Structural highlights
Publication Abstract from PubMed
The first example of an ammonium derivative that causes a specific modification of the active site of type I dehydroquinase (DHQ1), a dehydratase enzyme that is a promising target for anti-virulence drug discovery, is described. The resolution at 1.35 A of the crystal structure of DHQ1 from Salmonella typhi chemically modified by this ammonium derivative revealed that the ligand is covalently attached to the essential Lys170 through the formation of an amine. The detection by mass spectroscopy of the reaction intermediates, in conjunction with the results of Molecular Dynamics simulations, allowed us to explain the inhibition mechanism and the experimentally observed differences between Salmonella typhi and Staphylococcus aureus en-zymes. The results presented here reveal that the replacement of Phe225 in St-DHQ1 by Tyr214 in Sa-DHQ1 and its hydrogen bonding interaction with the conserved water molecule observed in several crystal structures protects the amino adduct against further dehydration/aromatization reactions. In contrast, for the St-DHQ1 enzyme, the carboxylate group of Asp114, with the assistance of this water molecule, would trigger the formation of a Schiff base that can undergo further dehydration reactions until full aromatization of the cyclohexane ring is achieved. Moreover, in vitro anti-virulence studies showed that the reported compound is able to reduce the ability of Salmonella Enteritidis to kill A459 respiratory cells. These studies have identified a good scaffold for the design of irreversible inhibitors that can be used as drugs and has opened up new opportunities for the development of novel anti-virulence agents by targeting the DHQ1 enzyme.
Chemical Modification of a Dehydratase Enzyme Involved in Bacterial Virulence by an Ammonium Derivative: Evidence of its Active Site Covalent Adduct.,Gonzalez-Bello C, Tizon L, Lence E, Otero JM, Raaij MJ, Martinez-Guitian M, Beceiro A, Thompson P, Hawkins AR J Am Chem Soc. 2015 Jul 6. PMID:26148116[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gonzalez-Bello C, Tizon L, Lence E, Otero JM, Raaij MJ, Martinez-Guitian M, Beceiro A, Thompson P, Hawkins AR. Chemical Modification of a Dehydratase Enzyme Involved in Bacterial Virulence by an Ammonium Derivative: Evidence of its Active Site Covalent Adduct. J Am Chem Soc. 2015 Jul 6. PMID:26148116 doi:http://dx.doi.org/10.1021/jacs.5b04080
