Molecular recognition of tyrosinyl adenylate analogues by prokaryotic tyrosyl tRNA synthetases

Brown, Pamela; Richardson, Christine M.; Mensah, Lucy; O’Hanlon, Peter J.; Osborne, Neal F.; Pope, Andrew J.; Walker, Graham C.

doi:10.1016/s0968-0896(99)00192-3

Cited by 51 publications

(22 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given that N-acylsulfonamide derivatives are high-affinity, slow-binding inhibitors of isoleucyl-tRNA synthetases (158)(159)(160) and have "drug-like" physical properties (161,162), a sulfonamide analog of the βAspAMP intermediate (6) (Figure 6) was also prepared and characterized for its ability to inhibit recombinant, wild-type human ASNS (24). These in vitro experiments clearly showed that sulfonamide derivative 6 is a slow-onset, tight-binding inhibitor that interacts with the free enzyme, and revealed the importance of carboxyl and amino groups in the recognition and binding of this class of βAspAMP analog.…”

Section: Sulfonamide Derivatives As Inhibitors Of Human Asparagine Symentioning

confidence: 99%

Asparagine Synthetase Chemotherapy

Richards

Kilberg

2006

Annu. Rev. Biochem.

204

221

View full text Add to dashboard Cite

Modern clinical treatments of childhood acute lymphoblastic leukemia (ALL) employ enzymebased methods for depletion of blood asparagine in combination with standard chemotherapeutic agents. Significant side effects can arise in these protocols and, in many cases, patients develop drug-resistant forms of the disease that may be correlated with up-regulation of the enzyme glutamine-dependent asparagine synthetase (ASNS). Though the precise molecular mechanisms that result in the appearance of drug resistance are the subject of active study, potent ASNS inhibitors may have clinical utility in treating asparaginase-resistant forms of childhood ALL. This review provides an overview of recent developments in our understanding of (a) the structure and catalytic mechanism of ASNS, and (b) the role that ASNS may play in the onset of drug-resistant childhood ALL. In addition, the first successful, mechanism-based efforts to prepare and characterize nanomolar ASNS inhibitors are discussed, together with the implications of these studies for future efforts to develop useful drugs.

show abstract

Section: Sulfonamide Derivatives As Inhibitors Of Human Asparagine Symentioning

confidence: 99%

Asparagine Synthetase Chemotherapy

Richards

Kilberg

2006

Annu. Rev. Biochem.

204

221

View full text Add to dashboard Cite

show abstract

“…It belongs to a group of synthetic aminoacyl adenylates called aminoacylsulfamoyladenosines in which the labile mixed anhydride function of the aminoacyladenylate intermediate in the aminoacylation reaction is replaced by an isosteric, nonhydrolyzable sulfamoyl group (84). Glu-SA is a strong competitive inhibitor of the E. coli GluRS (K i ϭ 2.8 nM) but is a weaker competitive inhibitor of mammalian (mouse liver) GluRS (K i ϭ 70 nM) (59).…”

Section: Substrate Ppasementioning

confidence: 99%

A Nondiscriminating Glutamyl-tRNA Synthetase in the Plasmodium Apicoplast

Mailu

Ramasamay

Mudeppa

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Plasmodium apicoplast protein synthesis is essential, but few apicoplast tRNA synthetases have been characterized. Results: Apicoplast glutamyl-tRNA synthetase aminoacylates tRNA Glu and tRNA Gln , is sensitive to a bacterial inhibitor, and is essential in blood stages. Conclusion: Formation of apicoplast Gln-tRNAGln is via indirect aminoacylation. Significance: We demonstrate that the apicoplast glutamyl-tRNA synthetase is a potential drug target.

show abstract

“…The acylsulfamate linkage, inspired from the natural product ascamycin 11 [28] has been extensively employed as a stable bioisostere of the labile acylphosphate linkage for the development of aaRS inhibitors (Figure 14.5) [29][30][31][32][33][34][35][36]. These inhibitors typically provide potent inhibition of the corresponding aaRSs.…”

Section: Background Of Siderophores: Molecular Target and Rationale Fmentioning

confidence: 99%

“…The high activity of acylsulfamide 14 was unexpected as this function has not been well tolerated with the related aminoacyl tRNA synthetases, typically resulting in greater than a 1000-fold loss in binding affinity [32,33]. Replacement of the central nitrogen atom of acylsulfamide 14 by a carbon atom in b-ketosulfonamide 16 resulted in a profound 870-fold loss in binding affinity (16 versus 14), while substitution with a CF 2 group in 17 led to more than a 20 000-fold loss of activity.…”

Section: Nature Of the Linkermentioning

confidence: 99%