Structural highlights
Function
[TGT_ZYMMO] Exchanges the guanine residue with 7-aminomethyl-7-deazaguanine in tRNAs with GU(N) anticodons (tRNA-Asp, -Asn, -His and -Tyr). After this exchange, a cyclopentendiol moiety is attached to the 7-aminomethyl group of 7-deazaguanine, resulting in the hypermodified nucleoside queuosine (Q) (7-(((4,5-cis-dihydroxy-2-cyclopenten-1-yl)amino)methyl)-7-deazaguanosine).[HAMAP-Rule:MF_00168]
Publication Abstract from PubMed
The intestinal disease shigellosis caused by Shigella bacteria affects over 120 million people annually. There is an urgent demand for new drugs as resistance against common antibiotics emerges. Bacterial tRNA-guanine transglycosylase (TGT) is a druggable target and controls the pathogenicity of Shigella flexneri. We report the synthesis of sugar-functionalized lin-benzoguanines addressing the ribose-33 pocket of TGT from Zymomonas mobilis. Ligand binding was analyzed by isothermal titration calorimetry and X-ray crystallography. Pocket occupancy was optimized by variation of size and protective groups of the sugars. The participation of a polycyclic water-cluster in the recognition of the sugar moiety was revealed. Acetonide-protected ribo- and psicofuranosyl derivatives are highly potent, benefiting from structural rigidity, good solubility, and metabolic stability. We conclude that sugar acetonides have a significant but not yet broadly recognized value in drug development.
Sugar Acetonides are a Superior Motif for Addressing the Large, Solvent-Exposed Ribose-33 Pocket of tRNA-Guanine Transglycosylase.,Movsisyan LD, Schafer E, Nguyen A, Ehrmann FR, Schwab A, Rossolini T, Zimmerli D, Wagner B, Daff H, Heine A, Klebe G, Diederich F Chemistry. 2018 Jul 11;24(39):9957-9967. doi: 10.1002/chem.201801756. Epub 2018, Jun 25. PMID:29939431[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Movsisyan LD, Schafer E, Nguyen A, Ehrmann FR, Schwab A, Rossolini T, Zimmerli D, Wagner B, Daff H, Heine A, Klebe G, Diederich F. Sugar Acetonides are a Superior Motif for Addressing the Large, Solvent-Exposed Ribose-33 Pocket of tRNA-Guanine Transglycosylase. Chemistry. 2018 Jul 11;24(39):9957-9967. doi: 10.1002/chem.201801756. Epub 2018, Jun 25. PMID:29939431 doi:http://dx.doi.org/10.1002/chem.201801756
