Mechanism of Phosphoryl Transfer Catalyzed by Shikimate Kinase from Mycobacterium tuberculosis

Hartmann, M.D.; Bourenkov, Gleb; Oberschall, Attila; Strizhov, N.; Bartunik, H.D.

doi:10.1016/j.jmb.2006.09.001

Cited by 60 publications

(140 citation statements)

References 39 publications

(42 reference statements)

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“…[21] More importantly,i tw as proposed that the phosphoryl-transfer reactionc atalysed by SK proceeds througha na ssociativem echanism with consequent generationo fapentacovalent phosphorane intermediate (Scheme 1B). [21] As ac onsequence, both substrates would be involved in the reactioni ntermediate.…”

Section: Resultsmentioning

confidence: 99%

Study of the Phosphoryl‐Transfer Mechanism of Shikimate Kinase by NMR Spectroscopy

Prado

Lence

Vallejo

et al. 2016

Chemistry A European J

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The phosphoryl-transfer mechanism of shikimate kinase from Mycobacterium tuberculosis and Helicobacter pylori, which is an attractive target for antibiotic drug discovery, has been studied by 1D (1)H and (31)P NMR spectroscopy. Metaphosphoric acid proved to be a good mimetic of the metaphosphate intermediate and facilitated the ready and rapid evaluation by NMR spectroscopic analysis of a dissociative mechanism. The required closed form of the active site for catalysis was achieved by the use of ADP (product) or two synthetic ADP analogues (AMPNP, AMPCP). Molecular dynamics simulation studies reported here also revealed that the essential arginine (Arg116/Arg117 in H. pylori and M. tuberculosis, respectively), which activates the γ-phosphate group of ATP for catalysis and triggers the release of the product for turnover, would also be involved in the stabilisation of the metaphosphate intermediate during catalysis. We believe that the studies reported here will be helpful for future structure-based design of inhibitors of this attractive target. The approach is also expected be useful for studies on the possible dissociative mechanism of other kinase enzymes.

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Section: Resultsmentioning

confidence: 99%

Study of the Phosphoryl‐Transfer Mechanism of Shikimate Kinase by NMR Spectroscopy

Prado

Lence

Vallejo

et al. 2016

Chemistry A European J

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“…These important features have encouraged diverse research groups to study in detail the substrate binding requirements of this enzyme [20][21][22][23][24][25]. As a result, several crystal structures of SK, mainly from M. tuberculosis, have been reported, either as binary complexes with ATP, ADP or shikimic acid (6) in the active site, or as tertiary complexes with ADP/shikimic acid (6) or ADP/shikimate 3-phosphate (7) [20][21][22][23]. These structures have been an excellent starting point for the structure-based design of inhibitors, which will be discussed below.…”

Section: Targeting Shikimate Kinasementioning

confidence: 99%

“…SK has three domains (Fig. 1A) [20]: (1) the CORE domain containing five-stranded parallel β-sheets and the P-loop [residues 9-17 in SK from M. tuberculosis (Mt-SK)], which forms the binding site for ATP and ADP; (2) the LID domain (residues 112-124 in Mt-SK), which closes over the active site and has residues that are essential for the binding of ATP; and (3) the substrate binding (SB) domain (residues 33-61 in Mt-SK), which is responsible for the recognition and binding of shikimic acid (6). The SB domain is highly conserved and involves a number of charged residues, specifically Arg136, Arg58, Glu61, Asp34, Arg117 and Lys15, and a lipophilic pocket formed by Phe49, Phe57, Pro118, Gly79, Gly80 and Gly81 (in Mt-SK).…”

Section: Substrate Recognitionmentioning

confidence: 99%

“…The SB domain is highly conserved and involves a number of charged residues, specifically Arg136, Arg58, Glu61, Asp34, Arg117 and Lys15, and a lipophilic pocket formed by Phe49, Phe57, Pro118, Gly79, Gly80 and Gly81 (in Mt-SK). Circular dichroism [21], fluorescence [22] and structural [20][21][22][23][24] studies suggested that ATP first binds to the enzyme and induces a large movement of the LID domain over the active site. Shikimic acid (6) subsequently binds to the active site and the LID domain closes over the active site and brings Arg110 and Arg117 into the ATP and SB domains, respectively [20].…”

Section: Substrate Recognitionmentioning

confidence: 99%

“…Circular dichroism [21], fluorescence [22] and structural [20][21][22][23][24] studies suggested that ATP first binds to the enzyme and induces a large movement of the LID domain over the active site. Shikimic acid (6) subsequently binds to the active site and the LID domain closes over the active site and brings Arg110 and Arg117 into the ATP and SB domains, respectively [20]. The available crystal structures of SK with shikimic acid (6) in the active site show that the substrate is strongly anchored to the active site by a salt bridge with the guanidinium group of Arg136 and by hydrogen bonding between the side chain of the essential Asp34 residue and the C4 hydroxyl group (Fig.…”

Section: Substrate Recognitionmentioning

confidence: 99%

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Inhibition of Shikimate Kinase and Type II Dehydroquinase for Antibiotic Discovery: Structure-Based Design and Simulation Studies

González‐Bello

2015

CTMC

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Abstract:The loss of effectiveness of current antibiotics caused by the development of drug resistance has become a severe threat to public health. Current widely used antibiotics are surprisingly targeted at a few bacterial functions -cell wall, DNA, RNA, and protein biosynthesis -and resistance to them is widespread and well identified. There is therefore great interest in the discovery of novel drugs and therapies to tackle antimicrobial resistance, in particular drugs that target other essential processes for bacterial survival. In the past few years a great deal of effort has been focused on the discovery of new inhibitors of the enzymes involved in the biosynthesis of aromatic amino acids, also known as the shikimic acid pathway, in which chorismic acid is synthesized. The latter compound is the synthetic precursor of L-Phe, L-Tyr, L-Phe, and other important aromatic metabolites. These enzymes are recognized as attractive targets for the development of new antibacterial agents because they are essential in important pathogenic bacteria, such as Mycobacterium tuberculosis and Helicobacter pylori, but do not have any counterpart in human cells. This review is focused on two key enzymes of this pathway, shikimate kinase and type II dehydroquinase. An overview of the use of structure-based design and computational studies for the discovery of selective inhibitors of these enzymes will be provided. A detailed view of the structural changes caused by these inhibitors in the catalytic arrangement of these enzymes, which are responsible for the inhibition of their activity, is described.

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Glycosylation, Sulfation and Phosphorylation

Křen

2020

Applied Biocatalysis

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Mechanism of Phosphoryl Transfer Catalyzed by Shikimate Kinase from Mycobacterium tuberculosis

Cited by 60 publications

References 39 publications

Study of the Phosphoryl‐Transfer Mechanism of Shikimate Kinase by NMR Spectroscopy

Study of the Phosphoryl‐Transfer Mechanism of Shikimate Kinase by NMR Spectroscopy

Inhibition of Shikimate Kinase and Type II Dehydroquinase for Antibiotic Discovery: Structure-Based Design and Simulation Studies

Glycosylation, Sulfation and Phosphorylation

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