Crystal structure of a bacterial sialidase (from Salmonella typhimurium LT2) shows the same fold as an influenza virus neuraminidase.

Crennell, S.J.; Garman, Elspeth F.; Laver, W.G.; Vimr, Eric R.; Taylor, G.L.

doi:10.1073/pnas.90.21.9852

Cited by 217 publications

(168 citation statements)

References 22 publications

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“…6). Neither mutation affected the residues involved in the predicted active site (R78, R97, D103, D135, R280, and R347) (Pshezhetsky et al 1997;Crennell et al 1993). …”

Section: Structural Modeling Of Wild-type and Mutant Lysosomal Neurammentioning

confidence: 99%

“…The crystal structure of neuraminidase from Salmonella typhimurium LT2 was determined (Crennell et al 1993) and deposited in the Protein Data Bank (PDB; Brookhaven National Laboratory, Upton, NY, USA) (Sussman et al 1998). On the basis of this information (PDB file: 2sil), models of the human wild-type lysosomal neuraminidase and its mutants were built, using molecular modeling software (SYBYL/COMPOSER; TRIPOS, St. Louis, MO, USA), installed on a PowerIndigo2 R8000 workstation (Silicon Graphics, Mountain View, CA, USA).…”

Section: Immunocytochemical Analysismentioning

confidence: 99%

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Molecular and structural studies of Japanese patients with sialidosis type 1

et al. 2000

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To gain insight into the pathogenesis of sialidosis type 1, we performed molecular investigations of two unrelated Japanese patients. Both of them are compound heterozygotes for base substitutions of 649 G-to-A and 727 G-to-A, which result in amino acid alterations V217M and G243R, respectively. Using homology modeling, the structure of human lysosomal neuraminidase was constructed and the structural changes caused by these missense mutations were deduced. The predicted change due to V217M was smaller than that caused by G243R, the latter resulting in a drastic, widespread alteration. The overexpressed gene products containing these mutations had the same molecular weight as that of the wild type, although the amounts of the products were moderately decreased. A biochemical study demonstrated that the expressed neuraminidase containing a V217M mutation was partly transported to lysosomes and showed residual enzyme activity, although a G243R mutant was retained in the endoplasmic reticulum/Golgi area and had completely lost the enzyme activity. Considering the data, we surmise that the V217M substitution may be closely associated with the phenotype of sialidosis type 1 with a late onset and moderate clinical course.

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“…6). Neither mutation affected the residues involved in the predicted active site (R78, R97, D103, D135, R280, and R347) (Pshezhetsky et al 1997;Crennell et al 1993). …”

Section: Structural Modeling Of Wild-type and Mutant Lysosomal Neurammentioning

confidence: 99%

Section: Immunocytochemical Analysismentioning

confidence: 99%

Molecular and structural studies of Japanese patients with sialidosis type 1

et al. 2000

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“…Active site residues are shown as black on yellow; ''Asp-box'' repeats are shown as black on blue; and novel missense mutations identi¢ed in the human sialidase gene are shown as black on pink. The b-sheets in the structures of bacterial sialidases [Gaskell et al,1995;Crennell et al,1993Crennell et al, ,1994 are indicated by arrows above the alignment.…”

Section: Missense Mutationsmentioning

confidence: 99%

Molecular pathology of NEU1 gene in sialidosis

Poupětová²,

et al. 2003

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Communicated by Mark H. PaalmanLysosomal sialidase (EC 3.2.1.18) has a dual physiological function; it participates in intralysosomal catabolism of sialylated glycoconjugates and is involved in cellular immune response. Mutations in the sialidase gene NEU1, located on chromosome 6p21.3, result in autosomal recessive disorder, sialidosis, which is characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides. Sialidosis type I is a milder, late-onset, normosomatic form of the disorder. Type I patients develop visual defects, myoclonus syndrome, cherry-red macular spots, ataxia, hyperreflexia, and seizures. The severe early-onset form, sialidosis type II, is also associated with dysostosis multiplex, Hurler-like phenotype, mental retardation, and hepatosplenomegaly. We summarize information on the 34 unique mutations determined so far in the sialidase gene, including four novel missense and one novel nonsense mutations found in two Czech and two French sialidosis patients. The analysis of sialidase mutations in sialidosis revealed considerable molecular heterogeneity, reflecting the diversity of clinical phenotypes that make molecular diagnosis difficult. The majority of sialidosis patients have had missense mutations, many of which have been expressed; their effects on activity, stability, intracellular localization, and supramolecular organization of sialidase were studied. A structural model of sialidase allowed us to localize mutations in the sialidase molecule and to predict their impact on the tertiary structure and biochemical properties of the enzyme. Hum Mutat 22:343-352,

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“…Recent kinetic and crystallographic studies have provided information about the molecular mechanism of exosialidase catalysis of sialyl linkages (17)(18)(19)(20)(21)(22). This paper describes a quantitative investigation of the equilibria and kinetics involved in KDNase Sm-catalyzed hydrolysis by the steady-state enzyme kinetics and 1 H NMR spectroscopy.…”

Section: -Deoxy-d-galacto-d-glycero-nonulosonic Acid (Kdn)mentioning

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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Crystal structure of a bacterial sialidase (from Salmonella typhimurium LT2) shows the same fold as an influenza virus neuraminidase.

Abstract: Sialidases (EC 3.2

Cited by 217 publications

References 22 publications

Molecular and structural studies of Japanese patients with sialidosis type 1

Molecular and structural studies of Japanese patients with sialidosis type 1

Molecular pathology of NEU1 gene in sialidosis

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