6qvl
Human SHMT2 in complex with pemetrexed
Structural highlights
FunctionGLYM_HUMAN Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Required to prevent uracil accumulation in mtDNA. Interconversion of serine and glycine. Associates with mitochondrial DNA.[1] Publication Abstract from PubMedSerine 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. Structural basis of inhibition of the human serine hydroxymethyltransferase SHMT2 by antifolate drugs.,Scaletti E, Jemth AS, Helleday T, Stenmark P FEBS Lett. 2019 Jul;593(14):1863-1873. doi: 10.1002/1873-3468.13455. Epub 2019 , Jun 10. PMID:31127856[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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