Abstract
Choline kinase (ChoK) is a cytosolic enzyme that catalyzes the phosphorylation of choline to form phosphorylcholine (PCho) in the presence of ATP and magnesium. ChoK is required for the synthesis of key membrane phospholipids and is involved in malignant transformation in a large variety of human tumours. Active compounds against ChoK have been identified and proposed as antitumor agents. The ChoK inhibitory and antiproliferative activities of symmetrical bispyridinium and bisquinolinium compounds have been defined using quantitative structure–activity relationships (QSARs) and structural parameters. The design strategy followed in the development of the most active molecules is presented. The selective anticancer activity of these structures is also described. One promising anticancer compound has even entered clinical trials. Recently, ChoKα inhibitors have also been proposed as a novel therapeutic approach against parasites, rheumatoid arthritis, inflammatory processes, and pathogenic bacteria. The evidence for ChoKα as a novel drug target for approaches in precision medicine is discussed.
Highlights
Alteration of cell metabolism is a frequent event in human diseases [1]
Evidence that Choline kinase α (ChoKα) plays a critical role in many human diseases is increasingly being accumulated, and ChoKα has become the focus of a targeted therapeutic strategy [2]
Phosphatidylethanolamine (PE) levels are unaffected in ChoKβ KO mice, a result which suggests that PE homeostasis is fully maintained when the ChoKα protein is intact [9]
Summary
Alteration of cell metabolism is a frequent event in human diseases [1]. In some instances are a necessary requirement, such as in the case of cancer onset and progression. Distinct genes, CHKB, code for the enzymes. Phosphatidylethanolamine (PE) levels are unaffected in ChoKβ KO mice, a result which suggests that PE homeostasis is fully maintained when the ChoKα protein is intact [9]. The crystal structure of human ChoK demonstrates that this enzyme forms a dimer (doi:10.2210/pdb2CKQ/pdb; doi:10.2210/pdb5EQY/pdb) [16,17]. This structural feature, confirmed in enzymatic analysis may have important biochemical and biological consequences since different levels of enzymatic activity for homo- and heterodimers have been reported, with the ChoKα homodimer as the most active and the ChoKβ homodimer as the least active [18,19]. Dimerization ratios may serve as a complex regulatory mechanism for enzyme function, though further work has to be done to clarify this system
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