In order to understand antimetabolites and how they work, it is necessary to briefly discuss the processes that are being targeted by these agents. The term metabolism refers to the many chemical reactions that take place in our bodies. We are constantly breaking down food into usable components and using those components to build our proteins, DNA and other cellular structures. Metabolite is a general term for the organic compounds that are synthesized, recycled, or broken down in cells. Materials that provide us with key metabolites enter our body as food. These compounds can be broken down into simpler structures that can be re-used in our cells. Examples include vitamins and amino acids. Metabolites that are the end products of a process or pathway may be excreted by the body. An example is urea, the end product of protein metabolism, excreted by the body as a component of urine.
Antimetabolites are structurally similar to metabolites, but they cannot be used by the body in a productive manner. In the cell, antimetabolites are mistaken for the metabolites they resemble, and are processed in the cell in a manner analogous to the normal compounds. The presence of the 'decoy' antimetabolites prevents the cells from carrying out vital functions and the cells are unable to grow and survive. Many of the antimetabolites used in the treatment of cancer interfere with the production of the nucleic acids, RNA and DNA.(1) If new DNA cannot be made, cells are unable to divide.
There are several different cellular targets for antimetabolites. Some common classes of antimetabolites are:
A Closer Look at Making Thymine from Uracil
Interaction with Thymidylate Synthase: A final way in which 5-FU may inhibit normal DNA synthesis is its ability to prevent the synthesis of thymine nucleotides from uracil nucleotides. Thymine differs from uracil by the presence of a methyl group (a one-carbon unit) on the 5th carbon in the pyrimidine ring. This methyl group is added on by an enzyme called thymidylate synthase. If a 5-FU molecule is in the nucleotide instead of a uracil, the enzyme cannot add a methyl group to the 5th carbon due to the fluoride atom at that location in 5-FU. This alteration from the normal pyrimidine gives the drug its name. The addition of methyl is required for the conversion of the uracil nucleotide into the thymine nucleotide, and without this step, the thymine nucleotides can not be made and are not available for DNA synthesis.
Shown below is the normal process (top) and the inhibtion of the process by 5-FU (bottom).