A single amino acid determines the toxicity of Ginkgo biloba extracts
Open Access
- 17 January 2012
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 26 (5), 1884-1891
- https://doi.org/10.1096/fj.11-192765
Abstract
Ginkgo biloba extracts are currently used for a wide range of health-related conditions. Some of the medical benefits of these extracts are controversial, but their lack of toxicity in humans is not in doubt. These extracts are, however, highly toxic to insects. Their active components (ginkgolides and bilobalide) have structures similar to the convulsant picrotoxin, a GABAA receptor antagonist, so their lack of toxicity in mammals is puzzling. Here, we show that the different compositions of insect and vertebrate GABA receptor pores are responsible for the differing toxicities. Insect GABA receptors contain Ala at their 2′ position in the pore. Substitution with Val, which is the equivalent residue in vertebrate GABAA receptor α-subunits, decreases ginkgolide potency by up to 10,000-fold. The reverse mutation in vertebrate GABAA α1 subunits increased the sensitivity of α1β2 and α1β2γ2 receptors to ginkgolides. Mutant cycle analysis demonstrates a strong interaction between the ginkgolides and the 2′ residue, a result supported by in silico docking of compounds into a model of the pore. We conclude that the insecticidal activity of G. biloba extracts can be attributed to their effects at insect GABA receptors, and the presence of a Val at the 2′ position in vertebrate GABAA receptors explains why these compounds are not similarly toxic to humans.—Thompson, A. J., McGonigle, I., Duke, R., Johnston, G. A. R., Lummis, S. C. R. A single amino acid determines the toxicity of Ginkgo biloba extracts. FASEB J. 26, 1884-1891 (2012). www.fasebj.orgKeywords
This publication has 27 references indexed in Scilit:
- Cysteine modification reveals which subunits form the ligand binding site in human heteromeric 5-HT3AB receptorsJournal Of Physiology-London, 2011
- Binding Sites for Bilobalide, Diltiazem, Ginkgolide, and Picrotoxinin at the 5-HT3 ReceptorMolecular Pharmacology, 2011
- Ginkgolide X Is a Potent Antagonist of Anionic Cys-loop Receptors with a Unique Selectivity Profile at Glycine ReceptorsOnline Journal of Public Health Informatics, 2010
- Pharmacokinetics of bilobalide, ginkgolide A and B after administration of three different Ginkgo biloba L. preparations in humansPhytotherapy Research, 2009
- Stoichiometric Pore Mutations of the GABAAR Reveal a Pattern of Hydrogen Bonding with PicrotoxinBiophysical Journal, 2008
- Stoichiometry of a pore mutation that abolishes picrotoxin‐mediated antagonism of the GABAA receptorJournal Of Physiology-London, 2006
- FUGUE: sequence-structure homology recognition using environment-specific substitution tables and structure-dependent gap penaltiesJournal of Molecular Biology, 2001
- Immunocytochemical mapping of a C-terminus anti-peptide antibody to the GABA receptor subunit, RDL in the nervous system of Drosophila melanogasterCell and tissue research, 1996
- Comparative Protein Modelling by Satisfaction of Spatial RestraintsJournal of Molecular Biology, 1993
- DRUG INTERACTIONS AT THE GABA RECEPTOR-IONOPHORE COMPLEXAnnual Review of Pharmacology and Toxicology, 1982