Stereochemistry of the 3-Deoxy-d-arabino-heptulosonate 7-Phosphate Synthetase Reaction and the Chorismate Synthetase Reaction

Floss, Heinz G.; Onderka, D. K.; Carroll, Mary J.

doi:10.1016/s0021-9258(19)45669-x

Cited by 113 publications

(27 citation statements)

References 55 publications

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“…5- 16 The phosphate cleavage proceeds via breaking of the C-O bond of PEP, and the reaction is stereospecific with respect to both substrates, with the si face of PEP C3 attacking the re face of E4P. 17- 20 The reaction requires the presence of a divalent metal ion, and the identity of the optimum metal ion for catalysis varies depending on the origin of the DAH7P synthase.…”

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confidence: 99%

Substrate and reaction intermediate mimics as inhibitors of 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase

2009

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3-Deoxy-D-arabino-heptulosonate 7-phosphate (DAH7P) synthase catalyses the aldol-like addition of phosphoenolpyruvate (PEP) to D-erythrose 4-phosphate in the first step of the shikimate pathway to aromatic amino acids. A series of compounds, designed to mimic intermediates in the enzyme-catalysed reaction, have been synthesised and tested as inhibitors for the DAH7P synthase from Escherichia coli. The most potent inhibitor was the vinyl phosphonate, (E)-2-methyl-3-phosphonoacrylic acid, with a K i of 4.7 lM.

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confidence: 99%

Substrate and reaction intermediate mimics as inhibitors of 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase

2009

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“…333 PEP is involved in a number of important enzymatic reactions, i.e., 5-enolpyru-vylshikimate 3-phosphate (EPSP) synthase, an enzyme of the shikimate pathway in plants; 3-deoxy-D-manno-2-octu-losonate-8-phosphate (KDO8P) synthase, an enzyme of the glycolysis; 2-dehydro-3-deoxyphosphoheptonate aldolase (DAHP, also referred to as DHAP). [336][337][338][339][340][341][342] During the reaction catalyzed by EPSP synthase 339,340 (Fig. 6, path I), C3 of PEP is protonated during initiation of the reaction, which implies, that this carbon is a hard base (because a proton is believed to be a hard acid).…”

Section: B On the Way Of Predicting The Regioselectivity Of Large Mol...mentioning

confidence: 99%

“…6, path II), this same carbon acts as a soft base and is used to attack an aldehyde carbon, which is believed to be a soft base, of the cosubstrate of the enzyme. As in the KD08P synthase catalyzed reaction, a soft base at C3 is needed for the reaction catalyzed by DAHP synthase to attack the carbonyl carbon [336][337][338] (Fig. 6, path III).…”

Section: B On the Way Of Predicting The Regioselectivity Of Large Mol...mentioning

confidence: 99%

Studies of regioselectivity of large molecular systems using DFT based reactivity descriptors

Roy

Saha

2010

Annu. Rep. Prog. Chem., Sect. C: Phys. Chem.

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“…Because of the absence of this pathway in eukaryotic organisms, its enzymes are interesting potential targets for rational drug design [1]. The chorismate synthase reaction involves an anti-1,4-elimi-nation of the 3-phosphate and the C(6proR) hydrogen, as shown in Scheme 1 [2,3].Although no net redox change occurs during the reaction, chorismate synthase activity is based on the supply of reduced FMN, which is bound in the active site of the enzyme [3][4][5]. Mechanistic studies have indicated a functional role of the reduced flavin [6,7] that comprises the transient donation of an electron (or a…”

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Replacement of two invariant serine residues in chorismate synthase provides evidence that a proton relay system is essential for intermediate formation and catalytic activity

et al. 2008

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Chorismate synthase is the last enzyme of the common shikimate pathway, which catalyzes the anti‐1,4‐elimination of the 3‐phosphate group and the C‐(6proR) hydrogen from 5‐enolpyruvylshikimate 3‐phosphate (EPSP) to generate chorismate, a precursor for the biosynthesis of aromatic compounds. Enzyme activity relies on reduced FMN, which is thought to donate an electron transiently to the substrate, facilitating C(3)–O bond breakage. The crystal structure of the enzyme with bound EPSP and the flavin cofactor highlighted two invariant serine residues interacting with a bound water molecule that is close to the C(3)–O of EPSP. In this article we present the results of a mutagenesis study where we replaced the two invariant serine residues at positions 16 and 127 of the Neurospora crassa chorismate synthase with alanine, producing two single‐mutant proteins (Ser16Ala and Ser127Ala) and a double‐mutant protein (Ser16AlaSer127Ala). The residual activity of the Ser127Ala and Ser16Ala single‐mutant proteins was found to be six‐fold and 70‐fold lower, respectively, than that of the wild‐type protein. No residual activity was detected for the Ser16AlaSer127Ala double‐mutant protein, and formation of the typical transient intermediate, characteristic for the chorismate synthase‐catalysed reaction, was not observed, in contrast to the single‐mutant proteins. On the basis of the structure of the enzyme, we propose that Ser16 and Ser127 form part of a proton relay system among the isoalloxazine ring of FMN, histidine 106 and the phosphate group of EPSP that is essential for the formation of the transient intermediate and for substrate turnover.

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Stereochemistry of the 3-Deoxy-d-arabino-heptulosonate 7-Phosphate Synthetase Reaction and the Chorismate Synthetase Reaction

Cited by 113 publications

References 55 publications

Substrate and reaction intermediate mimics as inhibitors of 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase

Substrate and reaction intermediate mimics as inhibitors of 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase

Studies of regioselectivity of large molecular systems using DFT based reactivity descriptors

Replacement of two invariant serine residues in chorismate synthase provides evidence that a proton relay system is essential for intermediate formation and catalytic activity

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