description
Since the 1940s, antifolates have played a pivotal role in drug treatment of malignant, microbial, parasitic and chronic inflammatory diseases. The molecular basis of the anti-proliferative activity of antifolates relies on inhibition of key enzymes in folate metabolism, which results in disruption of purine and thymidylate biosynthesis, inhibition of DNA replication and cell death. The anti-inflammatory properties of antifolate have been most strongly related to its ability to block the release of pro-inflammatory cytokines such as tumour necrosis factor (TNF)-alpha or interleukin (IL)-1beta. Cells may develop resistance to an antifolate drug by virtue of impaired drug transport into cells, augmented drug export, impaired activation of antifolates through polyglutamylation, augmented hydrolysis of antifolate polyglutamates, increased expression and mutation of target enzymes, and the augmentation of cellular tetrahydrofolate-cofactor pools in cells

external resources
NCBI:1440526
KEGG:hsa01523
PUBMED:17333344
PUBMED:23987246
PUBMED:11509639
PUBMED:24732946
PUBMED:8793930
PUBMED:15117425
PUBMED:22921318
PUBMED:16491071
PUBMED:26920997
PUBMED:22954694
PUBMED:17092765
PUBMED:17203006
PUBMED:23897011
PUBMED:21317831
PUBMED:18297517
PUBMED:14576850
PUBMED:16380836

genes
ALOX12 , ATIC , CHUK , ABCC2 , DHFR , FOLR1 , FOLR2 , FOLR3 , FPGS , GART , IKBKB , IL1B , IL6 , ABCC1 , MTHFR , NFKB1 , RELA , SHMT1 , SHMT2 , SLC19A1 , TNF , TYMS , IKBKG , ABCC3 , GGH , ABCG2 , ABCC5 , ABCC4 , SLC46A1 , DHFR2 , IZUMO1R ,