Phospholipids play a role as a source of lipid molecules and a structural role in membranes by creating the milieu in which membrane proteins function. Eukaryotic cell membranes contain many different phospholipid species with the most abundant one being phosphatidylcholine (PC), which is synthesized through the CDP-choline pathway, also known as the Kennedy pathway. Initially, choline is imported into the cell and is rapidly converted to phosphocholine by choline kinase[1].
In humans, two choline kinase genes have been found: choline kinase alpha (CHKA) and choline kinase beta (CHKB). CHKA is the most abundant in testis and liver whereas CHKB is ubiquitous. CHK is a homodimer (A/A or B/B) as well as a heterodimer (A/B)[1]. Alterations in phospholipids metabolism are linked to programmed cell death and oncogenic transformation. Increased CHK activity and elevated phosphocholine levels have been found in human cancer cells, suggesting that the upregulation of CHK participates in the generation of human tumors. Therefore, CHK isoforms may be potential targets for anticancer drug discovery[2, 3].
We have determined the crystal structures of CHK isoforms in complex with hemicholinium-3 (HC-3), which is well-known as a competitive inhibitor of CHK with a structural homology to a substrate choline[4]. These crystallographic data should provide useful clues for the design of more selective inhibitors against the cancer-specific CHK.
