A new target for shigellosis: rational design and crystallographic studies of inhibitors of tRNA-guanine transglycosylase11Edited by R. Huber

Grädler, Ulrich; Gerber, Hans Dieter; Goodenough-Lashua, Dee Anne M.; Garcia, George A.; Ficner, Ralf; Reuter, Klaus; Stubbs, Milton T.; Klebe, G.

doi:10.1006/jmbi.2000.4256

Cited by 74 publications

(106 citation statements)

References 31 publications

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“…In addition to predicting protein•protein interactions, computational docking programs are widely used to analyze protein•ligand interactions (33)(34)(35). An application of this technology to FAS II drug discovery was the use of the flexible docking program FlexX (36) to model the binding of thiolactomycin (TLM) to E. coli FabB (37).…”

Section: Downloaded Frommentioning

confidence: 99%

The application of computational methods to explore the diversity and structure of bacterial fatty acid synthase

Zhang

Marrakchi

White

et al. 2003

Journal of Lipid Research

100

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BACTERIAL FATTY ACID SYNTHESISFatty acid metabolism is a fundamental component of the cellular metabolic network. Fatty acids are the essential building blocks for membrane phospholipid formation. Most bacteria synthesize fatty acids using a series of discrete monofunctional proteins, each catalyzing one reaction in the pathway [reviewed in ref. (1-3)]. The bacterial system, also known as the dissociated, type II fatty acid synthase (FAS II), contrasts with the yeast and animal type I fatty acid synthases (FAS I). The type II system is a collection of individual enzymes encoded by separate genes, whereas the type I system is a polypeptide about 260 kDa in size with multiple active sites that perform all the catalytic reactions in the pathway. Although the structural organizations of FAS I and FAS II are different, the chemical reactions and the catalytic mechanisms for fatty acid synthesis are essentially the same.Escherichia coli FAS II has been extensively studied and the biochemical properties of the individual enzymes are the paradigm for type II fatty acid synthase (1). Figure 1 outlines the major steps in the bacterial FAS II. Acetyl-CoA carboxylase catalyzes the first committed reaction of fatty acid biosynthesis. The product of the reaction is malonylCoA and the malonate group is then transferred to ACP by malonyl-CoA:ACP transacylase (FabD) to form malonyl-ACP. Fatty acid synthesis is initiated by the Claisen condensation of malonyl-ACP with acetyl-CoA catalyzed by ␤ -ketoacyl-ACP synthase III (FabH) to form ␤ -ketobutyryl-ACP. Four enzymes catalyze each cycle of elongation. The ␤ -keto group is reduced by the NADPH-dependent ␤ -ketoacyl-ACP reductase (FabG), and the resulting ␤ -hydroxy intermediate is dehydrated by the ␤ -hydroxyacyl-ACP dehydratase (FabA or FabZ) to an enoyl-ACP. Next, the reduction of the enoyl chain by the NAD(P)H-dependent enoyl-ACP reductase (FabI, FabK, or FabL) produces an

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Section: Downloaded Frommentioning

confidence: 99%

The application of computational methods to explore the diversity and structure of bacterial fatty acid synthase

Zhang

Marrakchi

White

et al. 2003

Journal of Lipid Research

100

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“…Recently, the tgt gene has been implicated in the virulence of Shigella flexneri, a dysentery-causing bacterium (9,10). Given this, TGT presents itself as a potential novel antibiotic target (11,12).…”

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confidence: 99%

An Essential Role for Aspartate 264 in Catalysis by tRNA-Guanine Transglycosylase from Escherichia coli

Kittendorf

Sgraja

Reuter

et al. 2003

Journal of Biological Chemistry

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“…Nevertheless, our observation that B105 (Q − ) fails to compete with CA274 (Q + ) suggests that introduction of gene(s) from a library (Q + ) into B105, followed by multiple subculturing, may result in enrichment\ selection of transformants wherein the resident plasmid confers a growth advantage to the host due to queuosine modification. Thus, characterization of the E. coli B105 strain in this study will be helpful in the elucidation of the queuosine biosynthetic pathway, which may even be a boon to the field of cancer biology (Nishimura et al, 1983) and contribute to a better understanding of the virulence of Shigella (Gradler et al, 2001). …”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, in Shigella flexneri, vacC, a virulence-associated chromosomal locus, is homologous to tgt of E. coli and a vacC mutant is complemented by tgt from E. coli (Durand et al, 1994). The mutations in vacC in S. flexneri result in the loss of pathogenicity, suggesting tgt as a possible drug target for shigellosis (Gradler et al, 2001 T. K. Dineshkumar and others other hand, many tumours and neoplastic cell lines are deficient in queuosine modification (Aytac & Gunduz, 1994 ;Harada & Nishimura, 1972 ;Okada et al, 1979 ;Randerath et al, 1984). It has been suggested that queuosine modification in tRNA regulates protein synthesis and influences cellular growth and differentiation in tumour cells (Morris et al, 1999).…”

Section: Queuosinementioning

confidence: 99%

An unexpected absence of queuosine modification in the tRNAs of an Escherichia coli B strain

et al. 2002

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The post-transcriptional processing of tRNAs decorates them with a number of modified bases important for their biological functions. Queuosine, found in the tRNAs with GUN anticodons (Asp, Asn, His, Tyr), is an extensively modified base whose biosynthetic pathway is still unclear. In this study, it was observed that the tRNA Tyr from Escherichia coli B105 (a B strain) migrated faster than that from E. coli CA274 (a K-12 strain) on acid urea gels. The organization of tRNA Tyr genes in E. coli B105 was found to be typical of the B strains. Subsequent analysis of tRNA Tyr and tRNA His from several strains of E. coli on acid urea gels, and modified base analysis of tRNA preparations enriched for tRNA Tyr , showed that E. coli B105 lacked queuosine in its tRNAs. However, the lack of queuosine in tRNAs was not a common feature of all E. coli B strains. The tgt and queA genes in B105 were shown to be functional by their ability to complement tgt and queA mutant strains. These observations suggested a block at the step of the biosynthesis of preQ 1 (or preQ 0 ) in the B105 strain. Interestingly, a multicopy vector harbouring a functional tgt gene was toxic to E. coli B105 but not to CA274. Also, in mixed cultures, E. coli B105 was readily competed out by the CA274 strain. The importance of these observations and this novel strain (E. coli B105) in unravelling the mechanism of preQ 1 or preQ 0 biosynthesis is discussed.

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A new target for shigellosis: rational design and crystallographic studies of inhibitors of tRNA-guanine transglycosylase11Edited by R. Huber

Cited by 74 publications

References 31 publications

The application of computational methods to explore the diversity and structure of bacterial fatty acid synthase

The application of computational methods to explore the diversity and structure of bacterial fatty acid synthase

An Essential Role for Aspartate 264 in Catalysis by tRNA-Guanine Transglycosylase from Escherichia coli

An unexpected absence of queuosine modification in the tRNAs of an Escherichia coli B strain

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