Novel UDP-Glycal Derivatives as Transition State Analogue Inhibitors of UDP-GlcNAc 2-Epimerase

Stolz, Florian; Reiner, Martin; Blume, Astrid; Reutter, Werner; Schmidt, Richard R.

doi:10.1021/jo0353029

Cited by 64 publications

(42 citation statements)

References 36 publications

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“…In the light of our new results, it is not surprising that synthetic derivatives of UDP (41,42) have been found to effectively inhibit the enzyme. According to our studies, another apparent requirement for a potent inhibitor is the presence of two or three negative charges.…”

Section: Fig 5 Model For the Design Of Udp-glcnac 2-epimerase Inhibmentioning

confidence: 68%

Characterization of Ligand Binding to the Bifunctional Key Enzyme in the Sialic Acid Biosynthesis by NMR

Blume

Benie

Stolz

et al. 2004

Journal of Biological Chemistry

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The bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase is the key enzyme for the biosynthesis of sialic acids. As terminal components of glycoconjugates, sialic acids are associated with a variety of pathological processes such as inflammation and cancer. For the first time, this study reveals characteristics of the interaction of the epimerase site of the enzyme with its natural substrate, UDP-N-acetylglucosamine (UDP-GlcNAc) and derivatives thereof at atomic resolution. Saturation transfer difference NMR experiments were crucial in obtaining ligand binding epitopes and to rank ligands according to their binding affinities. Employing a fragment based approach, it was possible to assign the major component of substrate recognition to the UDP moiety. In particular, the binding epitopes of the uridine moieties of UMP, UDP, UDP-GalNAc, and UDP-GlcNAc are rather similar, suggesting that the binding mode of the UDP moiety is the same in all cases. In contrast, the hexopyranose units of UDP-GlcNAc and UDP-GalNAc display small differences reflecting the inability of the enzyme to process UDP-GalNAc. Surprisingly, saturation transfer difference NMR titrations show that UDP has the largest binding affinity to the epimerase site and that at least one phosphate group is required for binding. Consequently, this study provides important new data for rational drug design.

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Section: Fig 5 Model For the Design Of Udp-glcnac 2-epimerase Inhibmentioning

confidence: 68%

Characterization of Ligand Binding to the Bifunctional Key Enzyme in the Sialic Acid Biosynthesis by NMR

Blume

Benie

Stolz

et al. 2004

Journal of Biological Chemistry

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“…Furthermore, inhibition of sialic acid biosynthesis could render metastatic cells more susceptible to the immune system, because most metastatic cells are protected by a sialic acid shield from immune recognition (47). Because hGNE is the key enzyme in sialic acid biosynthesis and its impairment diminishes the level of sialic acid expression on cell surfaces (14), many UDP-GlcNAc and transition state analogs were synthesized as inhibitors for the epimerase activity of hGNE and tested to date (48,49). However, because of their hydrophilic nature, these inhibitors cannot penetrate the cell plasma membrane and are ineffective in cellular systems.…”

Section: Asp-517-omentioning

confidence: 99%

Crystal Structures of N-Acetylmannosamine Kinase Provide Insights into Enzyme Activity and Inhibition

Martinez

Nguyen

Hinderlich

et al. 2012

Journal of Biological Chemistry

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Background: UDP-GlcNAc-2 epimerase/ManNAc kinase is the key enzyme for sialic acid biosynthesis. Results: The crystal structure of ManNAc kinase in complex with its substrate ManNAc has been determined at 1.64 Å resolution. Conclusion: Insights into the mechanism of ManNAc phosphorylation have been gained from the substrate-bound structure. Significance: The new structural information presented here offers a basis for designing potential inhibitors of sialic acid biosynthesis.

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“…On this basis a mechanism for the epimerisation was postulated. [9,10] We recently reported the design and synthesis of some transition-state-based inhibitors for UDP-GlcNAc 2-epimerase, which showed binding affinities in the range of the natural substrate UDP-GlcNAc. [10] In this study we followed a different approach and turned our interest to mimics of the enzyme substrate, UDP-GlcNAc.…”

Section: Introductionmentioning

confidence: 99%

“…[9,10] We recently reported the design and synthesis of some transition-state-based inhibitors for UDP-GlcNAc 2-epimerase, which showed binding affinities in the range of the natural substrate UDP-GlcNAc. [10] In this study we followed a different approach and turned our interest to mimics of the enzyme substrate, UDP-GlcNAc. The results of previous studies [10,11] clearly indicated that the sugar moiety and the UDP residue are both important for binding to the active site of UDP-GlcNAc 2-epimerase.…”

Section: Introductionmentioning

confidence: 99%

C‐Glycosidic UDP‐GlcNAc Analogues as Inhibitors of UDP‐GlcNAc 2‐Epimerase

et al. 2004

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The first step in the biosynthesis of neuraminic acid, the “epimerisation” of UDP‐GlcNAc to ManNAc, is catalyzed by UDP‐GlcNAc 2‐epimerase. In this paper we report the synthesis of the C‐glycosidic UDP‐GlcNAc analogues 1−5 as substrate‐based inhibitors of this enzyme. The focus is on the optimal distance and geometry of the connection between the sugar and the UDP‐moiety, which are both important for recognition by UDP‐GlcNAc 2‐epimerase. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

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Novel UDP-Glycal Derivatives as Transition State Analogue Inhibitors of UDP-GlcNAc 2-Epimerase

Cited by 64 publications

References 36 publications

Characterization of Ligand Binding to the Bifunctional Key Enzyme in the Sialic Acid Biosynthesis by NMR

Characterization of Ligand Binding to the Bifunctional Key Enzyme in the Sialic Acid Biosynthesis by NMR

Crystal Structures of N-Acetylmannosamine Kinase Provide Insights into Enzyme Activity and Inhibition

C‐Glycosidic UDP‐GlcNAc Analogues as Inhibitors of UDP‐GlcNAc 2‐Epimerase

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