Structural analysis of secretory phospholipase A2 from Clonorchis sinensis: therapeutic implications for hepatic fibrosis

Abstract

Hepatic fibrosis is a common complication of the infection by the parasite, Clonorchis sinensis. There is a high incidence of this disease in the Asian countries with an increased risk of conversion to cancer. A secretory phospholipase A(2) (PLA(2)) enzyme from the parasite is implicated in the pathology. This is an attractive drug target in the light of extensive structural characterization of this class of enzyme. In this study, the structure of the enzyme was modeled based on its sequence homology to the group III bee venom PLA(2). On analysis, the overall structure essentially is comprised of three helices, two sets of β-wings and an elongated C-terminal extension. The structure is stabilized by four disulfide bonds. The structure is comprised of a calcium binding loop, active site and a substrate binding hydrophobic channel. The active site of the enzyme shows the classical features of PLA(2) with the participation of the three residues: histidine-aspartic acid-tyrosine in hydrogen bond formation. This is an interesting variation from the house keeping group III PLA(2) enzyme of human which has a histidine-aspartic acid and phenylalanine arrangement at the active site. This difference is therefore an important structural parameter that can be exploited to design specific inhibitor molecules against the pathogen PLA(2). Likewise, there are certain unique structural features in the hydrophobic channel and the putative membrane binding surface of the PLA(2) from Clonorchis sinensis that not only help understand the mechanism of action but also provide knowledge for a targeted therapy of liver fibrosis caused by the parasite.

<p>Human Secretary Phospholipase A2 Mutations and Their Clinical Implications</p>

“…7 Interestingly, sPLA 2 from the liver fluke parasite show classical features of histidine-aspartic acid-tyrosine in hydrogen bond formation at the active site. 19 This difference at the active site between the target enzyme and the housekeeping human isoform is, therefore, an important structural parameter that can be exploited to designspecific drug molecules against the parasite Clonorchis sinensis. 20 Unlike several sPLA 2 s in reptiles and scorpions that exist in solution as stable multichain complexes in the form of homodimers, homotrimers and heterodimers, native human sPLA 2 s do not have quaternary conformations.…”

The NF-κB signalling pathway and TM7SF3 contribute to liver fibrosis caused by secreted phospholipase A2 of Clonorchis sinensis

“…CssPLA2 is a 34-kDa protein, and we previously purified a recombinant MBP-CssPLA2 protein with a molecular weight of 76 kDa. CssPLA2 is a group III PLA2 and has been determined to cause liver fibrosis [16,17]. It is being considered as a potential drug target [16].…”

<p>Structural Modeling of Wild and Mutant Forms of Human Plasma Platelet Activating Factor-Acetyl Hydrolase Enzyme</p>

“…20,21 In accordance, the mutations such as V279F and Q281R on pPAF-AH too have been known to have critical and favorable cardiovascular outcomes. [22][23][24][25] Structural characterization of the PLA 2 group of enzymes has helped: (1) to understand the structure-function relationship of PLA 2 enzymes; 26 (2) to sub-classify the groups and sub-groups within the PLA 2 family; 27 (3) to understand the mechanism of PLA 2 induced toxicity; 28 (4) to delineate the structural elements of druggable PLA 2 s for potent drug design; 28,29 (6) to pave the way for personalised medicine in PLA 2 mediated diseases; 30 (7) to understand the effect of mutations on PLA 2 enzyme function and thereby their impact on clinical phenotypes. 31 In this study, we have carried out modeling studies of wild and mutant forms of pPAF-AH to understand the implications of mutations V279F, Q281R, V279F +Q281R on their respective structures.…”