The Crystal Structure of E.coli 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase in a Ternary Complex with the Antimalarial Compound Fosmidomycin and NADPH Reveals a Tight-binding Closed Enzyme Conformation

Sweeney, A. Mac; Lange, Roland; Fernandes, Roberta Pereira Miranda; Schulz, Henk; Dale, Glenn E.; Douangamath, A.; Proteau, Philip; Oefner, Christian

doi:10.1016/j.jmb.2004.10.030

Cited by 125 publications

(194 citation statements)

References 37 publications

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“…Although the overall sequence identity is ϳ40%, the central catalytic domain shows a higher degree of conservation (45-50% amino acid sequence identity) than the N-and C-terminal domains (40 and 35% amino acid sequence identity, respectively). A comparison of the various DXR structures also showed that there is variation in the way that the domains move relative to each other, triggered by the binding of cofactors, substrates and inhibitors, and differences in crystal forms (21). thy that the effective pK a difference between the donor and acceptor is reduced by about 7 pK units (equivalent to 10 kcal/ mol) making the predicted initial reaction step almost isoergonic.…”

Section: Mtdxr-ms Displays Octahedral Coordination Of the Mn 2ϩmentioning

confidence: 97%

“…In the PDB, 12 other DXR structures are currently available representing enzymes from E. coli (18 -22) and Zymomonas mobilis (23). Among the E. coli DXR (EcDXR) entries are two apo structures (PDB codes 1K5H and 1ONN) (18,19), one structure in complex with the inhibitor fosmidomycin and a Mn 2ϩ ion (PDB code 1ONP) (19), and one in complex with NADPH and the substrate DXP (PDB code 1Q0Q) (21). The two Z. mobilis entries represent structures in complex with an acetate ion and NADPH, respectively.…”

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confidence: 99%

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Structures of Mycobacterium tuberculosis 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase Provide New Insights into Catalysis

Henriksson

Unge

Carlsson

et al. 2007

Journal of Biological Chemistry

167

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The double mutant enzyme (D151N/E222Q) has lost its ability to bind the metal and, thereby, also its activity. Our structural information complemented with molecular dynamics simulations and free energy calculations provides the framework for the design of new inhibitors and gives new insights into the reaction mechanism. The conformation of fosmidomycin bound to the metal ion is different from that reported in a previously published structure and indicates that a rearrangement of the intermediate is not required during catalysis.

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Section: Mtdxr-ms Displays Octahedral Coordination Of the Mn 2ϩmentioning

confidence: 97%

mentioning

confidence: 99%

Structures of Mycobacterium tuberculosis 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase Provide New Insights into Catalysis

Henriksson

Unge

Carlsson

et al. 2007

Journal of Biological Chemistry

167

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“…A BLAST2 performed with P. falciparum DXR and E. coli DXR [43] as the first and second sequence respectively showed a good sequence similarity (bit score = 269 with E-value = 1e-76) (Fig. 9).…”

Section: Inhibition Of Dxrmentioning

confidence: 97%

Methylerythritol phosphate pathway to isoprenoids: Kinetic modeling andin silicoenzyme inhibitions inPlasmodium falciparum

Singh¹,

Ghosh²

2013

FEBS Letters

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a b s t r a c tThe methylerythritol phosphate (MEP) pathway of Plasmodium falciparum (P. falciparum) has become an attractive target for anti-malarial drug discovery. This study describes a kinetic model of this pathway, its use in validating 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) as drug target from the systemic perspective, and additional target identification, using metabolic control analysis and in silico inhibition studies. In addition to DXR, 1-deoxy-D-xylulose 5-phosphate synthase (DXS) can be targeted because it is the first enzyme of the pathway and has the highest flux control coefficient followed by that of DXR. In silico inhibition of both enzymes caused large decrement in the pathway flux. An added advantage of targeting DXS is its influence on vitamin B1 and B6 biosynthesis. Two more potential targets, 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase and 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate synthase, were also identified. Their inhibition caused large accumulation of their substrates causing instability of the system. This study demonstrates that both types of enzyme targets, one acting via flux reduction and the other by metabolite accumulation, exist in P. falciparum MEP pathway. These groups of targets can be exploited for independent anti-malarial drugs.

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“…8 Prompted by the instability of phosphonic acid 13, we set out on the synthesis of its bis(pivaloyloxymethyl)ester analogue 17.…”

Section: -Deoxy-d-xylulose 5-phosphate Reductoisomerase (Dxr) Catalymentioning

confidence: 99%

Synthesis of β- and γ-oxa isosteres of fosmidomycin and FR900098 as antimalarial candidates

Haemers

Wiesner

Giessmann

et al. 2008

Bioorganic & Medicinal Chemistry

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To expand the structure-activity relationships of fosmidomycin and FR900098, two potent antimalarials interfering with the MEP-pathway, we decided to replace a methylene group in β-position of the phosphonate moiety of these leads by an oxygen atom. β-oxa-FR900098 (11) proved equally active as the parent compound.When applied to 4-[hydroxyl(methyl)amino]-4-oxobutyl phosphonic acid, featuring a hydroxamate instead of the retrohydroxamate moiety, a β-oxa modification yielded a derivative (13) with superior activity against a 3D7 P. falciparum strain than fosmidomycin, while a γ-oxa modification resulted in less active derivatives.A bis(pivaloyloxymethyl)ester of phosphonate 13 proved twice as active in inhibiting cultured parasites than a similar prodrug of FR900098.

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The Crystal Structure of E.coli 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase in a Ternary Complex with the Antimalarial Compound Fosmidomycin and NADPH Reveals a Tight-binding Closed Enzyme Conformation

Cited by 125 publications

References 37 publications

Structures of Mycobacterium tuberculosis 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase Provide New Insights into Catalysis

Structures of Mycobacterium tuberculosis 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase Provide New Insights into Catalysis

Methylerythritol phosphate pathway to isoprenoids: Kinetic modeling andin silicoenzyme inhibitions inPlasmodium falciparum

Synthesis of β- and γ-oxa isosteres of fosmidomycin and FR900098 as antimalarial candidates

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