In the cell there are countless numbers of reactions taking place every second. The word metabolism refers to all these essential chemical reactions. A metabolite is a term for the organic (carbon and hydrogen containing) compounds which are constantly being made, regenereated, broken down in our cells. For example, amino acids, the monomer of proteins, is a metabolite.
Antimetabolites are compounds which have an almost identical structure to the metabolites, ie they mimic the structure, but do not perform the same function – due to slight structural differences, the body cannot use them. Thus, by flooding the body with these antimetabolites, vital metabolic reactions cease to function as they become use the antimetabolites instead of the correct compounds, in effect jamming the cellular machinery.
In cancer, antimetabolites jam the replication machinery. The specific metabolic pathways are those involved with the production of nucleic acids RNA and DNA – the blue-prints of proteins and life
Making Thymine from Uracil
One antimetabolite used in chemotherapy inhibits an essential enzyme. Normally, in the process of protein synthesis, the pyrimidine uracil must be converted to thymine – two building blocks which form part of RNA and DNA respectively, called ‘nucleotides’,
The enzyme Thymidylate Synthase usually adds a CH3 group (methyl) to the 5th Carbon on Uracil.
One chemotherapeutic agent is called ‘5-FU’. This mimics the uracil, but has a fluorine atom on the 5th carbon, where the CH3 group would go. Thus, no thymine can be made, so DNA can’t be produced. The name of the drug implies its function – attaches an F to the 5th carbon on Uracil.
Antifolates are ‘folate antagonists’. These are inhibitors of an enzyme dihydrofolate reductase (DHFR). This enzyme is involved with synthesis of nucleotides. If the enzyme is blocked, no nucleotides can be produced, so cell division halts. One example of an antifolate is methotrexate.
Folic acid is a key growth factor which plays a chief role in nucleotide synthesis – it is a co-enzyme (a non-protein compound necessary for the functioning of an enzyme) which brings CH3 groups to be attached to various compounds.
Folic acid is inactive until it is chemically reduced – ie hydrogens are added to it. DHFR is an enzyme which activates the folic acid by reducing it, making dihydrofolate and then tetrahydrofolate. Methotrexate is a competitive inhibitor of the enzyme DHFR, ie it binds reversibly but tightly to its active site. Thus, less DHFR can work, so the cell cannot produce new nucleotides, which are needed to make DNA. Consequently, the cell cannot replicate, since it would need to copy and double its DNA.