Abstract
Snakebites are one of the major causes of death and long-term disability in the developing countries due to the presence of various bioactive peptides and proteins in snake venom. In Japan, the venom of the habu snake (Protobothrops flavoviridis) causes severe permanent damage due to its myonecrotic toxins. Antivenom immunoglobulins are an effective therapy for snakebites, and antivenom was recently developed with effective suppressive activity against myonecrosis induced by snake venom. To compare the properties of an antivenom having anti-myonecrotic activity with those of conventional antivenom with no anti-myonecrotic activity, this study applied focused proteomics analysis of habu venom proteins using 2D gel electrophoresis. As a target protein for antivenom immunoglobulins with anti-myonecrotic activity, we identified a thrombin-like serine protease, TLSP2 (TLf2), which was an inactive proteolytic isoform due to the replacement of the active site, His43 with Arg. Additionally, we identified the unique properties and a novel synergistic function of pseudoenzyme TLf2 as a myonecrosis-enhancing factor. To our knowledge, this is the first report of a function of a catalytically inactive snake serine protease.
Highlights
Snake envenomation is a major cause of death and long-term disability in developing countries
Identification of Target Proteins Adsorbed to Anti-Myonecrosis-type Antiserum-Conjugated Column
The pathological diagnosis and autopsy in mice including antimyonecrosis activities of two types of habu antivenoms were determined against habu crude venom (Table 1)
Summary
Snake envenomation is a major cause of death and long-term disability in developing countries. We decoded the whole genome structure of the venomous habu snake (Protobothrops flavoviridis) and analyzed its transcriptomic data by next-generation sequencing, revealing that the production mechanisms of various venomous proteins are associated with accelerated evolution and alternative splicing (Shibata et al, 2018; Ogawa et al, 2019; Ogawa and Shibata, 2020) These venomous proteins, including metalloproteases (MPs), phospholipases A2 (PLA2s), serine proteases (SPs), C-type lectin like proteins (CTLPs), demonstrated several specific individual pharmacological activities, they acted cooperatively and synergistically as a cocktail of toxins (Xiong and Huang, 2018). These complexes, which formed through covalent and/or non-covalent interactions of either identical (homodimers) or dissimilar (heterodimers; in some cases subunits belong to different families of proteins) subunits, exhibit much higher levels of pharmacological activity and pathophysiological effects compared to individual components during envenomation (Doley and Kini, 2009)
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