutgers Cancer Institute of New Jersey, malignant tumors, was postulated to be the "main switch" that Robert Wood Johnson Medical School, Rutgers University, New enables mitochondria to produce additional one-carbon units for Brunswick, New Jersey. purine synthesis to enable rapid growth (6), and, as recently Corresponding Author: Joseph R. Bertino, The Cancer Institute of New Jersey, recognized, generates NADH necessary for protection from reac- 195 Little Albany Street, Room 3033, New Brunswick, NJ 08903. Phone: 732- tive oxygen species and macromolecular synthesis (7). In contrast, 235-5810; Fax: 732-235-8181; E-mail: [email protected] to MTHFD2, the NADP-dependent cytoplasmic trifunctional doi: 10.1158/1541-7786.MCR-15-0117 enzyme, MTHFD1, generates NADPH as well as formate, for Ó2015 American Association for Cancer Research. purine biosynthesis (Fig. 1B and C). Recent studies have shown www.aacrjournals.org 1361 Downloaded from mcr.aacrjournals.org on September 27, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst June 22, 2015; DOI: 10.1158/1541-7786.MCR-15-0117 Tedeschi et al. A Glucose B Cell membrane Cytoplasm Mitochondria Folate* Folate* Methionine THF THF Serine Serine CH3-THF 4 4m Glycine Glycine CH -THF CH -THF 2 THF 5 2 NADP+ NAD(P)+ dTMP 3 CO2 + NH2 m3 NADPH NAD(P)H CH+-THF CH+-THF 2 2m Purines CHO-THF CHO-THF ADP + Pi ADP + Pi 1 1m THF ATP ATP Formate Formate Slowly proliferang cells Glucose Serine C Cell membrane Cytoplasm Mitochondria Folate* Folate* Methionine THF THF Serine Serine CH3-THF 4 4m Glycine Glycine CH -THF CH -THF 2 THF 5 2 NADP+ NAD(P)+ dTMP MTHFD2 3 CO2 + NH2 m3 NADPH NAD(P)H CH+-THF CH+-THF 2 2m Purines CHO-THF CHO-THF ADP + Pi ADP + Pi 1 1m THF ATP ATP Formate Formate Rapidly proliferang cells 1362 Mol Cancer Res; 13(10) October 2015 Molecular Cancer Research Downloaded from mcr.aacrjournals.org on September 27, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst June 22, 2015; DOI: 10.1158/1541-7786.MCR-15-0117 MTHFD2 Is a Novel Anticancer Target that mitochondrial rather than cytoplasmic folate enzymes gen- In recent studies (11, 15), increased activity of the serine erate most of the formate used for purine synthesis via the biosynthesis pathway, one-carbon metabolism, and the glycine mitochondrial enzyme MTHFD1L, which only has formyl THF cleavage system (SOG pathway) was examined in a subset of synthetase activity (8). The mitochondrial counterpart of tumors, and was found to be upregulated in tumors in breast and MTHFD2 has now been identified as MTHFD2L. This enzyme prostate tumors with poor prognosis and was correlated with uses NADP as a cofactor and, unlike MTHFD2, is expressed at low increased sensitivity to antifolate inhibitors methotrexate and levels in early mouse embryos, increases by day 10.5, and is found pemetrexed (11). In tumors with high rates of proliferation, the in all adult tissues, with highest levels in lung and brain (9) and is SOG pathway contributed to increased ATP synthesis, which is likely a housekeeping enzyme. necessary for de novo purine synthesis. As shown in lymphoma and other tumor subtypes, expression of genes in the SOG pathway MTHFD2 as a Target for Drug Development showed increased levels of mitochondrial folate enzymes, includ- ing MTHFD2. In a study of mRNA profiles spanning 19 cancer types, Nisson and colleagues (10) showed that the mitochondrial folate path- way and in particular MTHFD2 mRNA and protein expression is MTHFD2 Structure and Characteristics for elevated in highly proliferating cancers. What makes MTHFD2 a Rational Drug Design novel target for drug development is its high expression in rapidly Given the importance of MTHFD2 for cell survival and prolif- proliferating tumors and its restricted expression in adult differ- eration, this enzyme could represent a possible target for anti- entiated and proliferating tissues (2). As it has a redundant neoplastic agents. Accordingly, we have looked into existing function to the cytoplasmic NADP-dependent trifunctional cyto- structures for strategies to rationally target MTHFD2 selectively. plasmic enzyme (MTHFD1), as well as the bifunctional mito- As both the cofactors NAD/NADP and the substrate MTHF are chondrial enzyme MTHFD2L, the question arises as to the role required for enzyme activity, competitive inhibitors based on MTHFD2 plays in cell metabolism. MTHFD2 may supply the either the cofactor or the substrate molecules can be considered increased demand in rapidly proliferating cells for formate and for drug design/development. ATP generation (11). Knockdown of this enzyme led to inhibition Several structural studies (mainly X-ray crystallography) of the of most tumor cell lines, providing the rationale for inhibitor three methylenetetrahydrofolate dehydrogenase enzymes have development (10). been reported in past years. Cygler and colleagues (16, 18) have – In a recent study of KRAS mutant non small cell lung cancer published several structures based on DC301,
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