Mechaism of Arthrobacter sialophilus neuraminidase: The binding of substrates and transition-state analogs

Miller, Carl A.; Wang, Philip; Flashner, Michael

doi:10.1016/0006-291x(78)91388-8

Cited by 61 publications

(22 citation statements)

References 25 publications

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“…1C). We propose that KDN2en is a transition-state analogue of KDNase Sm because it fulfills the following criteria (33,34). (i) A transition-state inhibitor binds more tightly to the enzyme than the substrate; (ii) the structure of the inhibitor mimics that of the substrate in the putative transition-state during the enzyme- Neu5Acyl2en derivatives, for N-acylneuraminidases, KDN2en can be referred to as a transition-state analogue for KDNase Sm.…”

Section: Effects Of 23-didehydro-23-dideoxy Derivatives Of Sialic Amentioning

confidence: 99%

Catalysis by a New Sialidase, Deaminoneuraminic Acid Residue-cleaving Enzyme (KDNase Sm), Initially Forms a Less Stable α-Anomer of 3-Deoxy-D-glycero-D-galacto-nonulosonic Acid and Is Strongly Inhibited by the Transition State Analogue, 2-Deoxy-2,3-didehydro-D-glycero-D-galacto-2-nonulopyranosonic Acid, but Not by 2-Deoxy-2,3-didehydro-N-acetylneuraminic Acid

Terada

Kitajima

Inoue

et al. 1997

Journal of Biological Chemistry

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Deaminoneuraminic acid residue-cleaving enzyme (KDNase Sm) is a new sialidase that has been induced and purified from Sphingobacterium multivorum. Catalysis by this new sialidase has been studied by enzyme kinetics and 1 H NMR spectroscopy. V max /K m values determined for synthetic and natural substrates of KDNase Sm reveal that 4-methylumbelliferyl-KDN (KDN␣2MeUmb, V max /K m ‫؍‬ 0.033 min ؊1 ) is the best substrate for this sialidase, presumably because of its good leaving group properties. The transition state analogue, 2,3-didehydro-2,3-dideoxy-D-galacto-D-glycero-nonulosonic acid, is a strong competitive inhibitor of KDNase Sm (K i ‫؍‬ 7.7 M versus K m ‫؍‬ 42 M for KDN␣2MeUmb). 2-Deoxy-2,3-didehydro-N-acetylneuraminic acid and 2-deoxy-2,3-didehydro-N-glycolylneuraminic acid are known to be strong competitive inhibitors for bacterial sialidases such as Arthrobacter ureafaciens sialidase; however, KDNase Sm activity is not significantly inhibited by these compounds. This observation suggests that the hydroxyl group at C-5 is important for recognition of the inhibitor by the enzyme.Reversible addition of water molecule (or hydroxide ion) to the reactive sialosyl cation, presumably formed at the catalytic site of KDNase Sm, eventually gives rise to two different adducts, the ␣-and ␤-anomers of free 3-deoxy-D-glycero-D-galacto-nonulosonic acid. 1 H NMR spectroscopic studies clearly demonstrate that the thermodynamically less stable ␣-form is preferentially formed as the first product of the cleavage reaction and that isomerization rapidly follows, leading to an equilibrium mixture of the two isomers, the ␤-isomer being the major species at equilibrium. Therefore, we propose that KDNase Sm catalysis proceeds via a mechanism common to the known exosialidases, but the recognition of the substituent at C-5 by the enzyme differs.

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Section: Effects Of 23-didehydro-23-dideoxy Derivatives Of Sialic Amentioning

confidence: 99%

Catalysis by a New Sialidase, Deaminoneuraminic Acid Residue-cleaving Enzyme (KDNase Sm), Initially Forms a Less Stable α-Anomer of 3-Deoxy-D-glycero-D-galacto-nonulosonic Acid and Is Strongly Inhibited by the Transition State Analogue, 2-Deoxy-2,3-didehydro-D-glycero-D-galacto-2-nonulopyranosonic Acid, but Not by 2-Deoxy-2,3-didehydro-N-acetylneuraminic Acid

Terada

Kitajima

Inoue

et al. 1997

Journal of Biological Chemistry

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“…A further template examined was one that had been suggested [92] to be a mimic of a transition state along the enzyme reaction pathway. The 2,3 unsaturated Neu5Ac derivative 14, designated Neu5Ac2en, has been found in small amounts in human serum and saliva [93].…”

Section: Template Selectionmentioning

confidence: 99%

“…Produced synthetically, it was shown to be a competitive inhibitor of viral [94], bacterial [95,96], and mamma lian [97] sialidases at around the micromolar level (e.g., inhibition of influenza A virus N2 sialidase, K i 4 μM [98]). The increased inhibitory activity of the unsaturated derivative 14 was suggested [92] to be due in part to the structural similarity of 14 [99] to the half-chair conformation of the putative oxocarbenium ion intermediate 2 of the enzyme mechanism (Scheme 22.1). Variations of the Neu5Ac2en template to map structure-activity relationships in inhibition of microbial sialidases had begun in the 1970s with the C5 substituent.…”

Section: Template Selectionmentioning

confidence: 99%

Development of Influenza Virus Sialidase Inhibitors

Pascolutti

Thomson

Itzstein

2016

Methods and Principles in Medicinal Chemistry

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“…A Figura 15 apresenta o estado de transição proposto para o mecanismo enzimático de ação da neuraminidase do vírus influenza 14,[47][48][49][50][51] . Em nível molecular, a neuraminidase promove a quebra da ligação glicosídica da glicoproteína ou do glicolipídio.…”

Section: Desenhando Fármacos Antiinfluenzaunclassified

Ácidos siálicos: da compreensão do seu envolvimento em processos biológicos ao desenvolvimento de fármacos contra o agente etiológico da gripe

Fátima¹,

Baptistella²,

Pilli³

et al. 2005

Quím. Nova

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Recebido em 4/2/04; aceito em 13/7/04; publicado na web em 23/11/04 SIALIC ACIDS -FROM THE COMPREHENSION OF THEIR INVOLVEMENT IN BIOLOGICAL PROCESSES TO ANTIINFLUENZA DRUG DESIGN. Sialic acids are nine-carbon carbohydrates that occur widely in nature and occupy the terminal portions of some glycoproteins and glycolipids of cell membranes. These carbohydrates are closely involved in cell-cell interactions and in processes such as microbial infection, inflammation, etc. Studies on the participation of sialic acids in biological processes have provided comprehension about their role in the infection by the influenza virus, the causal agent of flu. In this article, we present an overview of the importance of sialic acids in the influenza virus infection and how the knowledge of their involvement in this process has allowed the development of selective and efficient drugs against the virus.Keywords: sialic acid; flu and antiinfluenza drugs. INTRODUÇÃONão há vida sem célula. E a exemplo da própria vida, que tanta diversidade apresenta, variam as formas e funções das células. As células são as unidades estruturais e funcionais de todos os organismos e é possível reconhecer, em sua hierarquia estrutural, alguns níveis de complexidade, como aqueles presentes, por exemplo, em uma célula vegetal: o nível 3 onde se incluem complexos supramoleculares (cromossomo, membrana plasmática, parede celular, etc); o nível 2 representado por macromoléculas (DNA, proteínas, celulose, etc) e o nível 1 compreendendo as unidades monoméricas, como nucleotídeos, aminoácidos, carboidratos, etc 1-3 (Figura 1).A membrana plasmática, presente em células de todas as espécies, define a periferia da célula, separando o seu conteúdo da circunvizinhança. Ela serve como uma barreira de permeabilidade, que permite à célula manter uma composição citoplasmática e é composta de grande número de moléculas de lipídios e proteínas que se mantêm juntas principalmente por interações hidrofóbicas, formando uma bicamada lipídica fina, resistente e flexível, em volta da célula 1-3 . Algumas proteínas presentes na membrana celular permitem a passagem de certos íons e moléculas (proteínas transportadoras). Outras proteí-nas exercem o papel de receptores, transmitindo o sinal do exterior para o interior da célula. Há ainda proteínas que funcionam como enzimas, participando de reações que ocorrem em membranas.

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Mechaism of Arthrobacter sialophilus neuraminidase: The binding of substrates and transition-state analogs

Cited by 61 publications

References 25 publications

Development of Influenza Virus Sialidase Inhibitors

Ácidos siálicos: da compreensão do seu envolvimento em processos biológicos ao desenvolvimento de fármacos contra o agente etiológico da gripe

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