A defined α-helix in the bifunctional O-glycosylated natriuretic peptide TcNPa from the venom of Tropidechis carinatus

Reeks, Timothy, Jones, Alun, Brust, Andreas, Sridharan, Sindhuja, Corcilius, Leo, Wilkinson, Brendan L., Thaysen-Andersen, Morten, Payne, Richard J., Kini, R. Manjunatha, Daly, Norelle L., and Alewood, Paul F. (2015) A defined α-helix in the bifunctional O-glycosylated natriuretic peptide TcNPa from the venom of Tropidechis carinatus. Angewandte Chemie International Edition, 54 (16). pp. 4828-4831.

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Abstract

Natriuretic peptides (NP) play important roles in human cardiac physiology through their guanylyl cyclase receptors NPR-A and NPR-B. Described herein is a bifunctional O-glycosylated natriuretic peptide, TcNPa, from Tropidechis carinatus venom and it unusually targets both NPR-A and NPR-B. Characterization using specific glycosidases and ETD-MS identified the glycan as galactosyl-β(1-3)-N-acetylgalactosamine (Gal-GalNAc) and was α-linked to the C-terminal threonine residue. TcNPa contains the characteristic NP 17-membered disulfide ring with conserved phenylalanine and arginine residues. Both glycosylated and nonglycosylated forms were synthesized by Fmoc solid-phase peptide synthesis and NMR analysis identified an α-helix within the disulfide ring containing the putative pharmacophore for NPR-A. Surprisingly, both forms activated NPR-A and NPR-B and were relatively resistant towards proteolytic degradation in plasma. This work will underpin the future development of bifunctional NP peptide mimetics.

Item ID: 39354
Item Type: Article (Research - C1)
ISSN: 1521-3773
Funders: National Health and Medical Research Council (NHMRC)
Projects and Grants: NHMRC Program grant no 1063803
Date Deposited: 09 Jul 2015 05:44
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110106 Medical Biochemistry: Proteins and Peptides (incl Medical Proteomics) @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 100%
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