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Structural basis of inhibition of the human serine hydroxymethyltransferase SHMT 2 by antifolate drugs
Author(s) -
Scaletti Emma,
Jemth AnnSofie,
Helleday Thomas,
Stenmark Pål
Publication year - 2019
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13455
Subject(s) - serine hydroxymethyltransferase , antifolate , serine , biochemistry , chemistry , pemetrexed , enzyme , biology , antimetabolite , genetics , cancer , chemotherapy , cisplatin
Serine hydroxymethyltransferase ( SHMT ) is the major source of 1‐carbon units required for nucleotide synthesis. Humans have cytosolic ( SHMT 1) and mitochondrial ( SHMT 2) isoforms, which are upregulated in numerous cancers, making the enzyme an attractive drug target. Here, we show that the antifolates lometrexol and pemetrexed are inhibitors of SHMT 2 and solve the first SHMT 2‐antifolate structures. The antifolates display large differences in their hydrogen bond networks despite their similarity. Lometrexol was found to be the best hSHMT 1/2 inhibitor from a panel antifolates. Comparison of apo hSHMT 1 with antifolate bound hSHMT 2 indicates a highly conserved active site architecture. This structural information offers insights as to how these compounds could be improved to produce more potent and specific inhibitors of this emerging anti‐cancer drug target.