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Life has an unexplained and distinct l-homochirality. Proteins typically incorporate only l-amino acids into their sequences. In the present study, d-Val and d-gamma-hydroxyvaline (d-Hyv; V) have been found within ribosomally expressed polypeptide chains. Four conopeptides were initially isolated, gld-V/gld-V'from the venom of Conus gladiator and mus-V/mus-V' from the venom of Conus mus. Their complete sequences (gld-V/gld-V' = Ala-Hyp-Ala-Asn-Ser-d-Hyv-Trp-Ser and mus-V/mus-V' = Ser-Hyp-Ala-Asn-Ser-d-Hyv-Trp-Ser) were determined by a combination of nano/pico-NMR and MS/MS methods. The amino acid triad that contains the gamma-hydroxylated residue, Ser-d-Hyv-Trp, is a novel structural motif that is stabilized by specific interactions between the d-amino acid and its neighboring l-counterparts. These interactions inhibit lactonization, a peptide backbone scission process that would normally be initiated by gamma-hydroxylated residues. Conopeptides possessing the Ser-d-Hyv-Trp motif have been termed gamma-hydroxyconophans. We have also isolated analogous conopeptides (gld-V and mus-V) containing d-Val instead of d-Hyv; these are termed conophans. gamma-Hydroxyconophans and conophans are particularly atypical because (i) they are not constrained as most conopeptides, (ii) they are extremely short in length, (iii) they have a high content of hydroxylated residues, and (iv) their sequences have no close match with other peptides in sequence databases. Their modifications appear to be part of a novel hyperhydroxylation mechanism found within the venom of cone snails that enhances neuronal targeting. The finding of d-Val and d-Hyv within this family of peptides suggests the existence of a corresponding d-stereospecific enzyme capable of d-Val oxidation.

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