Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models

Ruszkowski, Milosz; Sekula, Bartosz; Ruszkowska, Agnieszka; Contestabile, Roberto; Nogues, Isabel; Angelaccio, Sebastiana; Szczepaniak, Andrzej; Dauter, Zbigniew

doi:10.1038/s41598-019-56043-4

Title: Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models

Journal Article · Sun Dec 01 00:00:00 EST 2019 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-019-56043-4· OSTI ID:1624518

^[1]; Sekula, Bartosz ^[2]; Ruszkowska, Agnieszka ^[3]; Contestabile, Roberto ^[4]; Nogues, Isabel ^[5]; Angelaccio, Sebastiana ^[4]; Szczepaniak, Andrzej ^[6]; Dauter, Zbigniew ^[2]

National Cancer Inst., Argonne, IL (United States). Synchrotron Radiation Research Section of MCL; Polish Academy of Sciences (PAS), Poznan (Poland). Inst. of Bioorganic Chemistry
National Cancer Inst., Argonne, IL (United States). Synchrotron Radiation Research Section of MCL
Polish Academy of Sciences (PAS), Poznan (Poland). Inst. of Bioorganic Chemistry; Univ. of Notre Dame, IN (United States). Dept. of Chemistry and Biochemistry
Univ. of Rome (Italy). Lab. affiliated to Inst. Pasteur Italia-Fondazione Cenci Bolognetti. Dept. of Biochemical Sciences
Italian National Research Council (INRC), Bologna (Italy). Research Inst. of Terrestrial Ecosystems
Poznan Univ. of Medical Sciences, Poznan (Poland). Dept. of Hematology and Bone Marrow Transplantation

Serine hydroxymethyltransferases (SHMTs) reversibly transform serine into glycine in a reaction accompanied with conversion of tetrahydrofolate (THF) into 5,10-methylene-THF (5,10-meTHF). In vivo, 5,10-meTHF is the main carrier of one-carbon (1C) units, which are utilized for nucleotide biosynthesis and other processes crucial for every living cell, but hyperactivated in over proliferating cells (e.g. cancer tissues). SHMTs are emerging as a promising target for development of new drugs because it appears possible to inhibit growth of cancer cells by cutting of the supply of 5,10-meTHF. Methotrexate (MTX) and pemetrexed (PTX) are two examples of antifolates that have cured many patients over the years but target different enzymes from the folate cycle (mainly dihydrofolate reductase and thymidylate synthase, respectively). Here we show crystal structures of MTX and PTX bound to plant SHMT isozymes from cytosol and mitochondria—human isozymes exist in the same subcellular compartments. We verify inhibition of the studied isozymes by a thorough kinetic analysis. We propose to further exploit antifolate scaffold in development of SHMT inhibitors because it seems likely that especially polyglutamylated PTX inhibits SHMTs in vivo. Structure-based optimization is expected to yield novel antifolates that could potentially be used as chemotherapeutics.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1624518

Journal Information:: Scientific Reports, Vol. 9, Issue 1; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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