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Discovery and Initial Characterisation
The cyclotides are a group of cyclic peptides from species of the Rubiaceae and Violaceae plant families. These peptides have the distinction of being both the largest group of cyclic peptides, with over 50 peptides so far characterised, and the first family of gene-expressed cyclic peptide discovered. The prototypic cyclotide, kalata B1, was first discovered in the Zaire in the 1970's when it was identified as being the active ingredient in a tea used by native women during childbirth [14,16,17,15]. This tea was made from the leaves of the plant Oldenlandia affinis, or kalata-kalata as it was called by the native people. The tea was taken to facilitate an easy labour, but the uterotonic activity of the tea often resulted in uterine spasms necessitating cesarean delivery [14,18]. A Red Cross doctor noticing the number of cesareans needed in the area analysed the tea and discovered a peptidic active ingredient that he named kalata B1 after the native name of the plant. Apart from its unusual stability, as evidenced by its use in native medicine, kalata B1 was also distinctive as Edman sequencing failed unless the peptide was first subject to proteolytic cleavage. Although the possibility of backbone cyclisation was floated at the time further research was not conducted for another 20 years.
In 1995 the structure, sequence and 3D structure of kalata B1 was reported [19] and surprisingly, apart from a cyclised backbone, the three-dimensional structure showed that two of the cystine bonds, along with the intervening backbone residues, formed a loop which was threaded by the third disulphide bond -- a structural motif called a cystine knot. When combined with the cyclised backbone kalata B1 displayed more topological complexity than any other characterised protein and could be considered the first knotted protein [20]. At around the same time bioassay directed screening led to the identification of further cyclotides from a variety of species in the Violaceae and Rubiaceae. These included viola peptide I with haemolytic activity [21], circulin A and circulin B, with anti-HIV activity [22], and cyclopsychotride, which inhibits neurotensin binding to cell membranes [23]. Since this time almost fifty cyclotides have been reported based on their characteristic late elution using reverse phase high performance liquid chromatography (RP-HPLC) [30,27,25,28,26,29,24] and the results of unpublished screening programs indicates that, eventually, the number of peptides in this family may number in the hundreds [31].
Next: Nomenclature and Sequence Conservation Up: The Cyclotides Previous: The Cyclotides Jason Mulvenna
2005-04-24
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