Human sialidases

As many conflicting observations have been made in this field, better characterization of human sialidases, especially those from the readily obtainable fibroblasts, is needed, as well as standardized, natural substrates and sialidase-assay conditions. 

The lipase-catalysed hydrolysis of methyl 2-fluoro-2-arylpropionates was proposed to proceed via a mechanism whereby, after ester hydrolysis, the enzyme facilitates the elimination of fluoride ion with the formation of a carbocation stabilized by the adjacent C02 group.230 Determination of the crystal structure of human sialidase Neu2, an enzyme that catalyses the hydrolysis of sialic acids, reveals a tyrosine residue that is positioned in the active site to stabilize the carbocation proposed as an intermediate in the hydrolysis.231 ll-Fluoro-all-frans-retinol is found to undergo isomerization to its 11 -cis form in the presence of visual cycle enzymes, in contrast to a previous study where no isomerization was reported.232 The result of the prior study was taken as evidence for a carbonium ion pathway in the isomerization. Although the authors of the present study do not rule out such a mechanism, they suggest that the isomerization mechanism remains unknown. Data obtained in a study of the oxidation of... 

Covalent inhibitors were synthesized by Withers and coworkers.148 149 The use of 3F-sialyl fluoride 136 as donor substrate allowed identification of the covalent mechanism for TcTS. Fluoride 136 completely inactivates the enzyme, but only at concentrations as high as 20 mM, and separation of excess inactivator caused recovery of the activity.148 Since the 3D structure of TcTS showed that the donor site is more spacious and hydrophobic than in a human sialidase, derivatives at C-9 of the fluoride 136 were synthesized by a chemoenzymatic method and tested as inhibitors (Fig. 10).149 Inhibition was analyzed with trifluoromethylumbelliferyl sialic acid for measuring hydrolase activity, however, as the site is the same for... 

Sialidases are enzymes that catalyze the removal of terminal sialic acids from sialosides (56, 57). Human sialidases play pivotal roles in sialic acid metabolism (58). They relate to a number of disease states such as sialidosis (59-62) and cancer (63-65). Bacterial and viral play significant roles in the pathogenesis and pathology of bacterial and viral infections (66, 67). Viral sialidases such as neuraminidases of influenza virus catalyze the removal of sialic acid from the surface of infected host cells to release the newly formed progeny virus (68). 

X. Amino Acid Sequence Variants in Human Sialidases... 

T. Miyagi, T. Wada, K. Yamaguchi, K. Shiozaki, I. Sato, Y. Kakugawa, H. Yamanami, and T. Fujiya, Human sialidase as a cancer marker, Proteomics, 8 (2008) 3303-3311. 

E. Monti, A. Preti, C. Nesti, A. Ballabio, and G. Borsani, Expression of a novel human sialidase encoded by the NEU2 gene, Glycobiology, 9 (1999) 1313-1321. 

S. Magesh, S. Moriya, T. Suzuki, T. Miyagi, H. Ishida, and M. Kiso, Design, synthesis, and biological evaluation of human sialidase inhibitors. Part 1 Selective inhibitors of lysosomal sialidase (NEUl), Bioorg. Med. Chem. Lett, 18 (2008) 532-537. 

K. Hata, K. Koseki, K. Yamaguchi, S. Moriya, Y. Suzuki, S. Yingsakmongkon, G. Hirai, M. Sodeoka, M. von Itzstein, and T. Miyagi, Limited inhibitory effects of oseltamivir and zanamivir on human sialidases, Antimicrob. Agents Chemother, 52 (2008) 3484-3491. 

E. Monti, M. T. Bassi, R. Bresciani, S. Civini, G. L. Croci, N. Papini, M. Riboni, G. Zanchetti, A. Ballabio, A. Preti, G. Tettamanti, B. Venerando, and G. Borsani, Molecular cloning and characterization of NEU4, the fourth member of the human sialidase gene family. Genomics, 83 (2004) 445-453. 

It was important to determine the effect of the 4-substituted Neu5Ac2en derivatives on endogenous human sialidases. Four human sialidases (Neul-4) have been identified to date (reviewed in [103,104]). Of these, Neu3 is predomi-nantiy localized in the plasma membrane, and both Neul and Neu4 have been... 

M., and Miyagi, T. (2008) Limited inhibitory effects of oseltamivir and zanamivir on human sialidases. 

S. (2010) Complexity in influenza virus targeted drug design interaction with human sialidases. Journal of Medicinal Chemistry, 53, 2998-3002. 

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