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Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor
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- Gustafsson, Robert (author)
- Stockholms universitet,Institutionen för biokemi och biofysik
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- Jemth, Ann-Sofie (author)
- Karolinska Institutet
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- Gustafsson, Nina M. S. (author)
- Karolinska Institutet
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- (creator_code:org_t)
- AMER ASSOC CANCER RESEARCH, 2017
- 2017
- English.
- In: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 77:4, s. 937-948
- Journal article (peer-reviewed)
Abstract
Subject headings
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- To sustain their proliferation, cancer cells become dependent on one-carbon metabolism to support purine and thymidylate synthesis. Indeed, one of the most highly upregulated enzymes during neoplastic transformation is MTHFD2, a mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase involved in one-carbon metabolism. Because MTHFD2 is expressed normally only during embryonic development, it offers a disease-selective therapeutic target for eradicating cancer cells while sparing healthy cells. Here we report the synthesis and preclinical characterization of the first inhibitor of human MTHFD2. We also disclose the first crystal structure of MTHFD2 in complex with a substrate-based inhibitor and the enzyme cofactors NAD(+) and inorganic phosphate. Our work provides a rationale for continued development of a structural framework for the generation of potent and selective MTHFD2 inhibitors for cancer treatment.
Subject headings
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
Keyword
- Biochemistry
- biokemi
Publication and Content Type
- ref (subject category)
- art (subject category)
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- Stockholm University
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