Biotransformation of maximakinin, a bradykinin‐related nonadecapeptide from toad venom, by mammalian kallikrein and salivary proteases

Abstract

Maximakinin is an N‐terminally extended bradykinin (DLPKINRKGPRPPGFSPFR) from the venom of a Chinese toad (Bombina maxima) that displays highly selective activity at mammalian arterial smooth muscle receptors. In this study, we report that incubation of maximakinin with either kallikrein or human saliva generates catabolites with enhanced bioactivity that retain the tissue selective effects of the parent molecule. In addition, we have observed that kallikrein rapidly cleaves the C‐terminal arginyl residue of both maximakinin and bradykinin – a cleavage hitherto considered to be performed by a carboxypeptidase that facilitates selective bradykinin receptor targeting. Maximakinin has thus evolved as a ‘smart’ defensive weapon in the toad with inherent resistance to the signal‐terminating protease hardware in the potential predator. Thus, natural selection of amphibian skin peptides for antipredator defence, through interspecies delivery by an exogenous secretory mode, produces subtle structural stabilization modifications that can potentially provide new insights for the design of orally active and selectively targeted peptide therapeutics.

The Chemistry and Biological Activities of Peptides from Amphibian Skin Secretions

“…Nevertheless, metabolites of maximakinin produced by incubation with mammalian kallikrein and salivary proteases have greater potency than the original maximakinin but the same discrete tissue and/or receptor selectivity. These results show that maximakinin is resistant to proteases and an efficient defensive weapon for toads against predators. , …”

“…These results show that maximakinin is resistant to proteases and an efficient defensive weapon for toads against predators. 43,44 2.1.2. Bombesins.…”

Bradykinin‐related peptides from Phyllomedusa hypochondrialis azurea: mass spectrometric structural characterisation and cloning of precursor cDNAs

“…This would appear to suggest that the toxins are released to inhibit ingestion by predators, with many of the compounds in the venom being orally active. Indeed, previous studies have demonstrated that certain snakes have exhibited oral dyskinesias following attempted ingestion of the African clawed frog, Xenopus laevis ,2 while peptides such as bradykinin and tachykinin have conveyed a contractual response on smooth muscle preparations derived from gut lining 3. Such a response in a potential predator would lead to a vomiting reflex, followed by eventual ejection of the prey 4…”