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Research discovers: How NMT inhibitors can stop tumor growth!
A new study by the University of Konstanz and partners is investigating N-myristoyltransferases, which serve as possible starting points for cancer and virus drugs.
Research discovers: How NMT inhibitors can stop tumor growth!
In a groundbreaking research project, scientists from the University of Konstanz, ETH Zurich and the California Institute of Technology are investigating a key component in protein synthesis: the N-myristoyltransferases (NMTs). These enzymes are crucial for the chemical modification of proteins and play an essential role in biological signaling pathways, whose dysregulation has been linked to cancer. The detailed analysis of NMTs could open up new ways to develop drugs against cancer and viral diseases, reports the University of Konstanz.
Proteins are essential molecular building blocks of life and are constantly produced and modified in cells. An imbalance in these processes can lead to serious illnesses. The first step in protein production is translating genes into amino acid sequences. Many proteins undergo chemical changes during their synthesis, with one of the most common modifications being the loss of methionine followed by the attachment of myristic acid by NMTs.
New approaches to cancer drugs
The study identifies a new starting point for the development of more selective drugs. Previous approaches targeted the active site of NMTs and often resulted in toxic side effects. However, scientists have discovered a new binding site that allows for more targeted inhibition of NMTs. This could help reduce the side effects of cancer treatments.
An important aspect of the study is that the nascent polypeptide-associated complex (NAC) coordinates the activity of the NMTs on the ribosome. NAC positions both the methionine cleavage enzyme and the NMTs at the ribosomal tunnel, giving the enzymes a temporal advantage.
Importance of NMTs in cancer research
The role of NMTs beyond protein synthesis continues to be explored. A study shows that NMT1 is also involved in cancer cell mitophagy, while its role in general autophagy remains unclear. In studies, lentiviral transduction of NMT1-specific shRNA reduced NMT1 expression in non-small cell lung carcinoma (H460) by 50-60% without observing a compensatory increase in NMT2.
Treatment of cancer cells with an NMT inhibitor resulted in increased numbers of LC3B-positive cells and an increase in LC3B-II, suggesting disruptive autophagic processes. These results demonstrate the necessity of NMT1 for maintaining autophagic flux in cancer cells.
Furthermore, NMT1 knockdown cells showed an increase in lysosomal vesicles, while inhibition of NMT1 impaired lysosomal degradation activity. Treatments with the NMT inhibitor DDD85646 showed promising results in reducing tumor growth in preclinical models without causing systemic toxic effects.
The findings of these studies show the potential of NMTs as target structures in cancer research and could ultimately lead to new therapeutic strategies. Detailed breakdown of the mechanism could advance the development of safe and effective drugs that affect both protein synthesis and signaling in cells.
For further information and details about the study, the original publications can be found at Molecular Cell and Nature can be viewed.