Structural basis of inhibition of the human serine hydroxymethyltransferase SHMT2 by antifolate drugs
(2019) In FEBS Letters 593(14). p.1863-1873- Abstract
Serine hydroxymethyltransferase (SHMT) is the major source of 1-carbon units required for nucleotide synthesis. Humans have cytosolic (SHMT1) and mitochondrial (SHMT2) 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 SHMT2 and solve the first SHMT2-antifolate structures. The antifolates display large differences in their hydrogen bond networks despite their similarity. Lometrexol was found to be the best hSHMT1/2 inhibitor from a panel antifolates. Comparison of apo hSHMT1 with antifolate bound hSHMT2 indicates a highly conserved active site architecture. This structural information offers insights as to how... (More)
Serine hydroxymethyltransferase (SHMT) is the major source of 1-carbon units required for nucleotide synthesis. Humans have cytosolic (SHMT1) and mitochondrial (SHMT2) 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 SHMT2 and solve the first SHMT2-antifolate structures. The antifolates display large differences in their hydrogen bond networks despite their similarity. Lometrexol was found to be the best hSHMT1/2 inhibitor from a panel antifolates. Comparison of apo hSHMT1 with antifolate bound hSHMT2 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.
(Less)
- author
- Scaletti, Emma LU ; Jemth, Ann-Sofie ; Helleday, Thomas and Stenmark, Pål LU
- organization
- publishing date
- 2019-05-25
- type
- Contribution to journal
- publication status
- published
- subject
- in
- FEBS Letters
- volume
- 593
- issue
- 14
- pages
- 1863 - 1873
- publisher
- Wiley-Blackwell
- external identifiers
-
- scopus:85067671829
- pmid:31127856
- ISSN
- 1873-3468
- DOI
- 10.1002/1873-3468.13455
- language
- English
- LU publication?
- yes
- additional info
- © 2019 Federation of European Biochemical Societies.
- id
- ba176264-336d-4330-a3a7-5831b21e5965
- date added to LUP
- 2019-06-11 21:03:03
- date last changed
- 2024-09-18 00:43:47
@article{ba176264-336d-4330-a3a7-5831b21e5965, abstract = {{<p>Serine hydroxymethyltransferase (SHMT) is the major source of 1-carbon units required for nucleotide synthesis. Humans have cytosolic (SHMT1) and mitochondrial (SHMT2) 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 SHMT2 and solve the first SHMT2-antifolate structures. The antifolates display large differences in their hydrogen bond networks despite their similarity. Lometrexol was found to be the best hSHMT1/2 inhibitor from a panel antifolates. Comparison of apo hSHMT1 with antifolate bound hSHMT2 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.</p>}}, author = {{Scaletti, Emma and Jemth, Ann-Sofie and Helleday, Thomas and Stenmark, Pål}}, issn = {{1873-3468}}, language = {{eng}}, month = {{05}}, number = {{14}}, pages = {{1863--1873}}, publisher = {{Wiley-Blackwell}}, series = {{FEBS Letters}}, title = {{Structural basis of inhibition of the human serine hydroxymethyltransferase SHMT2 by antifolate drugs}}, url = {{http://dx.doi.org/10.1002/1873-3468.13455}}, doi = {{10.1002/1873-3468.13455}}, volume = {{593}}, year = {{2019}}, }