PPC Synthetase Inhibitors
Chemical inhibitors of phosphoribosyl pyrophosphate synthetase (PPCS) can exert their inhibitory effects through various biochemical mechanisms, primarily by influencing the availability of substrates necessary for the enzyme's function. Methotrexate and Aminopterin, as folate analogs, interfere with dihydrofolate reductase (DHFR), an enzyme pivotal for maintaining the pool of tetrahydrofolate. This pool is crucial for the synthesis of purine nucleotides, which serve as substrates for PPCS. Consequently, the activity of PPCS is reduced due to a substrate deficit. Similarly, Pemetrexed acts by inhibiting several folate-dependent enzymes, including DHFR, which leads to a decrease in purine nucleotides and indirectly affects PPCS activity.
Continuing with the purine analogs, 6-Mercaptopurine and its prodrug Azathioprine, after metabolic activation, get incorporated into nucleic acids and disrupt purine synthesis via feedback inhibition. This disruption leads to a reduced pool of purine nucleotides, which are substrates for PPCS, thus diminishing its activity. Mycophenolate mofetil and Ribavirin both target inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the synthesis of guanine nucleotides. By inhibiting IMPDH, these drugs deplete guanine nucleotides, limiting the substrate availability for PPCS, and thereby diminishing its function. Hydroxyurea takes a different approach by targeting ribonucleotide reductase, resulting in a reduced pool of deoxyribonucleotides, which are also substrates for PPCS, leading to an indirect inhibition of the enzyme. Lastly, nucleoside analogs such as Clofarabine and Fludarabine are phosphorylated to active forms that inhibit DNA polymerase and ribonucleotide reductase, causing a decrease in deoxyribonucleotide pools. Similarly, Cladribine is phosphorylated and incorporated into DNA, which may lead to the inhibition of PPCS by reducing nucleotide substrate availability. All these agents, through their distinct biochemical pathways, converge on a common outcome: the functional inhibition of PPCS by diminishing the pool of nucleotide substrates required for its enzymatic activity.
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| Product Name | CAS # | Catalog # | QUANTITY | Price | Citations | RATING |
|---|---|---|---|---|---|---|
Methotrexate | 59-05-2 | sc-3507 sc-3507A | 100 mg 500 mg | $92.00 $209.00 | 33 | |
Methotrexate competes for the binding of folate and inhibits dihydrofolate reductase (DHFR), leading to a decrease in tetrahydrofolate and subsequently purine nucleotide synthesis. Since PPCS requires purine nucleotides for its activity, inhibition of their synthesis by Methotrexate results in functional inhibition of PPCS. | ||||||
Aminopterin | 54-62-6 | sc-202461 | 50 mg | $102.00 | 1 | |
Aminopterin, similar to Methotrexate, is a folate analog that inhibits DHFR, resulting in a reduction of purine nucleotide synthesis. As purine nucleotides are substrates required for PPCS activity, the inhibition of their synthesis by Aminopterin leads to a decrease in PPCS function. | ||||||
Pemetrexed Disodium | 150399-23-8 | sc-219564 | 10 mg | $133.00 | 5 | |
Pemetrexed inhibits several folate-dependent enzymes, including DHFR. By reducing the availability of tetrahydrofolate, Pemetrexed indirectly inhibits the synthesis of purine nucleotides, which are essential substrates for PPCS. This results in the functional inhibition of PPCS. | ||||||
Fluorouracil | 51-21-8 | sc-29060 sc-29060A | 1 g 5 g | $36.00 $149.00 | 11 | |
5-Fluorouracil is metabolized to 5-fluoro-2’-deoxyuridine-5’-monophosphate (FdUMP), which inhibits thymidylate synthase, thereby depleting thymidine triphosphate (dTTP). A lack of dTTP can cause an imbalance in deoxyribonucleotide pools, which indirectly inhibits PPCS by disrupting the balance of nucleotide substrates necessary for its function. | ||||||
6-Mercaptopurine | 50-44-2 | sc-361087 sc-361087A | 50 mg 100 mg | $71.00 $102.00 | ||
6-Mercaptopurine is a purine analog that gets incorporated into DNA and RNA, which can inhibit purine synthesis through feedback inhibition. By reducing the availability of purine nucleotides, which are necessary for PPCS function, 6-Mercaptopurine indirectly leads to the functional inhibition of PPCS. | ||||||
Azathioprine | 446-86-6 | sc-210853D sc-210853 sc-210853A sc-210853B sc-210853C | 500 mg 1 g 2 g 5 g 10 g | $199.00 $173.00 $342.00 $495.00 $690.00 | 1 | |
Azathioprine is a prodrug for 6-mercaptopurine, and therefore, through its metabolite, it inhibits purine synthesis and decreases the availability of purine nucleotides required for PPCS activity. This results in functional inhibition of PPCS. | ||||||
Mycophenolate mofetil | 128794-94-5 | sc-200971 sc-200971A | 20 mg 100 mg | $36.00 $107.00 | 1 | |
Mycophenolate mofetil inhibits inosine monophosphate dehydrogenase (IMPDH), leading to a decrease in guanine nucleotides. As guanine nucleotides are necessary for PPCS activity, their depletion by Mycophenolate mofetil results in the functional inhibition of PPCS. | ||||||
Ribavirin | 36791-04-5 | sc-203238 sc-203238A sc-203238B | 10 mg 100 mg 5 g | $62.00 $108.00 $210.00 | 1 | |
Ribavirin is a guanosine analog that inhibits IMPDH, resulting in decreased guanosine nucleotide synthesis. This reduction in guanosine nucleotides can impede PPCS by limiting its substrate availability, leading to functional inhibition of PPCS. | ||||||
Hydroxyurea | 127-07-1 | sc-29061 sc-29061A | 5 g 25 g | $76.00 $255.00 | 18 | |
Hydroxyurea inhibits ribonucleotide reductase, leading to a decrease in the deoxyribonucleotide pools. As PPCS requires certain deoxyribonucleotides for its activity, the reduction in their synthesis by Hydroxyurea indirectly inhibits PPCS function. | ||||||
Clofarabine | 123318-82-1 | sc-278864 sc-278864A | 10 mg 50 mg | $185.00 $781.00 | ||
Clofarabine is a nucleoside analog which inhibits ribonucleotide reductase and DNA polymerase. By reducing deoxyribonucleotide pools and interfering with DNA synthesis, Clofarabine can indirectly inhibit PPCS by disrupting the availability of nucleotide substrates necessary for its enzymatic function. | ||||||