Tagetitoxin

Chemical structure

When TGT was first isolated, it was only partially characterized. The first proposed chemical structure of TGT involved an eight-membered ring, but this was revised shortly afterward to a bicyclic structure (shown at right) based on NMR and mass spectrometry. This structure, however, has been questioned. The absolute configuration remains undetermined, and attempts at confirming the structure by organic synthesis are underway. In 2015, Porter et al. proposed an alternative structure of TGT based on extensive 2D NMR data.

Mechanism of action

TGT interferes with development of chloroplasts in young plant leaves thereby causing chlorosis. The natural target of the toxin is chloroplast RNA polymerase. Chloroplast RNA polymerase belongs to ubiquitous family of multisubunit RNA polymerases (RNAP) and is most closely related to bacterial enzymes. In vitro, TGT inhibits bacterial RNAPs from Escherichia coli and Thermus thermophilus, and eukaryotic RNA polymerase III. In contrast, eukaryotic RNA polymerase I and II as well as single-subunit viral RNA polymerases are relatively insensitive to the compound. TGT binds in the bacterial enzyme's active site and inhibits initiation and elongation phases of transcription as well as pyrophosphorolysis of the nascent RNA. However, the detailed mechanism of inhibition remains a subject of heated debate.

It has been suggested that TGT forms a ternary RNAP-NTP-TGT complex and inhibits phosphodiester bond synthesis either by binding an inhibitory magnesium ion or by trapping a flexible active site domain in an inactive conformation. The third theory suggests that TGT forms predominantly a binary RNAP-TGT complex and inhibits RNAP translocation along the DNA by mimicking the transcription byproduct pyrophosphate.

References

References

1. (1978). "Apical chlorosis and leaf spot of ''Tagetes'' spp. Caused by ''Pseudomonas tagetis'' Hellmers". Australian Journal of Agricultural Research.
2. (1981). "Tagetitoxin, a toxin produced by ''Pseudomonas syringae'' pv. ''tagetis'': purification and partial characterization". Physiological Plant Pathology.
3. (1983). "The structure of tagetitoxin, a phytotoxin of Pseudomonas syringae pv. Tagetis". Phytochemistry.
4. (1989). "A revised structure for tagetitoxin". Tetrahedron Lett..
5. (2005). "Tagetitoxin purification and partial characterization". Physiol. Mol. Plant Pathol..
6. (2009). "Thieme Chemistry Journal Awardees - Where Are They Now? Approaches to Tagetitoxin and its Decarboxy Analogue from d-Glucose". Synlett.
7. (2008). "Synthesis of the Tagetitoxin Core via Photo-Stevens Rearrangement". Organic Letters.
8. (1996). "Dihydroxylation and oxidative cleavage of olefins in the presence of sulfur". Tetrahedron Lett..
9. (1999). "Synthesis studies of structural analogues of tagetitoxin: 2-phosphate". Tetrahedron.
10. (2006). "Synthesis of the bicyclic core of tagetitoxin". Chemical Communications.
11. (2012). "Inter- and intramolecular reactions of 1-deoxy-1-thio-1,6-anhydrosugars with α-diazoesters: synthesis of the tagetitoxin core by photochemical ylide rearrangement". Org. Biomol. Chem..
12. (September 2012). "Studies towards the total synthesis of tagetitoxin". University College London}}{{page needed.
13. (2015-12-15). "The structure of tagetitoxin". Organic & Biomolecular Chemistry.
14. (1985). "Tagetitoxin affects plastid development in seedling leaves of wheat". Planta.
15. (1990). "Tagetitoxin: A New Inhibitor of Eukaryotic Transcription by RNA Polymerase III". The Journal of Biological Chemistry.
16. (2005). "Structural basis for transcription inhibition by tagetitoxin". Nature Structural & Molecular Biology.
17. (2012). "The binding site and mechanism of the RNA polymerase inhibitor tagetitoxin: An issue open to debate". Transcription.
18. (2012). "Response to Klyuyev and Vassylyev: On the mechanism of tagetitoxin inhibition of transcription". Transcription.
19. (2011). "Tagetitoxin Inhibits RNA Polymerase through Trapping of the Trigger Loop". The Journal of Biological Chemistry.
20. (2012). "Active site opening and closure control translocation of multisubunit RNA polymerase". Nucleic Acids Research.