The Classified Progression in Binding Modes of Autotaxin (Atx) Inhibitors
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2018, Vol 7, Issue 3
Abstract
Autotaxin (ATX) is a secreted enzyme which hydrolyzes lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA) and choline. The ATX-LPA axis has attracted increasing interest recently for both ATX and LPA are involved in various pathological conditions such as tumor progression and metastasis, fibrotic diseases, arthritis, autoimmune diseases and obesity. Thus, great efforts have been devoted in identifying synthetic ATX inhibitors as new agents for treating various diseases including cancer and fibrotic diseases. Herein, this mini review mainly focused on the binding modes of the reported ATX inhibitors and their indications correspondingly.ATX is part of the seven membered family of ectonucleotide pyrophosphatases/phosphodiesterases (ENPPs), which are characterized by their ability to catalyze the hydrolysis of pyrophosphate or phosphodiester bonds in nucleotides. ATX is distinguished from ENPPs with its function as a lysophospholipase D (lysoPLD), catalyzing the transformation of LPC into the signaling LPA (Figure 1A) [1]. The ATX-LPA axis has been concerned with a wide range of pathological conditions, including tumor progression, inflammation and multiple sclerosis (Figure 1A) [2]. Given its emerging role in diseases, ATX is actively pursued as a challenging therapeutic target accompanied with publication of several reviews [3-5] discussing ATX and its inhibitors. The aim of this mini review is to summarize different binding modes of the uncovered ATX inhibitors and describe their utilities briefly.ATX was firstly isolated in 1992 from A2058 melanoma cells and characterized as a 125 kDa glycoprotein (Figure1B). Structurally, ATX comprises two somatomedin B (SMB)-like domains located at N-terminus, a central catalytic phosphodiesterase (PDE) domain and a catalytically invalid nuclease (NUC)-like domain situated at the C-terminus. The hydrolytic activity comes from a threonine residue (Thr210) in the enzyme’s active site, located in the PDE domain, near two zinc ions coordinated by conserved aspartate and histidine residues [6]. ATX appears to have a hydrophobic tunnel formed by SMB1 and catalytic domains as a second LPA-binding site, which connects to the hydrophobic pocket and catalytic site, consequently forming a ‘T-junction’ (Figure 1C). The channel seems likely to serve as an exit site that releases LPA into the cellular microenvironment to activate its receptors or as an entrance for the LPC substrates [7].Since the first report of ATX structure, plenty of endogenous ligands and synthetic inhibitors have been described. Confusingly, according to the cocrystal structures, they exhibited a diversity of binding modes, which can be classified into four types [8] at this stage as illustrated in Figure 2. a. Type I inhibitors, such as LPA species, HA-155 and PF- 8380 (Figure 2A), simulate the binding mode of LPC substrate and occupy the catalytic site [9-10]. They generally have a Zn2+ binding group and a hydrophobic tail taken up the hydrophobic pocket. Such inhibitors leave the hydrophobic channel unoccupied, which explains why many type I inhibitors exist a secondary compound (blue dots) occupying this channel, generally a species from the solution with amphiphilic properties such as cholesterol or LPA derivatives. b. Type II inhibitors occupy the hydrophobic pocket by largely utilizing their intrinsic plasticity. Interestingly, they take up the bottleneck between the hydrophobic channel and the catalytic site but not fully occupy any of them. PAT-078 (Figure 2B), PAT-494 as well as CRT0273750 represent such type II inhibitors [11]. In contrast to type I inhibitors,
Authors and Affiliations
Hongrui Lei, Fang Jia, Ming Guo, Dajun Zhang, Xin Zhai
Keywords
Related Articles
- EP ID EP589171
- DOI 10.26717/BJSTR.2018.07.001496
- Views 166
- Downloads 0
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