Article pubs.acs.org/jnp
Proposed Systematic Nomenclature for Orbitides Youn Young Shim,*,†,‡ Lester W. Young,† Paul G. Arnison,§ Edward Gilding,⊥ and Martin J. T. Reaney*,†,‡ †
Department of Plant Sciences, University of Saskatchewan, 51 Campus Drive, Saskatoon, Saskatchewan S7N 5A8, Canada Prairie Tide Chemicals Inc., 102 Melville Street, Saskatoon, Saskatchewan S7J 0R1, Canada § Botanical Alternatives Inc., 176, 8B-3110 Eighth Street E, Saskatoon, Saskatchewan S7H 0W2, Canada ⊥ Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia ‡
S Supporting Information *
ABSTRACT: Orbitides are short (5−11 amino acid residue), ribosomally synthesized homodetic plant cyclic peptides characterized by N-to-C amide bonds rather than disulfide bonds. Orbitides can be discovered using mass spectrometry of plant extracts or by identifying DNA sequences coding for the precursor protein. The number of orbitides that have been characterized to date, by a number of different research groups, is modest. The nomenclatural system currently used for the Type VI cyclic peptides has been developed in an ad hoc fashion and is somewhat arbitrary. We propose a systematic naming system specifically for the Type VI cyclic peptides that reflects the taxonomic name of the species producing the orbitides and a numbering system that enables systematic representation of amino acid residues and modifications. The proposed naming system emulates the IUPAC Nomenclature for Natural Products and UniProt, both of which use abbreviations of taxonomic names for the compounds in question. Nomenclature for post-translational modifications also follows the IUPAC precedent, as well as the cyclic peptide literature. Furthermore, the proposed system aims to maintain agreement with the precedents set by the pre-existing literature. An example of the proposed nomenclature is provided using the methioninecontaining homodetic peptides of Linum usitatissimum (flaxseed).
T
an and Zhou1 classified cyclic peptides of plants into eight types based on chemical structures (Figure 1). Type VI (Caryophyllaceae-type cyclopeptides) peptides are cyclic compounds that contain amino acids that are cyclized by
fusion of the terminal amino and carboxy residues in a peptide bond. In contrast, cyclotides (Type VIII) are cyclized by both the fusion of the terminal amino and cysteine double bonds. Recently, Covello et al.2 published the RNA sequences of peptides from plants of the Caryophyllaceae and Rutaceae demonstrating clearly the ribosomal synthesis of Type VI peptides and the fact that post-translational modifications take place.2 In a review of peptide nomenclature it was proposed that the Type VI peptides be collectively termed orbitides.3 By definition, orbitide precursor proteins are encoded in plant DNA, are transcribed and translated, and undergo posttranslational modification and cyclization to form N-terminal to C-terminal covalent bonds. DNA and RNA sequences encoding orbitides have been confirmed in the Rutaceae, Caryophyllaceae, Linaceae, and Euphorbiaceae.2−4 Orbitide sequences from Linaceae were presented in a patent application2 and a peer-reviewed publication,4 while the precursor sequences of Jatropha were included in the review of Arnison et al.3 Of the 102 Type VI peptides presented in the cybase database (http://cybase.org.au), 78 are either known to
Figure 1. Classification of plant cyclopeptides modified from Tan and Zhou1 and Shim et al.5 © 2015 American Chemical Society and American Society of Pharmacognosy
Received: October 13, 2014 Published: March 18, 2015 645
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heterophylla are known both as heterophyllins and pseudostellarins. A letter is included in most Type VI compound names, reflecting the order of discovery of orbitides from the same species. However, Roman numerals following the peptide name have also been used (e.g., citrusin I). The letters and numbers can cause confusion if different authors use the same symbols for different compounds. For example, cyclolinopeptides J and K were first defined as the sequences cyclo-(MetO2-Leu-ValPhe-Pro-Leu-Phe-Ile) and cyclo-(MetO2-Leu-Ile-Pro-Pro-PhePhe-Val-Ile).6 Subsequently, the compounds cyclo-(Pro-LeuPhe-Ile-Met-Leu-Val-Phe) and cyclo-(Pro-Phe-Phe-Trp-IleMet-Leu-Leu) were, respectively, referred to as cyclolinopeptides J and K.7 Peptide amino acid sequences are typically reported in the order that they occur in MS/MS fragmentation. When proline is present in Type VI peptides, it is often reported to be at the peptide N-terminal (64/102 peptides reported on http://www. cybase.org.au, cybase). However, 25 of 102 peptides lacked proline altogether (cybase). Glycine is reported as the first amino acid in 32 Type VI peptides described in cybase. Orbitides that are reported to begin with glycine fragment during MS/MS with glycine as the N-terminal of the parent ion. These orbitides lack proline residues. A small subset of these compounds has been renumbered based on DNA sequences that place glycine at the N-terminal of the encoded precursor.3 The nonsystematic nomenclature for the Type VI orbitides can lead to ambiguities and needs standardization. One example of a consistent nomenclatural system for a complex array of molecules is the IUPAC Nomenclature for Natural Products. In this article, we propose a more systematic nomenclature for naming the Type VI orbitides. The proposed nomenclature retains most of the features of previously published orbitides to maintain continuity with pre-existing literature, but also borrows from IUPAC and UniProt to develop a systematic naming system. We also demonstrate how the proposed nomenclature can help identify orbitides yet to be observed by mass spectrometry, by giving them a meaningful nomenclature and numbering that is consistent with those already discovered. This demonstration will use the already published flax genome sequence and orbitides.
be orbitides or likely to be orbitides, as they occur in plant families that are known to produce orbitides.5 Considerable precedence is provided in the literature for naming of orbitides from a wide variety of plant sources (Table 1). Authors have used various strategies to derive unique Table 1. Current Nomenclature for Type VI Peptides
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a
Common name: satsuma mandarin. bFormer species name indicated as follows: Clerodendrum myricoides. cFormer species name indicated as follows: Pseudostellaria heterophylla. dFormer species name indicated as follows: Vaccaria segetalis.
RESULTS AND DISCUSSION
As described in the introduction, the Type VI peptide names are in disarray. The use of a systematic nomenclature will allow researchers to avoid confusion and duplicated research efforts, allow differentiation between similar orbitides, and provide specificity to discriminate between orbitides with different amino acid sequences and post-translational modifications, and finally could provide structural and species-origin information in a precise manner. Additionally, the proposed nomenclature should also maintain features of nomenclature from the current literature to retain continuity with previous naming systems. We propose a systematic nomenclature for the Type VI cyclic peptides that draws from three sources, specifically, IUPAC,8 UniProt (http://www.uniprot.org), and the recent review by Arnison et al.3 The IUPAC Nomenclature for Natural Products supports the use of taxonomic names for the development of compound trivial names, while UniProt utilizes standard organism names as well as organism mnemonics in the naming of proteins.
orbitide names. Virtually all nomenclature includes reference to the taxonomic name of the source plant. Use of the Linnaeus genus name in the naming of orbitides is common (e.g., microtoenin A from Microtoena prainiana), as is the use of species names (e.g., pohlianin A from Jatropha pohliana) and the use of genus and species names together (e.g., annomuricatin A from Annona muricata). At least one peptide name, labatidin from Jatropha multif ida, appears to be based on the given name of the discoverer, Labadie. Other examples of Type VI peptide nomenclature include reference to the cyclic nature of the compound. This appellation has been included both before (e.g., cyclolinopeptide) and after (e.g., curcacycline) the taxonomic name portion of the name. Occasionally orbitides from one species have received more than one type of name. As an example, the orbitides of Pseudostellaria 646
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Table 2. Elements of Orbitide Names
a Proposed orbitide name: [1−#-NαC] (red), linkage occurs between amino acid 1 and amino acid “#” through the α-amino group that is a N-C cyclization of the core peptide. Use the en dash (−) as in ranges and place in square brackets; [#-Xaa,#-Xaa] (green), methionine S-oxide has a chiral sulfur. Two diastereomers are designated as Ss and Rs. Identical amino acid substituents are numbered and grouped; lin- (maroon), genus name is recognized by three letters or from UniProt list; -us- (orange), species name is recognized by 2 letters or name from UniProt list; -orb (blue), common suffix for orbitide. bName used in first literature description. cThe methionine residues of amino acid sequences are highlighted in Figure 2. Abbreviations of the methionine residues are MetO for methionine S-oxide and MetO2 for methionine S,S-dioxide. dAFSQ01016651.1. e AFSQ01011783.1 and AFSQ01009065.1. fAFSQ01016651.1.
[1−#‐NαC ],[#‐Xaa, #‐Xaa]‐linusorb #
using abbreviations found in UniProt and IUPAC. A comma separates multiple post-translational modifications. Taxonomic Name Abbreviation -linus. The first three letters of the genus name and first two letters of the species name are used to identify the origin of the orbitide. This is based on the list of species maintained by UniProt (http:// www.uniprot.org/docs/speclist). Common Suffix (-orb). Short for orbitide.
(1)
Linkage [1−#-NαC]. This occurs between amino acid 1 and amino acid “#” through the α-amino group that is a N-C cyclization of the core peptide. The en dash (−) is used and placed in square brackets. Modifications [#-Xaa,#-Xaa]. The notation utilizes a prefix code of 3, 4 characters. It specifies the position and type of modified amino acid(s) in the peptide. Each modified amino acid is identified by its position in the core peptide sequence 647
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Figure 2. Structures of linusorbs A−E. Abbreviations are Ile for isoleucine, Gly for glycine, Met for methionine, MetO for methionine S-oxide, and MetO2 for methionine S,S-dioxide. Predicted products of NCBI genes: AFSQ01025165.1 (1−11, blue, g38655), AFSQ01016651.1 (12−18 and 22− 28, green, g24175), AFSQ01016651.1 (19, 20, pink, g24174), AFSQ01011783.1 (21, yellow, g16701), and AFSQ01009065.1 (21, yellow, g12294).
Amino Acid Residue Numbering (#). Residue numbering begins at the N-terminal-most amino acid residue of the orbitide, based on DNA sequence. Notation for any posttranslational modifications starts with the lowest number and proceeds to the highest number. Where multiple identical modifications are present, they are grouped together as illustrated for Met groups in [1−8-NαC],[1,3-(Rs,Ss)-MetO]linusorb A1 (Table 2 and Figure 2; formerly cyclolinopeptide G, CLG). This more descriptive name for CLG reflects the complexity of fully and appropriately naming these compounds as they contain the chiral amino acid methionine S-oxide.
Clearly, what was formerly recognized as CLG is actually four distinct compounds.9 New full names for all “cyclolinopeptide” variants are suggested in Table 2. Use of Abbreviated Taxonomic Name for Orbitides. The use of a systematic mnemonic based on taxonomic name is particularly important, as a high degree of structural and sequence diversity has been observed in orbitides from closely related species. This structural and sequence diversity demands that a broad range of different names be utilized. That is, if the orbitide sequences are different between closely related species, the names of the orbitides present in each should also reflect 648
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Table 3. UniProt List of Species That Produce Type VI Peptides and Recommended Peptide Nomenclature
a UniProtKB user manual for a description of the rules followed for the creation of the organism (species) identification codes. Species list taken from http://www.uniprot.org/docs/speclist. bThe letter “E” that follows each code indicates which taxonomic “kingdom” an organism belongs to. E = eukaryota (=eukarya). cThe one- to six-digit number is used to indicate to which taxonomic node in the NCBI taxonomy an organism is assigned. d Proposed root peptide name. eNR: not reported.
this difference. Differentiating orbitide names based on their species of origin will take advantage of an already existing distinction between species that allows discrimination between them without the need to invent a new system. Furthermore, the relationships between species could be supported by conservation of the orbitide sequence or orbitide precursor sequence. It is anticipated that by conservation of specific orbitide sequences in related species or through convergent evolution that some orbitides will occur in more than one species. This occurrence is likely rare due to the large number of possible orbitides and the observation that there has not yet been an orbitide observed that occurs in more than one species. To be consistent with the current practice, when identical orbitides are discovered that share a fundamental parent skeleton, we suggest that the name given to the first orbitide discovered will take precedence over any later discoveries of orbitides arising from the same sequence. The precedence for naming compounds based on their taxonomic name comes from the IUPAC Natural Products nomenclature,10 which recommends that trivial names should be based on the taxonomic (family or genus or species name) designation of the biological material from which the compound has been isolated. Furthermore, it is not recommended that presumed or real metabolic activity be used in nomenclature of natural products. Where the known or likely distribution of a natural product is available it is recommended that this is used in the nomenclature. An additional precedent for including taxonomic names in the name of Type VI peptides lies with the UniProt nomenclature for ribosomally synthesized peptides. A list of species curated by UniProt is available online at http://www. uniprot.org/docs/speclist (Table 3). The mnemonics available through UniProt appear to be compatible with IUPAC. Although substantial variation in orbitides from members of the same genus is possible, a large number of mnemonic designations are also possible (Table 4). Organism identification codes of five characters are used in the UniProt Knowledgebase (UniProtKB) entry names. This code includes the first three letters of the genus name followed by the first
Table 4. Recommended UniProt-like Mnemonics for Naming Peptides
two letters of the species name. UniProt also maintains a controlled vocabulary of species from which nonredundant identification of species names may be developed. We suggest that orbitide precursor peptide and orbitide nomenclature include the UniProt conventions. Table 2 provides a list of recommended root names for orbitides. Inclusion of Post-translational Modifications in the Orbitide Name. The other component of the proposed nomenclature is categorization of post-translational modifications. IUPAC recommends naming peptides with modified, substituted, inserted, or deleted amino acids with an appropriate abbreviation. We can use the IUPAC recommendation for naming of oxidation variants of sulfur-containing amino acids as an example: MetO and MetO2 as abbreviations for methionine S-oxide and methionine S,S-dioxide, respectively. Further suggested abbreviations for possible use are provided in file S1 of the Supporting Information.11 Thus, [1− 8-NαC]-linusorb A2 becomes [1−8-NαC],[1-(Rs,Ss)-MetO]linusorb A2 and [1−8-NαC],[1-MetO2]-linusorb A2 upon a single and double oxidation of the sulfur atom on the methionine, respectively. A database of naturally occurring modifications is curated and available through UniProtKB (http://www.uniprot.org/docs/speclist). Arnison et al. developed and reported a shorthand linear notation for ribosomally 649
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Table 5. Propeptide Sequences of Flax Linusorbs A−Ea
a
The ribosomally synthesized and post-translationally modified core peptides putatively encoding {[1−8-NαC]-linusorb A1, MLMPFFWI; [1−8NαC]-linusorb A2, MLLPFFWI; [1−8-NαC]-linusorb A3, MLMPFFWV; [1−8-NαC]-linusorb B1, MLVFPLFI; [1−9-NαC]-linusorb B2, MLIPPFFVI; [1−9-NαC]-linusorb B3, ILVPPFFLI; [1−9-NαC]-linusorb C1, MLKPFFFWI; [1−9-NαC]-linusorb D1, GIPPFWLTL; [1−9-NαC]linusorb E1, GMLVFPLFI; [1−10-NαC]-linusorb E2, GMLIPPFFVI; and [1−10-NαC]-linusorb E3, GILVPPFFLI}12 are highlighted in black. The proteins comprise a signal sequence (gray) and a leader sequence as a pro-region (yellow). Underlined text is a conserved portion of leader sequence. An N-terminal region (pink) is characterized by the presence of three to five acidic residues. A C-terminal region (cyan) follows each core peptide. The region between the N- and C-terminal repeated sequences is a more variable sequence (bright green). The repeat region(s) is followed at the Cterminal end by a nonconserved domain (olive green).
synthesized peptides.3 The relevant abbreviations for the proposed orbitide nomenclature specifically are shown in Table 2, Figure 2, and file S1 of the Supporting Information. Many peptide researchers have not adopted the IUPAC nomenclature, and in the recent review by Arnison et al.3 both designations for Met oxidation products were recommended. We acknowledge that the conflicting nomenclature adopted by Arnison et al.3 was a compromise and recommend, with our proposed systematic nomenclature, that the IUPAC/UniProt convention be used to name peptides. Fundamental Parent Structures. The use of fundamental parent structures that describe the skeleton of molecules and exclude nonterminal heteroatoms and heterogroups in nomenclature is necessary to limit the proliferation of natural product trivial names. It is necessary to name orbitides with a fundamental name that is based on a common cyclic amino acid sequence to be consistent with this principle of good nomenclature. IUPAC recommends that natural products be named using a fundamental parent structure and supplies rules for selection and nomenclature of such.10 Orbitide nomenclature of flaxseed orbitides has not used this principle. The sulfur atoms of methionine in these orbitides are not terminal heteroatoms. Where the sulfur of methionine becomes oxidized, the introduced heteroatoms in the resulting compounds are in terminal positions with respect to their parent structure. Orbitide variants containing methionine
substituted with MetO and MetO2 are products of the same fundamental parent structure and thus should have a common designation based on the skeleton. The proliferation of named variants of flaxseed orbitides, in which there are several orbitides with readily oxidized methionine, is an example of the effects of not using a fundamental parent structure as the basis of the name. IUPAC recommends that compounds with a shared skeleton have a common name and that the variants be named using “well-defined operations and principles of organic nomenclature”. We suggest that both gene sequence and physical evidence be required before declaring that a peptide be categorized as an orbitide. Gene sequence evidence of orbitide genes includes DNA or mRNA sequence as confirmation, while physical evidence consists of detection of orbitide ions by mass spectrometry and/or other techniques (such as HPLC or Xray crystallography). The presence of a DNA sequence in a genome that appears to code for an orbitide that has homology to existing orbitides is not sufficient to definitively categorize an orbitide, as this information does not provide information about the post-translational modifications that would lead to an orbitide. Furthermore, evidence of mRNA and precursor peptide formation is insufficient to confirm the presence of a cyclic product. Similarly, chemical evidence demonstrating the presence of a NαC-linked peptide composed of proteinogenic amino acids is not sufficient, as this datum does not provide 650
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sufficiently robust to allow naming of products of alternate routes of cyclization in the formation of orbitides.
information that will allow the numbering of amino acid residues in the orbitide. Furthermore, it is possible that nonribosomal synthesis may still be possible for some Type VI peptides. Identification of an Orbitide. Simple MS providing the empirical formulas of compounds is not adequate for identification of a compound. In a single-stage MS, the molecular ion should have a mass of 18 (H2O) less than the respective uncyclized linear peptide. MS/MS fragment analysis of a parent ion is a minimal requirement, though multiple modes of fragmentation can confuse the determination of sequence. Nuclear magnetic resonance (NMR) spectroscopic analysis can afford a complete solution structure and may definitively prove a peptide as NαC linked.12 NMR analysis requires substantial amounts of peptide. Where crystallization is possible, X-ray crystallography provides the best opportunity to define the covalent linkages present in a molecule. Unfortunately large amounts of orbitide could be required for definitive NMR or the production of crystals. Various methods of chemical structure analysis may not provide unambiguous data. MS alone cannot discern amino acid enantiomers present in a peptide, while interpretation of NMR data can be difficult in molecules that are not rigid or have redundant structures often found in orbitides. MS can differentiate between leucine and isoleucine fragments of immonium ions.13 Only a combination of physical proof of an orbitide and an orbitide gene, transcript, or precursor peptide can be considered unequivocal. Other lines of evidence that would make an orbitide designation appear likely include the relation of the peptide-producing species to a species that produces orbitides or the ability of cellfree extracts of an organism to convert a precursor peptide to a NαC-linked peptide (Table 5). Multistage mass spectrometry of cyclic peptides is inherently complex, but progress has been made in interpreting their spectra. New algorithms have been developed for interpreting the MS/MS spectra of cyclic peptides of both ribosomal and nonribosomal origin by Mohimani et al.14 and Kavan et al.15 One program elucidated the structure of 11 dianthins, of which five were previously reported, and six new compounds, likely orbitides, were partially sequenced. The authors noted that previous studies described just one cyclic peptide, but their study showed the ability of using mass tags and suitable algorithms led to the full or partial identification of 31 compounds. The authors recommended the development of large data sets of annotated spectra of cyclic peptides. Although it has not been observed, it is feasible that some orbitides are chimeric and produced by concatenation and cyclization of peptides from different domains or proteins. This has been observed for θ-defensins.16 Nomenclature of chimeric orbitides is possible using the attached proposal, but numbering of the amino acids would require the adaptation of this nomenclatural system. Recently, we have reported that flaxseed orbitide precursor proteins can be cyclized to include different N-termini.17 As the alternate cyclization leads to new parent structures, we have given the products of this cyclization a new designation, linusorb E. In conclusion, a series of publications on the peptides arising from flax have exposed the lack of rigor in orbitide nomenclature. Recommendations are provided for the numbering of these compounds based on the sequence found in their precursor proteins. A complete nomenclature and numbering system is provided for future naming of cyclic peptides of flax and other species. The nomenclatural system is
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EXPERIMENTAL SECTION
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
Identification Methods. NMR Spectroscopy. Proton NMR spectra were recorded on a 500 MHz Bruker Avance spectrometer (inverse triple resonance probe, TXI, 5 mm; XWIN-NMR 3.5 software). The 1H NMR spectra (500 MHz) chemical shift (δ) values are reported in parts per million (ppm) relative to the internal standard TMS. HPLC/MS. An Agilent high-pressure liquid chromotography (HPLC, 1200 series) equipped with a quaternary pump, an autosampler, a DAD (190−300 nm), and a degasser directly connected to a Bruker micrOTOF-Q II mass spectrometer (Hybrid Quadrupole-TOF MS/ MS; Bruker, Bremen, Germany) with Apollo II ESI ion source (operated with nebulizer gas at 4.0 bar and dry gas temperature held at 200 °C) was used in HPLC/MS analysis. A Chromolith FastGradient RP-18e column (3 μm particle size silica, 50 × 2.0 mm i.d., Merck KGaA, Darmstadt, Germany) was used to separate compounds prior to MS analysis. The mobile phase consisted of a linear gradient of 0.1% (v/v) formic acid in water and 0.1% (v/v) formic acid in acetonitrile (60:40 for 2 min, to 10:90 in 8 min, to 60:40 in 0.5 min, to equilibration for 5.5 min), with a flow rate of 0.40 mL/min. Search Parameters. Linum usitatissimum DNA Sequences. A database search of a developing flaxseed expressed sequence tag (EST) library was screened, with putative DNA sequences comprising known orbitides identified in Covello et al.2 The EST sequence was used as a query to search the putative flax proteome archived in GenBank using BLASTx 2.2.22+.18 The genomic DNA sequences of four genes (AFSQ01025165.1, AFSQ01016651.1, AFSQ01011783.1, and AFSQ01009065.1) were identified.19 S Supporting Information *
Supplemental file: [8-citrulline] vasopressin, [Cit8] vasopressin; [5-isoleucine, 7-alanine] angiotensin I, [Ile5, A1a7] angiotensin I (file S1). This material is available free of charge via the Internet at http://pubs.acs.org. Corresponding Authors
*(Y. Y. Shim) Tel: +1 306 9665050. Fax: +1 306 9665015. Email:
[email protected]. *(M. J. T. Reaney) Tel: +1 306 9665027. Fax: +1 306 9665015. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Strategic Research Program and Agriculture Development Funds (Projects 20080205, 20120099, and 20120146) of the Saskatchewan Ministry of Agriculture, Genome Canada, Total Utilization Flax GENomics (TUFGEN), and Canadian Foundation for Innovation (CFI 23426).
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REFERENCES
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