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Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor Robert Gustafsson1, Ann-Sofie Jemth2, Nina M.S

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Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor Robert Gustafsson1, Ann-Sofie Jemth2, Nina M.S Published OnlineFirst November 29, 2016; DOI: 10.1158/0008-5472.CAN-16-1476 Cancer Therapeutics, Targets, and Chemical Biology Research Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor Robert Gustafsson1, Ann-Sofie Jemth2, Nina M.S. Gustafsson2, Katarina Farnega€ rdh3, Olga Loseva2, Elisee Wiita2, Nadilly Bonagas2, Leif Dahllund4, Sabin Llona-Minguez2, Maria Haggblad€ 5, Martin Henriksson2, Yasmin Andersson4, Evert Homan2, Thomas Helleday2, and Pa l Stenmark1 Abstract To sustain their proliferation, cancer cells become dependent while sparing healthy cells. Here we report the synthesis and on one-carbon metabolism to support purine and thymidylate preclinical characterization of the first inhibitor of human synthesis. Indeed, one of the most highly upregulated enzymes MTHFD2. We also disclose the first crystal structure of MTHFD2 during neoplastic transformation is MTHFD2, a mitochondrial in complex with a substrate-based inhibitor and the enzyme þ methylenetetrahydrofolate dehydrogenase and cyclohydrolase cofactors NAD and inorganic phosphate. Our work provides a involved in one-carbon metabolism. Because MTHFD2 is rationale for continued development of a structural framework for expressed normally only during embryonic development, it offers the generation of potent and selective MTHFD2 inhibitors for a disease-selective therapeutic target for eradicating cancer cells cancer treatment. Cancer Res; 77(4); 937–48. Ó2017 AACR. Introduction scheme shown in Fig. 1A (3, 4). In mitochondria, the 1C unit usually derived from serine by serine hydroxymethyltransferase Rapidly dividing cells depend on a high and steady supply of (SHMT) or from glycine by the glycine cleavage system, is attached 10-formyltetrahydrofolate to sustain several vital anabolic reac- to tetrahydrofolate (THF; see Fig. 1C) yielding methylene-THF tions, for example the synthesis of purines. Targeting this pathway (CH2-THF), which is subsequently oxidized to formate. The is one way to specifically target cancer cells, and one successful formate is released to the cytoplasm, where it is again attached example is the antifolate drug methotrexate that has been used in to a THF molecule that is either used for de novo purine synthesis cancer therapies since the 1950s (1). or reduced further and used for thymidylate or methionine In eukaryotes, the folate-dependent one-carbon metabolism is synthesis (3). It has been shown that the majority of the 1C units highly compartmentalized between cytoplasm and mitochondria used in the cytoplasm are derived from the mitochondria (5). The (2, 3). These compartments are metabolically connected by the entire pathway is upregulated in cancer cells (6) as well as transport of the one-carbon (1C) donors serine, glycine, and embryonic cells (7). It is important for maintaining the ratios of formate across the mitochondrial membrane. Depending on the þ þ NAD to NADH and NADP to NADPH, thus affecting the redox different redox environments in the mitochondria and cytoplasm, balance of the cells and their ability to scavenge and reduce the metabolic flow occurs mostly in the clockwise direction in the reactive oxygen species (8). One enzyme of specific interest is MTHFD2, responsible for the oxidation of methylene-THF to 1Department of Biochemistry and Biophysics, Stockholm University, Stockholm, 10-formyl-THF in mitochondria, which is highly overexpressed in 2 Sweden. Science for Life Laboratory, Division of Translational Medicine and cancer cells and embryonic cells, but not in normal adult tissues. Chemical Biology, Department of Medical Biochemistry and Biophysics, Kar- 3 Thus, development of inhibitors targeting MTHFD2 is an attrac- olinska Institutet, Stockholm, Sweden. Drug Discovery and Development fi Platform, Science for Life Laboratory, Department of Organic Chemistry, Stock- tive opportunity to speci cally target cancer cells (9). holm University, Solna, Sweden. 4Drug Discovery and Development Platform, The enzyme family responsible for the conversion between Science for Life Laboratory, School of Biotechnology, Royal Institute of Tech- methylene-THF and formate is the methylenetetrahydrofolate nology, Solna, Sweden. 5Biochemical and Cellular Screening, Science for Life dehydrogenase (MTHFD) family that performs three main reac- Laboratory, Department of Biochemistry and Biophysics, Stockholm University, tions in the 1C metabolism: the 5,10-methylene-THF (CH2-THF) Stockholm, Sweden. þ dehydrogenase, 5,10-methenyl-THF (CH -THF) cyclohydrolase Note: Supplementary data for this article are available at Cancer Research and 10-formyl-THF (10-CHO-THF) synthetase activities Online (http://cancerres.aacrjournals.org/). (see Fig. 1B; refs. 10, 11). Corresponding Authors: Pa l Stenmark, Stockholm University, Svante In mitochondria, the 5,10-methylene-THF dehydrogenase Arrhenius vag€ 16C, Stockholm 106 91, Sweden. Phone: 46-816-3729; Fax: and 5,10-methenyl-THF cyclohydrolase activities are per- 46-815-5597; E-mail: [email protected]; and Thomas Helleday, formed by two enzymes, MTHFD2 and MTHFD2L (12). [email protected] MTHFD2 was first discovered in Ehrlich ascites tumor cells doi: 10.1158/0008-5472.CAN-16-1476 (13) already in 1960 and later described as a mitochondrial þ Ó2016 American Association for Cancer Research. NAD -dependent methylene-THF dehydrogenase and www.aacrjournals.org 937 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst November 29, 2016; DOI: 10.1158/0008-5472.CAN-16-1476 Gustafsson et al. Figure 1. A, Mammalian 1C metabolism. Reactions 1–4 occur in both the cytoplasmic and the mitochondrial (m) compartments. Reactions 1, 2, and 3 are catalyzed by trifunctional MTHFD1 in the cytoplasm using 10-formyl-THF synthetase, 5,10-methenyl-THF cyclohydrolase, and 5,10-methylene-THF dehydrogenase activity, respectively. In mammalian mitochondria, reaction 1m is catalyzed by monofunctional MTHFD1L, and reactions 2m and 3m are catalyzed by bifunctional MTHFD2 or MTHFD2L. Reactions 4 and 4m are catalyzed by serine hydroxymethyltransferase and reaction 5 by the glycine cleavage system. Hcy, homocysteine; Met, methionine; AdoMet, S-Adenosyl methionine; THF, tetrahydrofolate. Adapted from Shin and colleagues (36). B, The three activities, 5,10-methylene-THF dehydrogenase, 5,10-methenyl-THF cyclohydrolase, and 10-formyl-THF synthetase, mediated by the MTHFD family. C and D, Chemical structures of tetrahydrofolate (THF; C) and LY345899 (D). 938 Cancer Res; 77(4) February 15, 2017 Cancer Research Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst November 29, 2016; DOI: 10.1158/0008-5472.CAN-16-1476 Structure of Human MTHFD2 and Identification of an Inhibitor cyclohydrolase expressed in embryonic and transformed cells (40). MTHFD1L mRNA has also been found to be upregulated in (14–19). However, it has been demonstrated that MTHFD2 human colon adenocarcinoma (41). mRNA is expressed at low levels in all tissues but not confirmed In the cytosol, all three enzymatic functions are performed by to be translated (20). MTHFD2 has been shown to play an MTHFD1. MTHFD1 functions as a dimer where each monomer essential role in embryonic development for mammals because comprises two functional units, one DC-domain containing the gene inactivation in mice resulted in embryonic lethality (21). dehydrogenase (D) and cyclohydrolase (C) activities with a Theproteinhasbeenshowntobeimportantforrapidgrowing common active site (42) as demonstrated by both substrate cells, such as embryonic cells or cancer cells, mainly by sup- channeling (43, 44) and X-ray crystallographic structures with þ porting the high level of purine synthesis needed (21, 22). NADP (10) and with folate-analogues (45). The second domain MTHFD2-null mutant fibroblasts have previously been is responsible for the 10-formyl-THF-synthetase (S) activity. þ reported to be glycine auxotrophs (23), a condition that can MTHFD1 uses NADP as cofactor for the dehydrogenase activity þ þ be rescued by expression of an NAD -orNADP -dependent, (10) and the rate-limiting step of the D/C activities is the cyclo- mitochondrially targeted methylene-THF-dehydrogenase- hydrolase (46). MTHFD1 is expressed in all adult tissues exam- þ cyclohydrolase (24). For its dehydrogenase activity with NAD ined (47). MTHFD2 has an absolute requirement for inorganic phosphate Computer-generated homology models of both MTHFD2 (14) 2þ (Pi)andMg (14, 18, 19, 25). MTHFD2 displays activity also and MTHFD2L (9) have been published, based on the human þ with NADP , although lower, and in such case only requires MTHFD1 structure and in the case of the MTHFD2 homology 2þ thepresenceofMg and not Pi (25). It appears to have evolved model, also based on the Escherichia coli (48) and Saccharomyces from a tri-functional enzyme through the loss of the synthetase cerevisiae (49) homologs. So far no structure based on empirical þ þ domain and the change of specificity from NADP to NAD ,Pi data has been presented for any of these two proteins. þ and Mg2 (14, 26). Here we identify the first MTHFD2 inhibitor LY345899 MTHFD2 mRNA and protein are upregulated in many (Fig. 1D) and the target engagement of this substrate-based cancers and their overexpression is associated with tumor cell inhibitor, as well as present the first structure of the human þ proliferation (9). MTHFD2 depletion by RNA interference mitochondrial NAD
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