Synthetic N- and O- Glycosyl Derivatives of L-Asparagine, L-Serine, and L-Threonine

Garg, Hari G.; Jeanloz, Roger W.

doi:10.1016/s0065-2318(08)60068-2

Cited by 91 publications

(16 citation statements)

References 150 publications

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“…Synthesis of Glycopeptides-We have chemically synthesized a number of glycopeptides to systematically study the substrate requirement of glycoamidases A and F. The chemical construction of the glycosylamine-␤-L-aspartyl bond has been achieved with protected sugars and protected Asp by various methods (34 -37), and the Asp was further extended to glycopeptides (38,39). When we, as well as others (40,41), followed a published method (34) for glycopeptide synthesis, the target compounds could be obtained only after extensive purification, and the yields were low.…”

Section: Discussionmentioning

confidence: 99%

Detailed Studies on Substrate Structure Requirements of Glycoamidases A and F

Fan

Lee

1997

Journal of Biological Chemistry

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Glycoamidases (peptide-N 4-(N-acetyl-␤-glucosaminyl)-asparagine amidase, EC 3.5.1.52; also known as peptide: N-glycanases (PNGases) release N-linked oligosaccharides from glycopeptides and/or glycoproteins by hydrolyzing the glycosylated ␤-amide bond of the asparagine side chain. The most widely used glycoamidases are those from Flavobacterium meningosepticum (glycoamidase F or PNGase F) and almond emulsin (glycoamidase A or PNGase A). To study the substrate structure requirement of these enzymes systematically, we synthesized >30 glycopeptides containing cellobiose, lactose, GlcNAc, and di-N,N-acetylchitobiose (CTB). The length of the peptide was varied from one to five amino acids, and glycosylamines were linked to either Asn or Gln located at different positions in the peptide, including NH 2 and COOH termini. Neither enzyme could cleave cellobiose and lactose glycopeptides, indicating that the 2-acetamido group on the Asn-linked GlcNAc is important in the recognition by both glycoamidases A and F. GlcNAc peptides could be cleaved by both enzymes, albeit not as effectively as CTB glycopeptides. Neither enzyme requires the Asn-Xaa-(Ser/Thr) sequence (required for N-glycosylation) for activity. Glycoamidase A could even hydrolyze a Gln-bound CTB glycopeptide, whereas the action of glycoamidase F on this substrate is minimal. While glycoamidase A could act on CTB dipeptides, glycoamidase F preferred a tripeptide or longer. The K m and V max values of glycoamidase A for t-butoxycarbonyl-(CTB)-Asn-Ala-Ser-OMe were 2.1 mM and 0.66 mol/min/mg, respectively. A natural glycodipeptide, Man 9 -GlcNAc 2 -Asn-Phe, was also completely hydrolyzed by glycoamidase A.

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Section: Discussionmentioning

confidence: 99%

Detailed Studies on Substrate Structure Requirements of Glycoamidases A and F

Fan

Lee

1997

Journal of Biological Chemistry

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“…Work with these had to wait for effective synthetic methodology, which is exemplified by the work of Paulsen 93 and Jeanloz. 94 In the author's laboratory, several O-linked glycopeptide analogs of enkephalin were synthesized and studied. 95 Classical pharmacological theories of BBB transport suggest that peptides are not lipophilic enough to diffuse into the brain.…”

Section: O-linked Glycopeptides and The ''Biousian Hypothesis''mentioning

confidence: 99%

Glycosylated neuropeptides: A new vista for neuropsychopharmacology?

Polt

Dhanasekaran

Keyari

2005

Medicinal Research Reviews

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The application of endogenous neuropeptides (e.g., enkephalins) as analgesics has been retarded by their poor stability in vivo and by their inability to effectively penetrate the blood-brain barrier (BBB). Effective BBB transport of glycosylated enkephalins has been demonstrated in several labs now. Analgesia (antinociception) levels greater than morphine, and with reduced side effects have been observed for several glycopeptides related to enkephalin. Somewhat paradoxically, enhanced BBB transport across this lipophilic barrier is achieved by attaching water-soluble carbohydrate groups to the peptide moieties to produce biousian glycopeptides that can be either water-soluble or membrane bound. Transport is believed to rely on an endocytotic mechanism (transcytosis), and allows for systemic delivery and transport of the water-soluble glycopeptides. Much larger endorphin/dynorphin glycopeptide analogs bearing amphipathic helix address regions also have been shown to penetrate the BBB in mice. This holds forth the possibility of transporting much larger neuropeptides across the BBB, which may encompass a wide variety of receptors beyond the opioid receptors.

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“…peptides containing N-glycosides via P-amide of asparagine (Asn-Glyc) (Garg and Jeanloz, 1985;Meldal, 1994). The classic method of preparing an Asnlinked oligosaccharide is to start with glycosyl halide, which is converted to glycosyl azide.…”

Section: Glycosylamine Derivativesmentioning

confidence: 99%