Design and Synthesis of 2‘-Deoxy-2‘-Fluorodisaccharides as Mechanism-Based Glycosidase Inhibitors That Exploit Aglycon Specificity

McCarter, John D.; Yeung, Wai; Chow, Jack; Dolphin, David; Withers, Stephen G.

doi:10.1021/ja9627454

Cited by 47 publications

(36 citation statements)

References 19 publications

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“…The aglycon of 2-F-GTL is identical to that of glucotropaeolin, the natural substrate, evidencing that the aglycon does not need any additional "pull." Again, this observation cannot be taken as evidence for or against a participation of the sulfate group, because optimal binding interactions of the enzyme with the aglycon can considerably increase the leaving group ability of the aglycon (43).…”

Section: Statistics On the Data Sets And The Refined Structuresmentioning

confidence: 99%

High Resolution X-ray Crystallography Shows That Ascorbate Is a Cofactor for Myrosinase and Substitutes for the Function of the Catalytic Base

Burmeister¹,

Cottaz²,

Rollin³

et al. 2000

Journal of Biological Chemistry

172

174

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Myrosinase, an S-glycosidase, hydrolyzes plant anionic 1-thio-␤-D-glucosides (glucosinolates) considered part of the plant defense system. Although O-glycosidases are ubiquitous, myrosinase is the only known Sglycosidase. Its active site is very similar to that of retaining O-glycosidases, but one of the catalytic residues in O-glycosidases, a carboxylate residue functioning as the general base, is replaced by a glutamine residue. Myrosinase is strongly activated by ascorbic acid. Several binary and ternary complexes of myrosinase with different transition state analogues and ascorbic acid have been analyzed at high resolution by x-ray crystallography along with a 2-deoxy-2-fluoro-glucosyl enzyme intermediate. One of the inhibitors, D-gluconhydroximo-1,5-lactam, binds simultaneously with a sulfate ion to form a mimic of the enzyme-substrate complex. Ascorbate binds to a site distinct from the glucose binding site but overlapping with the aglycon binding site, suggesting that activation occurs at the second step of catalysis, i.e. hydrolysis of the glycosyl enzyme. A water molecule is placed perfectly for activation by ascorbate and for nucleophilic attack on the covalently trapped 2-fluoroglucosyl-moiety. Activation of the hydrolysis of the glucosyl enzyme intermediate is further evidenced by the observation that ascorbate enhances the rate of reactivation of the 2-fluoro-glycosyl enzyme, leading to the conclusion that ascorbic acid substitutes for the catalytic base in myrosinase.Glucosinolates are anionic ␤-D-S-glucosides found prominently in plants of the genus Brassica (cabbage, mustard, rapeseed, and other Cruciferae). They constitute a large family of S-glucosides that differ by their aglycon (Ref. 1 and Fig. 1a). The same plants produce myrosinase (thioglucoside glucohydrolase, EC 3.2.3.1), an S-glucosidase hydrolyzing glucosinolates. Myrosinase and glucosinolates are stored in different compartments of the plant, especially in the seeds. Mixing of enzyme and substrate (for example through mastication) induces glucosinolate hydrolysis. The biological function of myrosinase and glucosinolates is only partly elucidated; it has been suggested that they represent a defense system of the plant. Glucosinolates may as well serve to store inactive precursors of hormones such as 3-indolylacetic acid. 3-Indolyl acetonitrile and related indoles (2) are released from indolyl glucosinolates by myrosinase (3). Cleavage of indol-3-ylmethyl glucosinolate (glucobrassicin) by myrosinase in the presence of ascorbic acid produces ascorbigen, a condensation product of ascorbic acid with 3-hydroxymethylindole (4). Thus, the myrosinase system could be involved in the storage and in the inactivation of ascorbic acid. A detailed review on myrosinase is given by Bones and Rossiter (3).Myrosinase hydrolyzes the S-glycosides with retention of the anomeric configuration (5). Retaining glycosidases operate by a double displacement at the anomeric center promoted by two carboxylic residues acting as acid/base and as nucleophile, respec...

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Section: Statistics On the Data Sets And The Refined Structuresmentioning

confidence: 99%

High Resolution X-ray Crystallography Shows That Ascorbate Is a Cofactor for Myrosinase and Substitutes for the Function of the Catalytic Base

Burmeister¹,

Cottaz²,

Rollin³

et al. 2000

Journal of Biological Chemistry

172

174

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“…Deoxyfluoro analogs of monosugars (galactose 20, glucose 1, 21–24, fucose 25, xylose 26, and celobiose 27, 28) were utilized in studies on various enzymatic reactions. The 19 F NMR technique with 3‐deoxy‐3‐fluoro‐ D ‐glucose as molecular probe is used in studies of metabolism of sugars 29–31 in muscles, the liver, and eyes.…”

Section: Introductionmentioning

confidence: 99%

When, in the context of drug design, can a fluorine atom successfully substitute a hydroxyl group?

Hoffmann

Rychlewski

2002

Int J of Quantum Chemistry

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ABSTRACT:In this article, we deal with the question of whether a fluorine atom can substitute a hydroxyl group in such a way that will lead to a compound showing a desired biologic activity, that is, a potential new drug. It is obvious that a fluorine atom differs from a hydroxyl group, as it cannot donate hydrogen bonds. However, it can accept them. Moreover, both fluorine and oxygen are of similar size and are the most electronegative elements. Therefore, a fluorine atom is thought to be a good substitute for a hydroxyl group. However, it was shown that for conformationally labile aliphatic compounds a replacement of a hydroxyl by a fluorine increases conformational diversity, so the fluorinecontaining aliphatic molecules are present in equilibrium at room temperature as a mixture of several different conformers. In contrast, for cyclic compounds the substitution of an OH group by an F atom does not much change shape and electrostatic potential around corresponding conformers. Moreover, these compounds are present in equilibrium at room temperature in aqueous solution as a mixture of the same most favored structures.

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“…[68,69] Eine groûe Vielzahl von Molekülen ist synthetisiert worden, welche den vorgeschlagenen Übergangszustand verschiedener Glycosid-hydrolysierender Enzyme nachahmen. Der verzerrte Ring wird durch Ringe anderer Gröûe, durch den Einbau eines oder mehrerer sp 2 -Zentren in den Ring (z.…”

Section: Ohunclassified

“…Die Verknüpfung dieser Verbindungen mit einer Abgangsgruppe (einem Zucker) oder einem Mimetikum liefert selektivere Glycosidase-Inhibitoren. [68,70] Die Anbindung an Nucleotide führt dagegen häufig zu Inhibitoren der verwandten Glycosyltransferasen. Viele der so erhaltenen Verbindungen, einige sind in Abbildung 17 dargestellt, sind starke Inhibitoren von Glycosidasen.…”

Section: Ohunclassified

“…[71] Ein alternativer Ansatz zur Inhibierung von konfigurationserhaltenden Glycosidasen, der über einen doppelten Inversion-Mechanismus mit einem kovalent gebundenen Enzym-Substrat-Intermediat verläuft, [72,73] ist die Verwendung eines Substrates, das ein stabiles kovalent gebundenes Intermediat bildet, wie 2-oder 5-Fluoroglycoside. [68,69] Bei Verwendung eines Fluoroglycosids mit einer guten Abgangsgruppe (entweder ein aktiviertes Glycosid wie das 2,4-Dinitrophenolat oder einfach das vom Enzym bevorzugte Aglycon [68] ) kann das Enzym den ersten Schritt, die Freisetzung der Abgangsgruppe und die Bildung des kovalent gebundenen Intermediats, katalysieren. Die anschlieûende Hydrolyse ist wegen der Destabilisierung des Oxocarbenium-Übergangszustandes durch das Fluor allerdings erschwert.…”

Section: Ohunclassified

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Kohlenhydratmimetika: ein neuer Lösungsansatz für das Problem der kohlenhydratvermittelten biologischen Erkennung

Sears

Wong

1999

Angewandte Chemie

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Design and Synthesis of 2‘-Deoxy-2‘-Fluorodisaccharides as Mechanism-Based Glycosidase Inhibitors That Exploit Aglycon Specificity

Cited by 47 publications

References 19 publications

High Resolution X-ray Crystallography Shows That Ascorbate Is a Cofactor for Myrosinase and Substitutes for the Function of the Catalytic Base

High Resolution X-ray Crystallography Shows That Ascorbate Is a Cofactor for Myrosinase and Substitutes for the Function of the Catalytic Base

When, in the context of drug design, can a fluorine atom successfully substitute a hydroxyl group?

Kohlenhydratmimetika: ein neuer Lösungsansatz für das Problem der kohlenhydratvermittelten biologischen Erkennung

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