Specific synthesis of neurostatin and gangliosides O-acetylated in the outer sialic acids using a sialate transferase

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DOIResolve DOI: http://doi.org/10.1371/journal.pone.0049983
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Journal titlePLoS ONE
Article numbere49983
Subjectacyltransferase; antineoplastic agent; cholic acid; ganglioside; ganglioside GD 1b; glycosphingolipid; neurostatin; sialate transferase; sialic acid; transferase; unclassified drug; acetylation; antineoplastic activity; article; concentration (parameters); drug determination; drug structure; drug synthesis; hydrolysis; intermethod comparison; matrix assisted laser desorption ionization time of flight mass spectrometry; molecular interaction; molecular weight; proton nuclear magnetic resonance; Acetylation; Acetyltransferases; Campylobacter jejuni; Carbohydrate Sequence; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Gangliosides; Glycosphingolipids; Magnetic Resonance Spectroscopy; Molecular Sequence Data; Recombinant Proteins; Sialic Acids; Spectrometry, Mass, Electrospray Ionization; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Campylobacter jejuni
AbstractGangliosides are sialic acid containing glycosphingolipids, commonly found on the outer leaflet of the plasma membrane. O-acetylation of sialic acid hydroxyl groups is one of the most common modifications in gangliosides. Studies on the biological activity of O-acetylated gangliosides have been limited by their scarcity in nature. This comparatively small change in ganglioside structure causes major changes in their physiological properties. When the ganglioside GD1b was O-acetylated in the outer sialic acid, it became the potent inhibitor of astroblast and astrocytoma proliferation called Neurostatin. Although various chemical and enzymatic methods to O-acetylate commercial gangliosides have been described, O-acetylation was nonspecific and produced many side-products that reduced the yield. An enzyme with O-acetyltransferase activity (SOAT) has been previously cloned from the bacteria Campylobacter jejuni. This enzyme catalyzed the acetylation of oligosaccharide-bound sialic acid, with high specificity for terminal alpha-2,8-linked residues. Using this enzyme and commercial gangliosides as starting material, we have specifically O-acetylated the gangliosides' outer sialic acids, to produce the corresponding gangliosides specifically O-acetylated in the sialic acid bound in alpha-2,3 and alpha-2,8 residues. We demonstrate here that O-acetylation occurred specifically in the C-9 position of the sialic acid. In summary, we present a new method of specific O-acetylation of ganglioside sialic acids that permits the large scale preparation of these modified glycosphingolipids, facilitating both, the study of their mechanism of antitumoral action and their use as therapeutic drugs for treating glioblastoma multiform (GBM) patients. © 2012 Romero-Ramírez et al.
Publication date
AffiliationNational Research Council Canada (NRC-CNRC); Human Health Therapeutics (HHT-TSH)
Peer reviewedYes
NPARC number21269194
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Record identifier1bc4a95f-315e-48e7-89e1-6743f520e4ac
Record created2013-12-12
Record modified2016-05-09
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