Sandbox Reserved 693

From Proteopedia

6-Mercaptopurine activity and targeting

6-Mercaptopurine (6-MP) is an anti-cancer drug used for decades to treat acute lymphoblastic leukemia, and in recent years for other conditions such as inflammatory bowel disease. The drug is a purine derivative that resembles guanine, except that it has a thiol on the C6 of the base ring structure instead of a carbonyl, and is missing the amine on C2 (although this is later added before it is fully converted to 6-TGMP). Within the cell, 6-MP is converted to 6-thioguanosine monophosphate (6-TGMP) via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) because it fits into the same active site as guanine, which is converted by the same enzyme to . Some of the 6-MP and 6-TGMP are deactivated by xanthine oxidase or thiopurine methyltransferase, but some of the 6-TGMP is able to inhibit cell division, attacking the cancer. It's interaction with HGPRT is analogous to the .
It can be seen in the above structure that human HGPRT has two identical subunits, shown in green and blue, each of which catalyzes one reaction. highlights the main structural motifs of the enzyme, with helices in green and sheets in blue.

After 6-MP is converted to 6-TGMP, it can be either inserted into a growing DNA strand which will cause problems with replication of the "infected" strand, or it can inhibit purine biosynthesis. This primarily happens at the enzyme glutamine phosophribosyl-pyrophosphate (PRPP) amidotransferase, which is used to start building the purine structure on a phosphorylated sugar. The can be seen here, with four subunits each shown in different colors. , it is easier to see where the nucleotides (AMP - black) are bound to the enzyme, and how they are held in place by a cation (in green), which stabilizes the negative charges on the phosphates. This cation is likely a divalent metal ion, such as Mg²⁺. shows the negative residues in purple, the positive in navy blue, and the neutral in teal. It can easily be seen that the that stabilizes the AMP phosphate group. It can also be seen that the normal ligand (green)is stabilized by . The reaction that glutamine PRPP amidotransferase typically catalyzes involves dephosphorylation of PRPP, yielding a pyrophosphate group (PPi), and adds an amine to the same carbon. This would suggest that the NNPs (here AMP, or in the case of the drug 6-TGNPs) are competitive inhibitors of the active site, because the ion that supports the negative phosphate charge on the AMP above would also be used to shield that charge on PRPP and facilitate leaving of PPi.