Aspartic Acid Isomerization Characterized by High Definition Mass Spectrometry Significantly Alters the Bioactivity of a Novel Toxin from <i>Poecilotheria</i>
Research in toxinology has created a pharmacological paradox. With an estimated 220,000 venomous animals worldwide, the study of peptidyl toxins provides a vast number of effector molecules. However, due to the complexity of the protein-protein interactions, there are fewer than ten venom-derived mo...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-03-01
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| Series: | Toxins |
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| Online Access: | https://www.mdpi.com/2072-6651/12/4/207 |
| _version_ | 1817987823402221568 |
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| author | Stephen R. Johnson Hillary G. Rikli |
| author_facet | Stephen R. Johnson Hillary G. Rikli |
| author_sort | Stephen R. Johnson |
| collection | DOAJ |
| description | Research in toxinology has created a pharmacological paradox. With an estimated 220,000 venomous animals worldwide, the study of peptidyl toxins provides a vast number of effector molecules. However, due to the complexity of the protein-protein interactions, there are fewer than ten venom-derived molecules on the market. Structural characterization and identification of post-translational modifications are essential to develop biological lead structures into pharmaceuticals. Utilizing advancements in mass spectrometry, we have created a high definition approach that fuses conventional high-resolution MS-MS with ion mobility spectrometry (HDMS<sup>E</sup>) to elucidate these primary structure characteristics. We investigated venom from ten species of “tiger” spider (Genus: <i>Poecilotheria</i>) and discovered they contain isobaric conformers originating from non-enzymatic <i>Asp</i> isomerization. One conformer pair conserved in five of ten species examined, denominated PcaTX-1a and PcaTX-1b, was found to be a 36-residue peptide with a cysteine knot, an amidated C-terminus, and <i>isoAsp</i>33<i>Asp</i> substitution. Although the isomerization of <i>Asp</i> has been implicated in many pathologies, this is the first characterization of <i>Asp</i> isomerization in a toxin and demonstrates the isomerized product’s diminished physiological effects. This study establishes the value of a HDMS<sup>E</sup> approach to toxin screening and characterization. |
| first_indexed | 2024-04-14T00:27:02Z |
| format | Article |
| id | doaj.art-032124469a6544bf8fa370a5348d193e |
| institution | Directory Open Access Journal |
| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-04-14T00:27:02Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxins |
| spelling | doaj.art-032124469a6544bf8fa370a5348d193e2022-12-22T02:22:41ZengMDPI AGToxins2072-66512020-03-0112420710.3390/toxins12040207toxins12040207Aspartic Acid Isomerization Characterized by High Definition Mass Spectrometry Significantly Alters the Bioactivity of a Novel Toxin from <i>Poecilotheria</i>Stephen R. Johnson0Hillary G. Rikli1Carbon Dynamics Institute LLC, Sherman, IL 62684, USACollege of Liberal Arts & Sciences, University of Illinois Springfield, Springfield, IL 62703, USAResearch in toxinology has created a pharmacological paradox. With an estimated 220,000 venomous animals worldwide, the study of peptidyl toxins provides a vast number of effector molecules. However, due to the complexity of the protein-protein interactions, there are fewer than ten venom-derived molecules on the market. Structural characterization and identification of post-translational modifications are essential to develop biological lead structures into pharmaceuticals. Utilizing advancements in mass spectrometry, we have created a high definition approach that fuses conventional high-resolution MS-MS with ion mobility spectrometry (HDMS<sup>E</sup>) to elucidate these primary structure characteristics. We investigated venom from ten species of “tiger” spider (Genus: <i>Poecilotheria</i>) and discovered they contain isobaric conformers originating from non-enzymatic <i>Asp</i> isomerization. One conformer pair conserved in five of ten species examined, denominated PcaTX-1a and PcaTX-1b, was found to be a 36-residue peptide with a cysteine knot, an amidated C-terminus, and <i>isoAsp</i>33<i>Asp</i> substitution. Although the isomerization of <i>Asp</i> has been implicated in many pathologies, this is the first characterization of <i>Asp</i> isomerization in a toxin and demonstrates the isomerized product’s diminished physiological effects. This study establishes the value of a HDMS<sup>E</sup> approach to toxin screening and characterization.https://www.mdpi.com/2072-6651/12/4/207voltage-gated sodium channelvenom<i>poecilotheria</i>poecilotheriatoxindeamidationisomerizationhigh definition mass spectrometryion mobilitysupplemental activation |
| spellingShingle | Stephen R. Johnson Hillary G. Rikli Aspartic Acid Isomerization Characterized by High Definition Mass Spectrometry Significantly Alters the Bioactivity of a Novel Toxin from <i>Poecilotheria</i> Toxins voltage-gated sodium channel venom <i>poecilotheria</i> poecilotheriatoxin deamidation isomerization high definition mass spectrometry ion mobility supplemental activation |
| title | Aspartic Acid Isomerization Characterized by High Definition Mass Spectrometry Significantly Alters the Bioactivity of a Novel Toxin from <i>Poecilotheria</i> |
| title_full | Aspartic Acid Isomerization Characterized by High Definition Mass Spectrometry Significantly Alters the Bioactivity of a Novel Toxin from <i>Poecilotheria</i> |
| title_fullStr | Aspartic Acid Isomerization Characterized by High Definition Mass Spectrometry Significantly Alters the Bioactivity of a Novel Toxin from <i>Poecilotheria</i> |
| title_full_unstemmed | Aspartic Acid Isomerization Characterized by High Definition Mass Spectrometry Significantly Alters the Bioactivity of a Novel Toxin from <i>Poecilotheria</i> |
| title_short | Aspartic Acid Isomerization Characterized by High Definition Mass Spectrometry Significantly Alters the Bioactivity of a Novel Toxin from <i>Poecilotheria</i> |
| title_sort | aspartic acid isomerization characterized by high definition mass spectrometry significantly alters the bioactivity of a novel toxin from i poecilotheria i |
| topic | voltage-gated sodium channel venom <i>poecilotheria</i> poecilotheriatoxin deamidation isomerization high definition mass spectrometry ion mobility supplemental activation |
| url | https://www.mdpi.com/2072-6651/12/4/207 |
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