Phosphatidylcholine-Specific Phospholipase C as a Promising Drug Target

Abstract

Phosphatidylcholine-specific phospholipase C (PC-PLC) is an enzyme that catalyzes the formation of the important secondary messengers phosphocholine and diacylglycerol (DAG) from phosphatidylcholine. Although PC-PLC has been linked to the progression of many pathological conditions, including cancer, atherosclerosis, inflammation and neuronal cell death, studies of PC-PLC on the protein level have been somewhat neglected with relatively scarce data. To date, the human gene expressing PC-PLC has not yet been found, and the only protein structure of PC-PLC that has been solved was from Bacillus cereus (PC-PLC_Bc). Nonetheless, there is evidence for PC-PLC activity as a human functional equivalent of its prokaryotic counterpart. Additionally, inhibitors of PC-PLC_Bc have been developed as potential therapeutic agents. The most notable classes include 2-aminohydroxamic acids, xanthates, N,N'-hydroxyureas, phospholipid analogues, 1,4-oxazepines, pyrido[3,4-b]indoles, morpholinobenzoic acids and univalent ions. However, many medicinal chemistry studies lack evidence for their cellular and in vivo effects, which hampers the progression of the inhibitors towards the clinic. This review outlines the pathological implications of PC-PLC and highlights current progress and future challenges in the development of PC-PLC inhibitors from the literature.

Keywords: atherosclerosis; cancer; drug discovery; inflammation; inhibitors.

Figure 1

PC-PLC hydrolysis of phosphatidylcholine to diacylglycerol (DAG) and phosphocholine.

Figure 2

The structure of the wild-type PC-PLC_Bc enzyme (PDB ID: 1AH7) and its catalytic site. The protein α-helixes are shown as red tubes. The trinuclear metal center consists of catalytic Zn²⁺ ions shown as grey spheres, whereas the water molecules are shown as red spheres. Amino acid residues coordinating to the Zn²⁺ ions are depicted and labelled. Figure edited from Eurtivong et al. [8].

Figure 3

The chemical structure and potency of pyrido[3,4-b]indole derivative 22_10 as well as the predicted binding mode of (1R,3S)-22_10 derivative in the PC-PLC binding site. Figure edited from Eurtivong et al. [8].