The structure of helokinestatin-5 and its biosynthetic precursor from Gila monster (Heloderma suspectum) venom: Evidence for helokinestatin antagonism of bradykinin-induced relaxation of rat tail artery smooth muscle

Zhang, Yao; Wang, Lei; Zhou, Z.; Chen, Xiaole; Kwok, HangFai; Ivanyi, Craig; Shaw, Chris

doi:10.1016/j.peptides.2010.04.030

Cited by 10 publications

(9 citation statements)

References 21 publications

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“…Two TPHs identified from Phyllomedusa rohdei (Table ) have shown to affect on liver protein synthesis and body weight , and recently, the investigation on TPHs by our research group find out that some T‐3 peptides can attenuate the bradykinin‐induced relaxation response in rat tail arterial smooth muscle preparations . Such bradykinin antagonism effects are very similar to the effect of helokinestatins, which were identified in Gila monster venom . Moreover, the helokinestatins are also a group of proline‐rich peptides, and some of them contain the ‐Pro‐Pro‐Pro‐ domain.…”

Section: Discussionmentioning

confidence: 61%

Molecular Cloning of a Novel Tryptophyllin Peptide from the Skin of the Orange‐Legged Monkey Frog, Phyllomedusa hypochondrialis

et al. 2014

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Tryptophyllins are a group of small (4-14 amino acids), heterogenous peptides, mostly from the skins of hylid frogs from the genera, Phyllomedusa and Litoria. To date, more than forty TPHs have been discovered in species from these two genera. Here, we describe the identification of a novel tryptophyllin type 3 peptide, PhT-3, from the extracts of skin of the orange-legged monkey frog, Phyllomedusa hypochondrialis, and molecular cloning of its precursor-encoding cDNA from a cDNA library constructed from the same skin sample. Full primary structural characterization was achieved using a combination of direct Edman degradation, mass spectrometry and deduction from cloned skin-derived cDNA. The open-reading frame of the precursor cDNA was found to consist of 63 amino acid residues. The mature peptide arising from this precursor contains a post-translationally modified N-terminal pyroglutamate (pGlu) residue, formed from acid-mediated cyclization of an N-terminal Gln (Q) residue, and with the structure: pGlu-Asp-Lys-Pro-Phe-Trp-Pro-Pro-Pro-Ile-Tyr-Pro-Met. Pharmacological assessment of a synthetic replicate of this peptide on phenylephrine preconstricted rat tail artery segments, revealed a reduction in relaxation induced by bradykinin. PhT-3 was also found to mediate antiproliferative effects on human prostate cancer cell lines.

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Section: Discussionmentioning

confidence: 61%

Molecular Cloning of a Novel Tryptophyllin Peptide from the Skin of the Orange‐Legged Monkey Frog, Phyllomedusa hypochondrialis

et al. 2014

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“…Each of the chimeric or mutant INSL3 peptides were prepared by optimized solid phase synthesis of the separate A- and B-chains followed by their combination via regioselective disulfide bond formation as previously described (Zhang et al, 2010). Overall yields of purified peptides averaged 10–14% based on starting material in the form of cleaved B-chain and each was comprehensively chemically characterized by analytical RP-HPLC and MALDI-TOF mass spectrometry.…”

Section: Methodsmentioning

confidence: 99%

The Structural Determinants of Insulin-Like Peptide 3 Activity

Bathgate¹,

Zhang²,

Hughes³

et al. 2012

Front. Endocrin.

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Insulin-like peptide 3 (INSL3) is a hormone and/or paracrine factor which is a member of the relaxin peptide family. It has key roles as a fertility regulator in both males and females. The receptor for INSL3 is the leucine rich repeat (LRR) containing G-protein coupled receptor 8 (LGR8) which is now known as relaxin family peptide receptor 2 (RXFP2). Receptor activation by INSL3 involves binding to the LRRs in the large ectodomain of RXFP2 by residues within the B-chain of INSL3 as well as an interaction with the transmembrane exoloops of the receptor. Although the binding to the LRRs is well characterized the features of the peptide and receptor involved in the exoloop interaction are currently unknown. This study was designed to determine the key INSL3 determinants for RXFP2 activation. A chimeric peptide approach was first utilized to demonstrate that the A-chain is critical for receptor activation. Replacement of the INSL3 A-chain with that from the related peptides INSL5 and INSL6 resulted in complete loss of activity despite only minor changes in binding affinity. Subsequent replacement of specific A-chain residues with those from the INSL5 peptide highlighted that the N-terminus of the A-chain of INSL3 is critical for its activity. Remarkably, replacement of the entire N-terminus with four or five alanine residues resulted in peptides with near native activity suggesting that specific residues are not necessary for activity. Additionally removal of two amino acids at the C-terminus of the A-chain and mutation of Lys-8 in the B-chain also resulted in minor decreases in peptide activity. Therefore we have demonstrated that the activity of the INSL3 peptide is driven predominantly by residues 5–9 in the A-chain, with minor additional contributions from the two C-terminal A-chain residues and Lys-8 in the B-chain. Using this new knowledge, we were able to produce a truncated INSL3 peptide structure which retained native activity, despite having 14 fewer residues than the parent peptide.

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“…The pharmacological evaluations revealed that even acting in the same pathway, they can show distinct biological activities compared to BK, including potentiating its effects by inhibition of its degradation or by acting on receptors and/or molecules involved in the BK signaling pathway, including activating or blocking the BK receptors [10,35]. As such, the BRPs also include BPPs and the Bradykinin Inhibitor Peptides (BIPs) [13,29,32,36].…”

Section: Cdna Cloning Identification and Characterization Of Brpsmentioning

confidence: 99%

“…However, the additionally encoded tandem-repeat peptides are non-canonical BPPs, based on their primary structural characteristics or in terms of the amino acid cleavage site, presenting characteristics of a recognition site typical of propeptide convertase enzymes, that eventually might be the potential responsible for the release of the mature BIPs from the respective biosynthetic precursors [36]. However, the BPP/ CNP biosynthetic precursors of the bushmaster (Lachesis muta), the tropical rattlesnake (Crotalus durissus terrificus), and the massasauga rattlesnake from desert (Sistrurus catenatus ewardsi) showed that, in addition to the classical BPPs and a NP sequence, they all also encode single copies of a BIP exhibiting a closer structural similarity, and a propeptide convertase cleavage site that allows the release of the BIP helokinestatins, whose sequences are [TPPAGPDVGPR] or [TPPAGPDGGPR] [36] (Figure 1). On the other hand, putative helokinestatins peptides could not be identified in the BPP/CNP precursor of snakes as Bothrops jararaca, Bothrops jararacussu, and Agkistrodon blomhoffi ( Figure 1).…”

Section: Brps and Npsmentioning

confidence: 99%

“…Other family of BRPs, which should be considered in the treatment of pain and inflammation, are the antagonists of BK receptors (BIPs), namely helokinestatins. Although these BRPs were described as vasoactive peptides, due to their ability to antagonize the relaxation effect induced by BK [35,36], they could potencially be employed in the therapy of hyperalgesia.…”

Section: Application Of Bips In the Treatment Of Pain And Inflammationmentioning

confidence: 99%

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Venom Bradykinin-Related Peptides (BRPs) and Its Multiple Biological Roles

Lameu¹,

Neiva²,

Hayashi³

2013

An Integrated View of the Molecular Recognition and Toxinology - From Analytical Procedures to Biomedical Applications

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The structure of helokinestatin-5 and its biosynthetic precursor from Gila monster (Heloderma suspectum) venom: Evidence for helokinestatin antagonism of bradykinin-induced relaxation of rat tail artery smooth muscle

Cited by 10 publications

References 21 publications

Molecular Cloning of a Novel Tryptophyllin Peptide from the Skin of the Orange‐Legged Monkey Frog, Phyllomedusa hypochondrialis

Molecular Cloning of a Novel Tryptophyllin Peptide from the Skin of the Orange‐Legged Monkey Frog, Phyllomedusa hypochondrialis

The Structural Determinants of Insulin-Like Peptide 3 Activity

Venom Bradykinin-Related Peptides (BRPs) and Its Multiple Biological Roles

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