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All living organisms are constantly synthesizing new deoxyribonucleic acid (DNA) and repairing damaged DNA. Thymidylate synthase (TS) is a protein that is found in all organisms that make DNA. It is involved in generating thymidine, one of the nucleic acids used in the biosynthesis and repair of DNA.
DNA is composed of a double helix that has two combinations of nucleic acids that can bind each other to form this structure. Cytosine binds guanidine, while adenosine binds thymidine. Thymidylate synthase is a key enzyme in the pathway for producing thymidine. It regulates the supply of the four precursors for these nucleic acids. Without this enzyme, organisms develop abnormally or die.
Compounds that are intermediaries in metabolism such as those involved in thymidine synthesis frequently have high-energy phosphate groups attached to them. Such chemicals are considered to be phosphorylated. The most energy one can obtain from phosphate molecules is obtained from a three molecule grouping called a triphosphate group. When the phosphate bonds are cleaved, the process generates energy.
Since thymidylate synthase is an enzyme, it catalyzes reactions to happen more quickly than they would in its absence. The nucleic acid substrate for TS is uridine monophosphate (dUMP). It catalyzes the addition of a methyl group, CH3, to the dUMP to produce thymidine monophosphate (dTMP). This molecule will have additional phosphate groups added by another enzyme to produce dTMP3. The highly phosphorylated compound will be used as a source for thymidine to incorporate into damaged and newly forming DNA chains.
The enzyme acts in concert with a reduced folic acid derivative called 5,10-methylenetetrahydrofolate, or 5, 10-M for short. An additional compound that is produced along with dTMP is dihdyrofolate. This is a derivative of folic acid, also known as Vitamin B9.
Considering thymidylate synthase has such an important role in DNA synthesis, it has been the target of pharmaceutical studies. Without this enzyme, DNA will not be synthesized. Frequently, cancer tissue grows faster than the surrounding normal tissue. Thus, such cancerous tissue is synthesizing DNA more quickly. Inhibitors of nucleic acid synthesis are logical candidates to test as anti-cancer agents.
Thymidylate synthase inhibitors have turned out to have potential for controlling certain types of cancers in humans. Colorectal cancers in particular seem susceptible to such compounds. Successful inhibitors include fluorouracil and chemicals similar to folate. The efficiency of TS inhibitors in cancer treatment appears to be higher for tumors that have low rates of TS expression compared to those that produce a greater amount of the enzyme.
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