Thymidylate synthase (TS) is an enzyme found in nearly all living organisms, including humans. This enzyme functions as a fundamental component of cellular processes, essential for the existence and propagation of cells throughout the body.
The Role of Thymidylate Synthase in Cell Division
Thymidylate synthase performs a specific job in the cell: it helps produce thymidylate (dTMP). This molecule is one of the four building blocks, or nucleotides, required to construct DNA. The enzyme facilitates the conversion of deoxyuridine monophosphate (dUMP) into dTMP by adding a methyl group, utilizing a cofactor called 5,10-methylenetetrahydrofolate.
Without sufficient thymidylate, a cell cannot replicate its genetic material. This process of DNA replication is a fundamental step that must occur before a cell can divide. Therefore, thymidylate synthase’s activity is directly linked to cell division, which is necessary for growth, tissue repair, and the replacement of old cells throughout the body. Impairment of this enzyme can lead to a state known as “thymineless death” in cells.
Targeting Thymidylate Synthase in Cancer Treatment
The biological function of thymidylate synthase makes it a specific target in oncology. Cancer is characterized by uncontrolled and rapid cell division, a process that demands a continuous supply of new DNA building blocks. Because cancer cells are dividing at an accelerated rate compared to healthy cells, they have a higher demand for thymidylate, and thus, a greater reliance on the enzyme thymidylate synthase.
This increased demand provides an opening for treatment. The strategy in targeting this enzyme involves disrupting its activity to selectively starve the most rapidly dividing cells—the cancer cells—of a molecule they need to multiply. By interfering with thymidylate synthesis, therapies aim to halt DNA replication in these fast-growing cells, thereby limiting tumor growth and spread. This approach exploits a difference between healthy and cancerous cell metabolism.
How Thymidylate Synthase Inhibitors Work
Drugs designed to block thymidylate synthase are known as thymidylate synthase inhibitors. An example is 5-fluorouracil (5-FU), which is a prodrug, meaning it must be converted into an active form within the body. Once activated, 5-FU transforms into fluorodeoxyuridine monophosphate (FdUMP).
FdUMP then acts as an impostor molecule. It mimics the natural substrate that thymidylate synthase works on, but it is structurally altered. This altered molecule binds irreversibly to the enzyme, forming a stable “ternary complex” with thymidylate synthase and its cofactor, 5,10-methylenetetrahydrofolate. This binding blocks the enzyme’s function, preventing it from producing thymidylate. The resulting depletion of thymidylate leads to DNA damage and ultimately triggers cell death.
Clinical Significance and Challenges
In clinical practice, the amount of thymidylate synthase present within a tumor serves as a predictive biomarker. Measuring the expression level of this enzyme offers insights into how likely a tumor is to respond to thymidylate synthase inhibitors, with higher levels often correlating with a reduced response to drugs like 5-FU. This information helps guide treatment decisions, to guide more personalized and effective therapeutic plans.
A challenge in using these inhibitors is the development of drug resistance. Some cancer cells can adapt by overproducing thymidylate synthase, overwhelming the inhibitory effects of the drug and continuing to divide. Furthermore, these drugs can affect all rapidly dividing cells in the body, not just cancerous ones. This lack of complete selectivity leads to common side effects, such as damage to cells in the digestive tract, resulting in nausea or diarrhea, and effects on hair follicles, which can cause hair loss.