Antimetabolites for cancer treatment

Antimetabolites are a diverse group of medications that are used for the treatment of various conditions including cancer, infections and autoimmune disorders.

In this video, we are focusing on the antimetabolites used in cancer treatment.

Alright, during the S phase of the cell cycle, the cell performs DNA replication.

DNA is composed of a sequence of deoxyribonucleotides and each deoxyribonucleotide is made out of a phosphate group, a five carbon sugar like deoxyribose, and a nucleobase, which can be either a pyrimidine like cytosine, or thymidine, or a purine like adenine or guanine.

Now, nucleotide synthesis starts with ribose-5-phosphate, which is specific for RNA, and an enzyme called ribose phosphate pyrophosphokinase uses an ATP to remove two phosphate groups from it, attaching them to ribose-5-phosphate, creating a phosphoribosyl pyrophosphate, or PRPP.

Because it catalyzes the synthesis of PRPP, the enzyme ribose phosphate pyrophosphokinase is also known as PRPP synthetase.

Next step is to make pyrimidines. The amino acid glutamine, bicarbonate, and water are used to form a molecule called carbamoyl phosphate which is then joined to aspartate and together, they form a ringed molecule called carbamoyl aspartic acid, which gets dehydrated to create a molecule called orotate.

Next, an enzyme moves the phosphoribose unit from PRPP to orotate and that forms orotidine monophosphate, or OMP.

Next, the enzyme UMP synthase converts orotidine monophosphate into uridine monophosphate, or UMP.

That UMP gets phosphorylated twice by nucleoside diphosphate kinase, to become uridine triphosphate, or UTP.

Finally, the enzyme CTP synthase, converts uridine triphosphate into cytidine triphosphate, or CTP.

Now, purine synthesis starts with the amino acids glutamine, aspartate, and glycine, together with bicarbonate and formate, which is the anion derived from formic acid.

These undergo a ten-step pathway and the result is inosine monophosphate, or IMP, which is sort of a generic purine.

IMP can be converted to AMP and GMP.

Okay, RNA nucleotides are usually in the monophosphate form, but to get to DNA nucleotides, we need them in the diphosphate form, so CDP, UDP, ADP, and GDP.

Next, an enzyme called ribonucleotide diphosphate reductase will reduce the ribose within them into deoxyribose, creating dCDP, dUDP dADP, and dGDP.

After this, they just need to lose a phosphate group, and we’ll have dCMP, dUMP, dAMP, and dGMP.

But, something is missing - dTMP. And here comes the folic acid, or vitamin B9, which is converted to tetrahydrofolic acid, or THF.

THF acts as a mediator and accepts a “methylene” group from the amino acid serine and transfers it to dUMP or deoxyuridine monophosphate.