Antimetabolites

In order to understand antimetabolitesDrugs that interfere with the formation of key biomolecules in cells. They often work by blocking the activity of enzymes. These drugs often prevent the normal replication of DNA and therefore cell division. and how they work, it is necessary to briefly discuss the processes that are being targeted by these agents. The term metabolismThe sum of all reactions in a cell or animal. Processes that lead to the creation of biomolecules such as proteins and nucleic acids are termed anabolic pathways. Processes in which biomolecules are broken down, such as the digestion of foods, are termed catabolic. Metabolism is a term that encompasses both sets of processes. 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, DNAAbbreviation for deoxyribonucleic acid. Composed of very long strings of nucleotides, which are abbreviated as A, C, G and T. DNA is the storage form of our genetic material. All of the instructions for the production of proteins are encoded in our 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 proteinOne of the four basic types of biomolecule. Proteins are polymers made up of strings of amino acids. Proteins serve many functions in organisms including transport of molecules, structure, cell adhesion and as signaling molecules such as hormones. Many transcription factors, including p53 and Rb are proteins. 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, RNAAlso: ribonucleic acid. RNA is a polymer comprised of the nucleotides A, C, G and U. RNA is the working form of our genetic information. RNA is produced via the process of transcription. Some RNA is used to help build ribosomes (rRNA) and some (mRNA) are used to guide the formation of proteins. Other forms of RNA are used to perform specialized functions in the nucleus. 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 enzymeA protein that speeds up the process of chemical reactions in the body without becoming altered in the process. Almost every biological process is driven by the activity of enzymes. Without enzyme catalysts, the complex reactions that build and break down cell parts would not happen at a rate compatible with life. Enzyme names usually describe the reaction that is being catalyzed and all of them end in -ase. called thymidylate synthase. If a 5-FU molecule is in the nucleotideA monomer building block of the nucleic acids DNA and RNA. There are approximately 3 billion nucleotides in the entire human genome. Each chromosome contains about 50-250 million nucleotides. Four nucleotides are used to form DNA abbreviated as A, C, G and T. RNA contains four nucleotides as well, but uses U instead of T, so RNA contains A, C, G and U. Some chemotherapy agents, like 5-Fluorouracil ( 5-FU) and ARA-C are chemically very similar to one of the nucleotides and work by interfering with DNA function. 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).

 

  • 1. Walsh, Declan. Palliative Medicine. 1st ed. Philadelphia: Saunders, 2009.