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A new study from the Newstead group at the Department of Biochemistry has solved the structure of the human folate transporter, paving the way for improved anticancer drugs.

Cell membrane

Many anticancer drugs result in severe side effects due to damage inflicted on healthy cells. An important goal in drug development is to target drugs in a way that will only kill cancerous cells.  Folate is an essential vitamin (B9) obtained via our diet and is essential for cell growth.  Anti-folate drugs kill cancerous cells but also damage healthy cells resulting in challenging side effects for patients. 

A new study from the Newstead group at the Department of Biochemistry, published in Nature, has uncovered the structure of the folate transporter, a protein that is involved in folate absorption into cells, laying the foundation for developing targeted anticancer drugs.

How anticancer drugs use PCFT to enter cells, and the structure of PCFT.How anticancer drugs use PCFT to enter cells, and the structure of PCFT.

Folate is transported into our cells through the proton coupled folate transporter (PCFT). PCFT transports dietary folates across the intestinal tract and into the brain. Importantly, this transporter is more active in cancerous cells due to their altered metabolism. This provides researchers with an opportunity to develop drugs that selectively target diseased tissue via PCFT. However, current antifolate drugs are also recognised by other folate transport systems required by healthy cells to survive. The key is to target only cancerous cells by selective transport via PCFT, through better understanding of the PCFT structure, so that selective drugs can be developed. 

In the latest research from the Newstead group and undertaken by Dr Jo Parker in collaboration with Dr Justin Deme & Prof Susan Lea in the National Cancer Institute at the National Institute of Health in the USA and Dr Zhiyi Wu & Prof. Philip Biggin in the Department of Biochemistry now reveals the structure of PCFT for the first time.

Crucially, PCFT was solved in complex with Pemetrexed, a chemotherapy agent used to treat non-small cell lung cancer and pleural mesothelioma. These new results now reveal the blueprint to modify antifolate cancer treatment drugs to target PCFT more effectively.

This is a very exciting finding, which our group now hopes to apply to drug improvement research in collaboration with other disciplines. This new fundamental research understanding could, in the long run, result in major advances in drug development and ultimately help more cancer patients.
- Dr Jo Parker, Department of Biochemistry

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