GATC Inhibitors

Chemical inhibitors of GATC can impede its function through various mechanisms that involve interference with DNA synthesis and methylation processes. Methotrexate directly targets the thymidine synthesis pathway by competitively inhibiting dihydrofolate reductase (DHFR), which is vital for DNA synthesis, thereby limiting the availability of thymidine triphosphate (TTP), a necessary substrate for DNA replication and subsequently for GATC's methylation activity. Similarly, 5-Azacytidine and Decitabine act as nucleoside analogs that get incorporated into DNA and RNA. These compounds inhibit DNA methyltransferases, thus reducing the methylation of DNA which is crucial for GATC function. By altering the normal methylation patterns, GATC's ability to interact with DNA and exert its methylation effects is inhibited.

Zebularine and RG108, both DNA methyltransferase inhibitors, prevent the methylation of DNA, creating an abnormal methylation landscape wherein GATC cannot perform its normal role in DNA methylation. SGI-1027 also inhibits DNA methyltransferases, which diminishes the methylation on which GATC depends for its activity. Procaine and Hydralazine, though not specific to any one DNA methyltransferase, reduce overall DNA methylation, which would lead to a decrease in the functional methylation activity of GATC. Epigallocatechin gallate further impedes DNA methyltransferases, resulting in the inhibition of GATC by decreasing the methylated DNA substrates necessary for its action. Disulfiram's capability to chelate copper, a cofactor essential for many enzymes, can interfere with the catalytic activity of GATC that requires metal ions. Mithramycin A binds preferentially to GC-rich sequences in DNA, which prevents proteins, including GATC, from accessing their DNA targets, thus inhibiting their activity. Finally, Cytarabine, a nucleoside analog of cytidine, incorporates into DNA and disrupts DNA polymerases. This disruption of DNA replication can inhibit GATC by preventing the normal progression of replication forks where GATC would typically be active, thereby hindering its ability to participate in DNA methylation.