Dihydrofolate Reductase Protein Structure and Function

I investigated the dihydrofolate reductase protein. This protein was very interesting to me because it is used for drug therapy and was the first to help in cancer chemotherapy. Knowing this I looked at the protein’s structure and function to support its role in cancer chemotherapy.

Dihydrofolate reductase is a small enzyme that plays a significant role in DNA construction. Dihydrofolate reductase controls the state of folate, an organic molecule that transports carbon atoms. By reducing dihydrofolic acid to tetrahydrofolic acid. Dihydrofolic acid is a folic acid derivative which transforms to tetrahydrofolic acid by the dihydrofolate reductase protein.  Tetrahydrofolate is needed to make purines and pyrimidines both being building blocks of DNA and RNA

The dihydrofolate reductase has a unique structure. It contains eight beta sheets and four alpha helixes. Dihydrofolate reductase has a long channel that binds to folate at one end and NADPH at the other end.  The protein encloses side chains around folate and NADPH resulting in them being in a very tight position close to each other. This way it can shuttle hydrogen atoms from NADPH to folate, reducing it. The backbone folding of this protein is mainly due to the beta pleated sheets which explains why the molecule is so rigid. This protein is highly stable due to the formation of the dimer. A dimer is a quaternary structure made by two non-covalently bounded macromolecules such as proteins or nucleic acids. In the beta sheets dimers interact to produce tight, high packing density.

Drugs, like aminopterin, bind to dihydrofolate reductase much tighter than folate and produce better clinical outcomes. These drugs kill active growing cells rather than inactive non growing cells and will have a major impact on cancer cells, considering they reproduce at a very high rate. Dihydrofolate reductase plays a major role in battling cancer because drugs are able to bind to it a thousand times tighter, preventing growth of certain cells.

Shown above is the overall Dihydrofolate Reductase protein structure.

Depicted above are the side chains that wrap all around the protein. Some of the side chains are circled in blue. The red circle shows one particular side chain of the Asn amino acid. Remember side chains enclose folate and NADPH to create a tightly bound protein.

Shown above are the beta pleated sheets in yellow and alpha helixes in lavender. There are more beta sheets than helixes therefore producing a more rigid protein structure.

Shown above are binding sites. These binds help in creating the shape of the protein.

Shown above is the primary structure of the Dihydrofolate reductase before it advances to its later protein structures. It contains Nitrogen, Hydrogen, and Oxygen.