Researchers in the UK and Sweden have found a way to block an enzyme that facilitates the division of cancerous cells.

Tumors comprising cancerous cells grow and spread rapidly because cancer cells are programmed to proliferate through uncontrolled cell division. Numerous enzymes are involved in the process. If these enzymes could be inhibited, it could be possible to prevent or at least reduce the cancerous cell division. Doing so is difficult, however, because designing a drug that targets specific enzymes within cancer cells is challenging.

Researchers from Uppsala University, Karolinska Institutet and the University of Oxford have done just that, however. The group focused on a membrane protein identified as a cancer target. The enzyme of interest is dihydroorotate dehydrogenase (DHODH). To design a highly targeted drug candidate, the researchers studied the binding behavior of DHODH with various lipids and inhibitors using nondenaturing mass spectrometry combined with extensive molecular dynamics simulations. 

These efforts revealed that one compound appeared to bind better to DHODH than others when lipid-like molecules were present. According to Michael Landreh of Karolinska Institutet, because DHODH binds certain lipids in the cell’s mitochondrial respiratory chain complex, it may use these lipids to locate the correct binding site on the cell membrane.

When DHODH anchors itself to the membrane by binding to these certain lipids, a portion of the enzyme folds into an adapter that allows the enzyme to lift its natural substrate out of the membrane, according to Erik Marklund of Uppsala University. The new compound they identified appears to use this same mechanism.