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Structural basis of inhibition of the human serine hydroxymethyltransferase SHMT2 by antifolate drugs

Scaletti, Emma LU ; Jemth, Ann-Sofie ; Helleday, Thomas and Stenmark, Pål LU orcid (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.

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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
FEBS Letters
volume
593
issue
14
pages
1863 - 1873
publisher
Wiley-Blackwell
external identifiers
  • pmid:31127856
  • scopus:85067671829
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
2024-06-11 15:30:57
@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}},
}