Hyaluronan breakdown by snake venom hyaluronidases: From toxins delivery to immunopathology
- PMID: 37006255
- PMCID: PMC10064005
- DOI: 10.3389/fimmu.2023.1125899
Free PMC article
2.1 Hyaluronidases
HYAs production has been observed along the phylogenetic tree, from bacteriophages and other viruses, pathogenic bacteria, fungi, and invertebrates to vertebrate animals (26–28). In vertebrates, different cell types produce these enzymes, and they are detected in the ECM of diverse organs, including the testis, eyes, skin, spleen, liver, kidney, and uterus, and in secretions, including serum, semen and animal venoms (29) (Table 1).
Table 1 Comparison between HYAL and SVHYA.
HYAs enzymes, also called hyaluronoglucosaminidases, are members of the class of hydrolases, a subclass of glycosylases (EC 3.2). These enzymes function as glycosidases (EC 3.2.1) due to their ability to hydrolyze O- and S-glycosyl compounds (30). HYAs are glycoproteins with a broad range of molecular weights from 7 to 320 kDa. The optimal pH for their action can vary from 3.3 to 7.0 (29). According to the molecular substrates and products generated by HYAs enzymatic reactions, these enzymes are classified into three main subclasses (26–30):
1. HYAs (EC 3.1.2.35): This subclass includes hyaluronoglucosaminidases present in semen, serum, tissues, and lysosomes, as well as in hymenopteran and snake venoms. They possess transglycosidase and hydrolytic activities. Among the substrates of these enzymes, hyaluronan is highlighted. In addition, these enzymes act on chondroitin sulfate A and C and to a lesser extent on dermatan sulfate (chondroitin sulfate B) and β-heparin. The main product of their catalytic activity is the tetrasaccharide GlcUA-GlcNAc-GlcUA-GlcNAc.
2. HYAs (EC 3.1.2.36): This subclass includes hyaluronoglucuronidases that hydrolyze hyaluronan, resulting in the release of tetra- and hexasaccharides. These enzymes have been reported in leeches, parasites, and crustaceans.
3. HYAs (EC 4.2.2.21): This HYA group is produced by bacterial species and is characterized as HA lyases. They degrade HA, dermatan sulfate, and chondroitin sulfate A and C. These enzymes are called endo-β-N-acetyl-D-hexosaminidases, which act via β elimination since their catalytic activity generates disaccharides.
The molecular mechanisms of catalysis and substrate specificity are dictated by the presence of positional and structural catalytic residues conserved in the species in which HYAs were identified. The amino acid residues that characterize this enzymatic class are Glu149, which is important for the catalytic mechanism; the Asp147, Tyr220, Trp341 triad, which is responsible for positioning the carbonyl acetamide group for catalysis; and Tyr265, which is responsible for the HYAs specificity for HA. The replacement of the Tyr265 residue for Cys265 switches HYA specificity to chondroitin (2, 29).
2.2 Snake venom hyaluronidases
The initial data for the SVHYA were obtained during the 1930s. These studies showed that venoms contained a spreading factor that was able to increase tissue and blood capillary permeability to Indian ink and to pathogenic bacterial species. Some authors postulated that this factor would be important for venom absorption by prey and human victims (35, 36). In subsequent decades, the presence of spreading factors involved in efficient toxin delivery was ubiquitously detected in snake venoms. These factors, which include snake venom metalloproteinases and SVHYA, are important factors in tissue destruction since their actions are responsible for ECM breakdown (2, 29). SVHYA potentiate hemorrhaging, swelling, muscle damage and lethal effects of purified venom toxins, since its inhibition by monoclonal antibodies and plant derivative inhibitors substantially decreased the toxic effects of the venoms (1, 31–34). Thus, based on the available data, SVHYA are considered the main snake venom spreading factors.
Similar to HYAL, SVHYA are glycoproteins; however, their molecular weight ranges from 33 to 110 kDa, and they are generally produced as single chain polypeptides (29). In addition, more than one isoform has been reported in some venoms (1, 31). Harrison and colleagues (2) scrutinizing cDNA libraries and protein sequences showed that SVHYA conserve positional and structural catalytic residues that characterize this enzyme group.
Although hyaluronidases are ubiquitously expressed in snake venoms, the mechanisms involved in their effect on HA, which is present in the ECM and bloodstream, and the inflammatory consequences of these actions are underexplored. Biochemical studies examining the structure and activity of SVHYA clustered these enzymes in the EC 3.2.1.35 subclass together with HYAL (2, 33), which were previously shown to trigger inflammatory events (3, 6–10). Additionally, like HYAL, SVHYA act on HA to generate tetra- and hexasaccharides, suggesting that they potentially exert immunopathological effects.
(Sitaatti otettu 8.5. 2023 tähän MMP blogiin, sillä kyynmyrkky on hyvin monen entsyymin seos, jossa vaikutukset eivät ole ainoastaan myrkyn metalloproteinaaseista SVMPs ja sen takia on aiheellista mainita muitakin myrkyllisyyden tekijöitä yhteydessä. Hyaluronaasien osuutena on myrkyn leviämisen edistäminen. Metalloproteinaasit hajoittavat basaalilaminaa. trombiinikaltaiset SVTLEs vaikuttvat veren reologian puolella. Kiniiniä vapauttavat vaikuttavat mikrovaskulaariseen permeabiliteettiin, turvotuksen lisäämiseen , hypovolemiaan. Lektiinit , PLA2 vaikuttavat mastsoluihin ja hepariinin vapautumiseen. Lihastoksinen PLA2 tekee myonekroosia , kehittyy endoteeliperäisiä sytokiineja, trombosytopeniaa havaitaan,, erytrosyyteissä muutoksia, leukosyyttejä verisuoniston ulkopuolelle -rheologisia ilmiöitä on laidasta laitaan- , vuotoa, trombeja, DIC- hypofyysi vaikuttuu, stressihormonit vaikuttuvat, verenmuodostus vaikuttuu. käärmeenpurema on aina otettava vakavasti- joskus tapahtumat ovat hiipiviä ja yllättäen tapahtuu pahenema-
Kuljetus hoitoon ja observaatio ovat tärkeät alkuvaiheet, että lääkärikunta pääsee tapahtumista ajoissa jyvälle.
Kuuma kesä on jälleen alussa ja käärmeet heräävät. .
https://pubmed.ncbi.nlm.nih.gov/20162537/ Käärmeenmyrkyn ACEI kaltainen vaikutus , bradykiniiniä vapauttavat entsyymit
Käärmeenmyrkyssä voi olla reniinin kaltaisuutta siten että se voi pilkkoa RaAS- järjestelmää spesifisesti siten että vaikutukset järjestelmässä ovat raflaavia; Snake Venom Aspartic proteases SVAPs
https://pubmed.ncbi.nlm.nih.gov/28734982/
- PMID: 28734982
- DOI: 10.1016/j.toxicon.2017.07.008
- Three aspartic proteases (SVAPs) have been isolated from venom of the saw-scaled viper, Echis ocellatus. In confirmation of prior transcriptomic predictions, all three forms match to sequences of either of the two SVAP transcripts (EOC00051 and EOC00123), have a molecular weight of 42 kDa and possess a single N-glycan. The SVAPs act in a renin-like manner, specifically cleaving human and porcine angiotensinogen into angiotensin-1 and possess no general protease activity. Their activity is completely inhibited by the aspartyl protease inhibitor Pepstatin A.
Mender M. Mender, ... Mark Young, in Advances in Protein Chemistry and Structural Biology, 2022
1.1 Geographical distribution and dietary acquisition of snakes
Venomous snakes occupy virtually all ecological niches (Vidal et al., 2007). Snakes such as Bitis arietans, Bitis. gabonica, Echis leucogaster, Echis ocellatus, Naja haje, Naja nigricollis, Naja melanoleuca, Dendroaspis jamesoni, Dendroaspis polylepis and Dendroaspis viridis are abundant in tropical and SSA (Tasoulis & Isbister, 2017). As shown in Fig. 1, these snakes occupy different regions of the African continent.
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