A Defined α‐Helix in the Bifunctional <i>O</i>‐Glycosylated Natriuretic Peptide TcNPa from the Venom of <i>Tropidechis carinatus</i>

Reeks, Timothy; Jones, Alun; Brust, Andreas; Sridharan, S.; Corcilius, Leo; Wilkinson, Brendan L.; Thaysen‐Andersen, Morten; Payne, Richard J.; Kini, R. Manjunatha; Daly, Norelle L.; Alewood, Paul F.

doi:10.1002/anie.201411914

Cited by 9 publications

(6 citation statements)

References 34 publications

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“…However, a natriuretic peptide isolated from Krait venom (known as KNP), was reported to have a putative α-helix, formed by its extended C-terminus [ 144 ]. Another study reported an O -glycosylated natriuretic peptide (TcNPa), from the venom of Tropichedis carinatus , and NMR analysis of TcNPa confirmed the presence of an α-helix as well [ 145 ].…”

Section: Snake Venom Peptides and Their Potential Pharmacological mentioning

confidence: 99%

Snake Venom Peptides: Tools of Biodiscovery

Munawar

Ali

Akrem

et al. 2018

Toxins

109

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Nature endowed snakes with a lethal secretion known as venom, which has been fine-tuned over millions of years of evolution. Snakes utilize venom to subdue their prey and to survive in their natural habitat. Venom is known to be a very poisonous mixture, consisting of a variety of molecules, such as carbohydrates, nucleosides, amino acids, lipids, proteins and peptides. Proteins and peptides are the major constituents of the dry weight of snake venoms and are of main interest for scientific investigations as well as for various pharmacological applications. Snake venoms contain enzymatic and non-enzymatic proteins and peptides, which are grouped into different families based on their structure and function. Members of a single family display significant similarities in their primary, secondary and tertiary structures, but in many cases have distinct pharmacological functions and different bioactivities. The functional specificity of peptides belonging to the same family can be attributed to subtle variations in their amino acid sequences. Currently, complementary tools and techniques are utilized to isolate and characterize the peptides, and study their potential applications as molecular probes, and possible templates for drug discovery and design investigations.

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Section: Snake Venom Peptides and Their Potential Pharmacological mentioning

confidence: 99%

Snake Venom Peptides: Tools of Biodiscovery

Munawar

Ali

Akrem

et al. 2018

Toxins

109

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“…An O-linked glycosylated natriuretic peptide isolated from T. carinatus showed drug lead potential by demonstrating bi-functionality to both NPR-A and NPR-B natriuretic peptide receptors [52]. Furthermore, the peptide showed α-helix secondary structure and relative stability in plasma and trypsin solution.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Deep venomics of the Pseudonaja genus reveals inter- and intra-specific variation

Reeks

Lavergne

Sunagar

et al. 2016

Journal of Proteomics

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Australian elapid venom remains an under-investigated resource of novel bioactive peptides. In this study, the venom gland transcriptomes and proteomes of the Australian western brown snakes, Pseudonaja aspidorhyncha and Pseudonaja nuchalis, were compared to Pseudonaja textilis. A deep venomics strategy incorporating high throughput 454 pyrosequencing gave a total of 200,911 raw reads for the three venoms. Subsequent annotation identified 5716 transcripts from 20 different toxin families with inter-specific variation between species observed in eight of the less abundant families. Integration of each venom proteome with the corresponding annotated reads identified 65 isoforms from six toxin families; high sequence coverage highlighted subtle differences between sequences and intra and inter-specific variation between species. High quality MS/MS data identified unusual glycoforms with natriuretic peptides from P. aspidorhyncha and P. nuchalis containing O-linked trisaccharides with high homology to the glycosylated region of TNPc. Molecular evolutionary assessments indicated the accelerated evolution of all toxin families with the exception of both natriuretic peptides and P. aspidorhyncha PLA2s that were found to be evolutionarily constrained under purifying selection pressures. This study has revealed a wide range of novel peptide sequences from six bioactive peptide families and highlights the subtle differences between toxins in these closely related species. Biological SignificanceMining Australia's vastly untapped source of toxins from its venomous creatures has been significantly advanced by employing deep venomics methodology.Technological advances in transcriptome analysis using next generation sequencing platforms and proteome analysis by highly sensitive tandem mass spectrometry allowed a more comprehensive interrogation of three underinvestigated brown snake (Pseudonaja) venoms uncovering many novel peptide sequences that are unique to these closely related species. This generic strategy will provide invaluable information when applied to other venomous snakes for a deeper understanding of venom composition, envenomation, venom evolution, as well as identifying research tools and drug leads.

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“…More recently, TcNPa isolated from T. carinatus venom was found to be the first member of the NP family to possess a significant secondary structure involving an α-helix. TcNPa has other interesting characteristics including an O -glycosylation site, activity at both NPR-A and NPR-B and strong resistance to proteolytic degradation in plasma [ 47 ]. Crystallographic structures of hNPR-C bound hCNP and hNPR-A bound hANP implicated the highly conserved residues within the NP internal ring as the likely pharmacophoric residues [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several recent studies have also highlighted the importance of post-translation modifications in modulating physiological activities of NPs. Reeks [ 47 ] described the first glycosylated NP in the venom of Tropidechis carinatus , TcNPa, and a recent glycoproteomics study [ 60 ] discovered O -glycans on mature human and mammalian NPs with two glycosites in ANP positioned in the highly conserved ring region. These post-translational modifications on mature ANP were found to have a major impact on stability and circulation time of ANP as well as receptor activation in vitro and in vivo [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

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Taipan Natriuretic Peptides Are Potent and Selective Agonists for the Natriuretic Peptide Receptor A

et al. 2023

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Cardiovascular ailments are a major cause of mortality where over 1.3 billion people suffer from hypertension leading to heart-disease related deaths. Snake venoms possess a broad repertoire of natriuretic peptides with therapeutic potential for treating hypertension, congestive heart failure, and related cardiovascular disease. We now describe several taipan (Oxyuranus microlepidotus) natriuretic peptides TNPa-e which stimulated cGMP production through the natriuretic peptide receptor A (NPR-A) with higher potencies for the rat NPR-A (rNPR-A) over human NPR-A (hNPR-A). TNPc and TNPd were the most potent, demonstrating 100- and 560-fold selectivity for rNPR-A over hNPR-A. In vivo studies found that TNPc decreased diastolic and systolic blood pressure (BP) and increased heart rate (HR) in conscious normotensive rabbits, to a level that was similar to that of human atrial natriuretic peptide (hANP). TNPc also enhanced the bradycardia due to cardiac afferent stimulation (Bezold–Jarisch reflex). This indicated that TNPc possesses the ability to lower blood pressure and facilitate cardiac vagal afferent reflexes but unlike hANP does not produce tachycardia. The 3-dimensional structure of TNPc was well defined within the pharmacophoric disulfide ring, displaying two turn-like regions (RMSD = 1.15 Å). Further, its much greater biological stability together with its selectivity and potency will enhance its usefulness as a biological tool.

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A Defined α‐Helix in the Bifunctional O‐Glycosylated Natriuretic Peptide TcNPa from the Venom of Tropidechis carinatus

Cited by 9 publications

References 34 publications

Snake Venom Peptides: Tools of Biodiscovery

Snake Venom Peptides: Tools of Biodiscovery

Deep venomics of the Pseudonaja genus reveals inter- and intra-specific variation

Taipan Natriuretic Peptides Are Potent and Selective Agonists for the Natriuretic Peptide Receptor A

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