Dxs as a Target for Structure-Based Drug Design

Gierse, Robin M.; Redeem, Eswar; Diamanti, Eleonora; Wrenger, Carsten; Groves, Matthew R.; Hirsch, A.

doi:10.4155/fmc-2016-0239

Cited by 13 publications

(25 citation statements)

References 68 publications

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“…The 2- C -methyl- d -erythritol 4-phosphate (MEP)-pathway offers seven new target enzymes for the development of anti-TB drugs, which should, with a new mode of action, break the resistance of TDR-TB 7 , 8 . For many bacteria, this pathway is the only source of the terpene building blocks dimethylallyl diphosphate (DMADP) and isopentenyl diphosphate (IDP), essential for the biosynthesis of secondary metabolites (Fig.…”

Section: Introductionmentioning

confidence: 99%

First crystal structures of 1-deoxy-d-xylulose 5-phosphate synthase (DXPS) from Mycobacterium tuberculosis indicate a distinct mechanism of intermediate stabilization

Gierse

Oerlemans

Madan

et al. 2022

Sci Rep

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The development of drug resistance by Mycobacterium tuberculosis and other pathogenic bacteria emphasizes the need for new antibiotics. Unlike animals, most bacteria synthesize isoprenoid precursors through the MEP pathway. 1-Deoxy-d-xylulose 5-phosphate synthase (DXPS) catalyzes the first reaction of the MEP pathway and is an attractive target for the development of new antibiotics. We report here the successful use of a loop truncation to crystallize and solve the first DXPS structures of a pathogen, namely M. tuberculosis (MtDXPS). The main difference found to other DXPS structures is in the active site where a highly coordinated water was found, showing a new mechanism for the enamine-intermediate stabilization. Unlike other DXPS structures, a “fork-like” motif could be identified in the enamine structure, using a different residue for the interaction with the cofactor, potentially leading to a decrease in the stability of the intermediate. In addition, electron density suggesting a phosphate group could be found close to the active site, provides new evidence for the D-GAP binding site. These results provide the opportunity to improve or develop new inhibitors specific for MtDXPS through structure-based drug design.

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Section: Introductionmentioning

confidence: 99%

First crystal structures of 1-deoxy-d-xylulose 5-phosphate synthase (DXPS) from Mycobacterium tuberculosis indicate a distinct mechanism of intermediate stabilization

Gierse

Oerlemans

Madan

et al. 2022

Sci Rep

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“… 1 , 2 While DXP synthase (DXPS) is essential in many bacterial pathogens, it is absent in humans, highlighting its potential as an antibacterial drug target. 3 − 8 DXPS has unique structural and mechanistic features compared to other ThDP-dependent enzymes 9 − 14 that can be exploited to specifically target DXPS. Among these features are its large active site volume and unique domain arrangement compared to those of the related human ThDP-dependent enzymes transketolase (TK) and the E1 subunit of pyruvate dehydrogenase, 12 , 15 − 17 as well as a random sequential mechanism involving ternary complex formation.…”

mentioning

confidence: 99%

Revealing Donor Substrate-Dependent Mechanistic Control on DXPS, an Enzyme in Bacterial Central Metabolism

Johnston

Meyers

2021

Biochemistry

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The thiamin diphosphate-dependent enzyme 1-deoxy- d -xylulose 5-phosphate synthase (DXPS) catalyzes the formation of DXP from pyruvate (donor) and d -glyceraldehyde 3-phosphate ( d -GAP, acceptor). DXPS is essential in bacteria but absent in human metabolism, highlighting it as a potential antibacterial drug target. The enzyme possesses unique structural and mechanistic features that enable development of selective inhibition strategies and raise interesting questions about DXPS function in bacterial pathogens. DXPS distinguishes itself within the ThDP enzyme class by its exceptionally large active site and random sequential mechanism in DXP formation. In addition, DXPS displays catalytic promiscuity and relaxed acceptor substrate specificity, yet previous studies have suggested a preference for pyruvate as the donor substrate when d -GAP is the acceptor substrate. However, such donor specificity studies are potentially hindered by a lack of knowledge about specific, alternative donor–acceptor pairs. In this study, we exploited the promiscuous oxygenase activity of DXPS to uncover alternative donor substrates for DXPS. Characterization of glycolaldehyde, hydroxypyruvate, and ketobutyrate as donor substrates revealed differences in stabilization of enzyme-bound intermediates and acceptor substrate usage, illustrating the influence of the donor substrate on reaction mechanism and acceptor specificity. In addition, we found that DXPS prevents abortive acetyl-ThDP formation from a DHEThDP carbanion/enamine intermediate, similar to transketolase, supporting the potential physiological relevance of this intermediate on DXPS. Taken together, these results offer clues toward alternative roles for DXPS in bacterial pathogen metabolism.

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“…[51][52][53] DXS is the first enzyme of the MEP pathway and catalyzes one of two rate-determining reactions in the pathway. 54 With the release of CO 2 , DXS catalyzes a condensation reaction joining Pyr and D-GAP to form DXP. DXS sits at a branch point in the pathway as, in addition to the production of isoprenoid precursors, it also plays an important role in the biosynthesis of vitamins B 1 and B 6 ( Figure 1).…”

Section: -Deoxy-d-xylulose 5-phosphate Synthase (Dxs)mentioning

confidence: 99%

“…As the product of a single gene copy, drug resistance due to a single point mutation in Mtb DXS is less likely to lead to resistance compared with enzymes that stem from several gene copies, offering possible redundancy. 54 In addition, the high conservation of the active site residues gives confidence that the risk of endogenous resistance through active site mutation is low. 60 The overexpression of DXS, as a second form of intrinsic drug resistance, could be downregulated by the downstream metabolites IPP and DMAPP, as mentioned above.…”

Section: -Deoxy-d-xylulose 5-phosphate Synthase (Dxs)mentioning

confidence: 99%

The Methylerythritol Phosphate Pathway: Promising Drug Targets in the Fight against Tuberculosis

Wang

Dowd

2018

ACS Infect. Dis.

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a severe infectious disease in need of new chemotherapies especially for drug-resistant cases. To meet the urgent requirement of new TB drugs with novel modes of action, the TB research community has been validating numerous targets from several biosynthetic pathways. The methylerythritol phosphate (MEP) pathway is utilized by Mtb for the biosynthesis of isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP), the universal five-carbon building blocks of isoprenoids. While being a common biosynthetic pathway in pathogens, the MEP pathway is completely absent in humans. Due to its unique presence in pathogens as well as the essentiality of the MEP pathway in Mtb, the enzymes in this pathway are promising targets for the development of new drugs against tuberculosis. In this Review, we discuss three enzymes in the MEP pathway: 1-deoxy-d-xylulose-5-phosphate synthase (DXS), 1-deoxy-d-xylulose-5-phosphate reductoisomerase (IspC/DXR), and 2 C-methyl-d-erythritol 2,4-cyclodiphosphate synthase (IspF), which appear to be the most promising antitubercular drug targets. Structural and mechanistic features of these enzymes are reviewed, as well as selected inhibitors that show promise as antitubercular agents.

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Dxs as a Target for Structure-Based Drug Design

Cited by 13 publications

References 68 publications

First crystal structures of 1-deoxy-d-xylulose 5-phosphate synthase (DXPS) from Mycobacterium tuberculosis indicate a distinct mechanism of intermediate stabilization

First crystal structures of 1-deoxy-d-xylulose 5-phosphate synthase (DXPS) from Mycobacterium tuberculosis indicate a distinct mechanism of intermediate stabilization

Revealing Donor Substrate-Dependent Mechanistic Control on DXPS, an Enzyme in Bacterial Central Metabolism

The Methylerythritol Phosphate Pathway: Promising Drug Targets in the Fight against Tuberculosis

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