Conotoxins feature a vast array of post translational modifications (PTMs). PTMs are chemical or structural changes to the residues of a peptide that are not encoded in the peptide gene. PTMs are introduced by specialized enzymes that change the nature of a specific residue. It is believed that the enzymes involved identify their targets by their signal and/or propeptide sequence.
The PTM best understood is the processing of the prepropeptide, which is encoded by the gene, into the mature conopeptide. In this process the N-terminal signal sequence and N-terminal and C-terminal propetides are cleaved to yield the mature peptide with their disulfide connectivity. Cleavage of C-terminal residues may result in an amidated C-terminus, often found in conotoxins. Cleavage of the N-termini of glutamine may result in the formation of pyroglutamic acid by formation of a cyclic amide from the glutamic acid side chain and N-terminus. Other chemical modifications like bromination, hydroxylation, γ-carboxylation or sulfation have also been discovered in conopeptides.
Post translational chemical modifications of amino acids found in conopeptides. 1: pyroglutamic acid (N-terminal, e.g Contulakin-G), 2: C-terminal amidation (often found on the last cysteine, e.g.SI), 3: γ-glutamic acid (e.g Conantokin-G), 4: 4-hydroxyproline (e.g MrIA), 5: sulfotyrosine (e.g EpI) and 6: 6-bromotryptophan (e.g GVIIIA).
Besides the introduction of small functional groups into an amino acid, PTMs can also introduce large molecules like carbohydrates to the side chain of an amino acid (glycosylation). Additionally, the stereo chemistry of amino acids can be changed yielding D-amino acids instead of the L-amino acid.
Post translational chemical modifications of amino acids found in conopeptides. 7: O-glycosylation of threonine (e.g Contulakin-G), 8: epimerized and chemically modified D-γ-hydroxy-valine (e.g.mus-V) and 9: D-phenyl alanine (e.g r11a)
|PTM name||# conopeptides||Wild type||Synthetics|
|Selenocystine (half)||10 (10)||0||10|
|S-cysteinylated cysteine||1 (1)||1||0|
|Pyroglutamic acid||45 (33)||16||17|
|N-Acetate (on N-terminus)||4 (4)||0||4|
|glycosylated threonine||5 (3)||3||0|
|glycosylated serine||5 (2)||2||0|
|Gamma carboxylic glutamic acid||105 (80)||58||22|
|D-aspartic acid||1 (1)||0||1|
|Carbabridge [C7 unsaturated] (half)||1 (1)||0||1|
|Carbabridge [C4 unsaturated] (half)||3 (3)||0||3|
|Carbabridge [C4 saturated] (half)||1 (1)||0||1|
|Carbabridge [C2 unsaturated] (half)||5 (5)||0||5|
|C-term amidation||688 (537)||175||362|
|Asymmetric dimethylarginine||2 (2)||0||2|
|alpha-aminobutyric acid||1 (1)||0||1|
|5-amino-3-oxo-pentanoic acid||1 (1)||0||1|
|2-amino-DL-dodecanoic acid||2 (2)||0||2|
|2-aminoethanethiol (cysteamine) cysteine||1 (1)||0||1|
Conopeptide amino acid post-translational modifications (PTMs) and corresponding number of conopeptides in ConoServer. The second column indicates the number of conopeptides in ConoServer for each PTM, and the numbers between parentheses indicate the numbers of synthetic and wild type conopeptides with experimental evidence of the PTM. Therefore the difference between the two numbers in the second column is the number of conopeptides for which the PTM was predicted in wild type conopeptides. The third column indicates the number of wild type conopeptides with experimental evidence of each PTM. The fourth column indicates the number of synthetic conopeptides synthesized with a PTM. Therefore the numbers between parentheses in the second column are the sum of the corresponding numbers in the third and fourth columns. Clicking on the numbers in violet gives access to the list of corresponding conopeptides.
Remark: There are presently no experimental evidence of the occurrence of D-methionine in conopeptides. Two sequences of conopeptides predicted from mRNA have been suggested to contain D-methionine because of a strong homology in a series of D-amino acid containing conopeptides.
ConoServer is managed at the Institute of Molecular Bioscience IMB, Brisbane, Australia.
The database and computational tools found on this website may be used for academic research only, provided that it is referred to ConoServer, the database of conotoxins (http://www.conoserver.org) and the above reference is cited. For any other use please contact David Craik (email@example.com).
Last updated: Wednesday 22 January 2020