Anthranilate phosphoribosyltransferase: Binding determinants for 5′-phospho-alpha- d -ribosyl-1′-pyrophosphate (PRPP) and the implications for inhibitor design

Evans, G.L.; Furkert, Daniel P.; Abermil, Nacim; Kundu, Preeti; Lange, Katrina M. de; Parker, E.J.; Brimble, Margaret A.; Baker, Edward N.; Lott, J.S.

doi:10.1016/j.bbapap.2017.08.018

Cited by 7 publications

(24 citation statements)

References 60 publications

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“…Unless otherwise stated, all chemicals were obtained from Sigma-Aldrich, Scharlau, or Pure Science. The purification of Mtb -AnPRT, as well as the synthesis and biochemical characterization of its inhibitors annotated as 8i , 8j and 8k ( Table 2 ), are outlined in the article entitled “ Anthranilate phosphoribosyltransferase: Binding determinants for 5′-phospho-alpha- d- ribosyl-1′-pyrophosphate (PRPP) and the implications for inhibitor design” [1] .…”

Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

“…The experimental and data processing details for 3 new protein:ligand structures of Mycobacterium tuberculosis anthranilate phosphoribosyl transferase ( Mtb -AnPRT) are described herein ( Table 1 ). The protein structures are complexed with Mtb -AnPRT inhibitors characterized in [1] and annotated as: 8k (2-(2-carboxyphenylamino)-5-(5-phosphonopentyloxy)benzoic acid) 8j (2-(2-carboxyphenylamino)-5-(4-phosphonobutoxy)benzoic acid) 8i (2-(2-carboxyphenylamino)-5-(3-phosphonopropoxy)benzoic acid) …”

Section: Datamentioning

confidence: 99%

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Datasets, processing and refinement details for Mtb -AnPRT: inhibitor structures with various space groups

et al. 2017

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There are twenty-five published structures of Mycobacterium tuberculosis anthranilate phosphoribosyltransferase (Mtb-AnPRT) that use the same crystallization protocol. The structures include protein complexed with natural and alternative substrates, protein:inhibitor complexes, and variants with mutations of substrate-binding residues. Amongst these are varying space groups (i.e. P21, C2, P21212, P212121). This article outlines experimental details for 3 additional Mtb-AnPRT:inhibitor structures. For one protein:inhibitor complex, two datasets are presented – one generated by crystallization of protein in the presence of the inhibitor and another where a protein crystal was soaked with the inhibitor. Automatic and manual processing of these datasets indicated the same space group for both datasets and thus indicate that the space group differences between structures of Mtb-AnPRT:ligand complexes are not related to the method used to introduce the ligand.

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Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

Section: Datamentioning

confidence: 99%

Datasets, processing and refinement details for Mtb -AnPRT: inhibitor structures with various space groups

et al. 2017

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“…Both 11 and 12 are intermediates in the synthesis of inhibitors of Mycobacterium tuberculosis (Mtb) anthranilate phosphoribosyltransferase (AnPRT), which catalyzes a key step in the tryptophan biosynthesis pathway. Tryptophan biosynthesis is essential for Mtb pathogenesis and, therefore, is a target for the development of anti-Mtb drugs [44][45][46][47][48]. Oomycetes, including Phytophthora, also use an AnPRT for tryptophan biosynthesis [49].…”

Section: Resultsmentioning

confidence: 99%

Screening a Natural Product-Inspired Library for Anti-Phytophthora Activities

et al. 2021

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Phytophthora is a genus of microorganisms that cause devastating dieback and root-rot diseases in thousands of plant hosts worldwide. The economic impact of Phytophthora diseases on crops and native ecosystems is estimated to be billions of dollars per annum. These invasive pathogens are extremely difficult to control using existing chemical means, and the effectiveness of the few treatments available is being jeopardized by increasing rates of resistance. There is an urgent need to identify new chemical treatments that are effective against Phytophthora diseases. Natural products have long been regarded as “Nature’s medicine chest”, providing invaluable leads for developing front-line drugs and agrochemical agents. Here, we have screened a natural product-inspired library of 328 chemicals against two key Phytophthora species: Phytophthora cinnamomi and Phytophthora agathidicida. The library was initially screened for inhibition of zoospore germination. From these screens, we identified twenty-one hits that inhibited germination of one or both species. These hits were further tested in mycelial growth inhibition studies to determine their half-maximal inhibitory concentrations (IC50s). Four compounds had IC50 values of approximately 10 µM or less, and our best hit had IC50s of approximately 3 µM against both Phytophthora species tested. Overall, these hits may serve as promising leads for the development of new anti-Phytophthora agrochemicals

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“…In contrast, the anthranilate-like inhibitor ACS172 could bind in the S2 site, while 4FA could bind to two sites (S1 and S3) in MtbAnPRT (Castell et al, 2013;Cookson et al, 2014). Numerous studies have reported the importance of the conserved residue Asn141 for anthranilate binding in AnPRT proteins (Cookson et al, 2014(Cookson et al, , 2015Marino et al, 2006;Castell et al, 2013;Evans et al, 2018); thus, ScAnPRT Gly141Asn was co-crystallized with the substrate analogue 4FA. Consistent with native ScAnPRT, the substrate analogue 4FA also interacts with the conserved residue Arg197 via a hydrogen bond (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…GTGGD, NVST and KHGN (Kim et al, 2002;Lee et al, 2006;Marino et al, 2006). In addition, the AnPRT enzyme also contains a conserved DE motif that directly or indirectly interacts with magnesium ion (Evans et al, 2018;Kim et al, 2002;Lee et al, 2006;Mayans et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Crystal structures of anthranilate phosphoribosyltransferase from Saccharomyces cerevisiae

Zhang

Kuang

et al. 2021

Acta Crystallogr F Struct Biol Commun

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Anthranilate phosphoribosyltransferase (AnPRT) catalyzes the transfer of the phosphoribosyl group of 5′-phosphoribosyl-1′-pyrophosphate (PRPP) to anthranilate to form phosphoribosyl-anthranilate. Crystal structures of AnPRTs from bacteria and archaea have previously been determined; however, the structure of Saccharomyces cerevisiae AnPRT (ScAnPRT) still remains unsolved. Here, crystal structures of ScAnPRT in the apo form as well as in complex with its substrate PRPP and the substrate analogue 4-fluoroanthranilate (4FA) are presented. These structures demonstrate that ScAnPRT exhibits the conserved structural fold of type III phosphoribosyltransferase enzymes and shares the similar mode of substrate binding found across the AnPRT protein family. In addition, crystal structures of ScAnPRT mutants (ScAnPRTSer121Ala and ScAnPRTGly141Asn) were also determined. These structures suggested that the conserved residue Ser121 is critical for binding PRPP, while Gly141 is dispensable for binding 4FA. In summary, these structures improved the preliminary understanding of the substrate-binding mode of ScAnPRT and laid foundations for future research.

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Anthranilate phosphoribosyltransferase: Binding determinants for 5′-phospho-alpha- d -ribosyl-1′-pyrophosphate (PRPP) and the implications for inhibitor design

Cited by 7 publications

References 60 publications

Datasets, processing and refinement details for Mtb -AnPRT: inhibitor structures with various space groups

Datasets, processing and refinement details for Mtb -AnPRT: inhibitor structures with various space groups

Screening a Natural Product-Inspired Library for Anti-Phytophthora Activities

Crystal structures of anthranilate phosphoribosyltransferase from Saccharomyces cerevisiae

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