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Review
. 2017 Dec 19;9(12):406.
doi: 10.3390/toxins9120406.

Secreted Phospholipases A₂ from Animal Venoms in Pain and Analgesia

Vanessa O Zambelli  1 , Gisele Picolo  2 , Carlos A H Fernandes  3 , Marcos R M Fontes  4 , Yara Cury  5
Affiliations
Review

Secreted Phospholipases A₂ from Animal Venoms in Pain and Analgesia

Vanessa O Zambelli et al. Toxins (Basel). .

Abstract

Animal venoms comprise a complex mixture of components that affect several biological systems. Based on the high selectivity for their molecular targets, these components are also a rich source of potential therapeutic agents. Among the main components of animal venoms are the secreted phospholipases A₂ (sPLA₂s). These PLA₂ belong to distinct PLA₂s groups. For example, snake venom sPLA₂s from Elapidae and Viperidae families, the most important families when considering envenomation, belong, respectively, to the IA and IIA/IIB groups, whereas bee venom PLA₂ belongs to group III of sPLA₂s. It is well known that PLA₂, due to its hydrolytic activity on phospholipids, takes part in many pathophysiological processes, including inflammation and pain. Therefore, secreted PLA₂s obtained from animal venoms have been widely used as tools to (a) modulate inflammation and pain, uncovering molecular targets that are implicated in the control of inflammatory (including painful) and neurodegenerative diseases; (b) shed light on the pathophysiology of inflammation and pain observed in human envenomation by poisonous animals; and, (c) characterize molecular mechanisms involved in inflammatory diseases. The present review summarizes the knowledge on the nociceptive and antinociceptive actions of sPLA₂s from animal venoms, particularly snake venoms.

Keywords: analgesia; animal venoms; catalytic activity; pain; secretory phospholipases A2.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cartoon representation of canonical tertiary structure of phospholipases A2 from (A) snake venoms of groups I and II; and, (B) bee venom of group III. The conserved structural motifs are highlighted: α-helices 1, 2, and 3 (h1, h2 and h3, respectively); the β-wing, the flexible C-terminal region, the Ca2+-binding loop (in orange) and the “elapid” loop, an insertion of two or three amino acids in region 52–65 present only in class IA enzymes. The conserved catalytic network formed by a histidine (H), two aspartic acids (D) and a tyrosine (Y) residues are also highlighted in cyan (in snake venom PLA2) and in yellow (in bee venom PLA2) sticks. The figures were generated using the crystal structures of group IA PLA2 from Naja naja venom (PDB ID 1PSH) and of group III PLA2 from Apis mellifera venom (PDB ID 1POC). Modified from Fernandes et al., 2014: Biochimica et Biophysica Acta (BBA)-Preoteins and Proteomics, volume 1844, pages 2265-2276, Elsevier, copyright 2014 [23].
Figure 2
Figure 2
A schematic overview of pain pathways. Noxious stimuli, such as high temperatures, injury-related chemicals, extreme mechanical pressures and venoms, are detected by nociceptors. The nociceptors are pseudounipolar neurons whose cell bodies (soma) are located in the dorsal root ganglia. They bifurcate, sending a peripheral axon to the skin, and other organs, and an axon to the central nerve system (CNS). C-fibers are unmyelinated small diameter axons with projections to superficial laminae I and II of the dorsal horn of the spinal cord. Aδ-fiber nociceptors are thinly myelinated axons with projections to superficial lamina I as well as to the deeper dorsal horn (lamina V). From the spinal cord the information proceeds to the brainstem and reaches the cerebral cortex, where the perception of pain occurs (ascending pathways-red). The descending pain modulatory circuits decrease the nociceptive input in the central nervous system by releasing neurotransmitters that can exert an inhibitory action (ascending pathways-blue). Illustration: Larissa Foronda.
Figure 3
Figure 3
Cartoon representation of the quaternary structure of (A) crotoxin (CTX), obtained by small angle X-ray scattering (SAXS); and (B) BthTX-I, a Lys49-PLA2 from the Bothrops jararacussu snake venom, as representative of PLA2-like proteins group, obtained by protein crystallography (PDB ID 3IQ3). In the CTX structural model (panel A), the two subunits that form the heterodimer; crotoxin B (CB; in light brown) and crotoxin A (CA) are shown. The α, β and γ polypeptides chains that constitute the structure of CA are highlighted in green, yellow and pink, respectively. The flexible loops that are not present in the CTX crystal structure (PDB ID 3R0L; [43]), but were modelled in CTX SAXS model as dummy residues [45], are showed as spheres. The tryptophan residues of CTX (W36 from α-chain of CA; W31, W70 and W90 from CB) and the catalytic network of CB (His48, Asp49; Tyr53 and Asp99) are highlighted in green and cyan sticks, respectively. The N-terminal exposed to the solvent of CB in CTX heterodimer is highlighted in blue. In the Lys49-PLA2 structural model (panel B), the most important structural aspects of these proteins are highlighted: the hydrophobic molecule in hydrophobic channel that causes the activation of the protein (a polyethylene glycol molecule, showed in cyan sticks); the Membrane Docking-Site (MDoS) formed by Lys20; Lys115; and, Arg118 residues from both monomers and responsible for the stabilization of the protein on the target membrane (green sticks); and the Membrane Disruption-Site (MDiS), formed by Leu121 and Phe125 from both monomers, that penetrates in the target membrane causing a disorganization of the lipid bilayer, allowing an uncontrolled influx of ions (i.e., Ca2+ and Na+), and, consequently, cell death. Modified from Fernandes et al., 2017: Scientific Reports, volume 7, page 43885, Spring Nature, copyright 2017 [68].
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