methotrexate transport

Definition

Target type: biologicalprocess

The directed movement of methotrexate, 4-amino-10-methylformic acid, into, out of or within a cell, or between cells, by means of some agent such as a transporter or pore. Methotrexate is a folic acid analogue and a potent competitive inhibitor of dihydrofolate reductase. [GOC:ai]

Methotrexate transport is a complex process involving multiple steps and mechanisms. Methotrexate, an antifolate drug, enters cells primarily through the reduced folate carrier (RFC1), a transmembrane protein that facilitates the uptake of folate and its analogs. RFC1 is highly expressed in rapidly proliferating cells, including cancer cells, making it a key target for methotrexate therapy.

The process begins with methotrexate binding to RFC1 on the cell surface. This binding event triggers a conformational change in the protein, opening a channel that allows methotrexate to enter the cell. Once inside, methotrexate can be transported further into the cell by other transporters, such as the multidrug resistance-associated protein 1 (MRP1).

Methotrexate's primary target inside the cell is dihydrofolate reductase (DHFR), an enzyme crucial for the synthesis of tetrahydrofolate (THF), a coenzyme essential for DNA and RNA synthesis. By inhibiting DHFR, methotrexate effectively blocks the production of THF, thereby disrupting DNA replication and cell division.

However, methotrexate can also be transported out of cells by efflux pumps, such as MRP1 and the breast cancer resistance protein (BCRP), which can limit its efficacy. The activity of these efflux pumps can vary depending on factors like cell type and drug resistance.

In addition to active transport mechanisms, methotrexate can also passively diffuse across cell membranes, especially at high concentrations. This passive diffusion may contribute to its intracellular accumulation, but it is generally less significant than active transport.

Overall, methotrexate transport is a multifaceted process involving various proteins and mechanisms. Understanding the intricacies of this process is crucial for optimizing methotrexate's therapeutic effects and minimizing its potential side effects.'
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Proteins (2)

Compounds (4)