Structure of the oligosaccharide chains in human alpha 1-protease inhibitor.

Hodges, Linda C.; Laine, Roger A.; Chan, S.K.

doi:10.1016/s0021-9258(19)86877-1

Cited by 70 publications

(18 citation statements)

References 16 publications

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“…10-8 M) in the isolated rabbit hepatocytes system (Lee et al, 1983), indicating that a bulk of the cluster effect can be generated with only three Gal residues and that neither a large molecular size nor the protein backbone is necessary for the expression of the cluster effect. The most potent bivalent oligosaccharide in these studies was PENTA-2,4 (Kd = 3 X 10~7 M), which represents a portion of the desialylated complex-type triantennary oligosaccharide chain of oq-protease inhibitor (Hodges et al, 1979). The most potent trivalent ligand was NONA I (Kd = 7 X 10"9 M), which contains structural elements of PENTA-2,4 and HEPTA and represents the outer portion of the above-mentioned triantennary oligosaccharide chain.…”

Section: Discussionmentioning

confidence: 92%

New synthetic cluster ligands for galactose/N-acetylgalactosamine-specific lectin of mammalian liver

Lee¹,

Lin²,

Lee³

1984

Biochemistry

182

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Synthetic ligands containing up to six residues of nonreducing terminal galactose were prepared. The synthesis involved coupling of carboxyl groups of N-benzyloxy-carbonylaspartic acid or of N-benzyloxycarbonyltyrosyl-gamma-glutamylglutamic acid to the omega-amino group of the aglycon of a glycoside that contained up to three lactosyl residues. The benzyloxycarbonyl group was removed by hydrogenolysis before these ligands were tested as inhibitors to the binding of 125I-asialoorosomucoid to the galactose/N-acetylgalactosamine lectin, both soluble and on the surface of freshly isolated mammalian hepatocytes. Each addition of a galactosyl residue to an existing ligand structure invariably increased the binding affinity of such a ligand. However, at each level of galactose valency, the binding constant varied as much as 1000-fold depending on the structure of the ligand. At a given level of valency, the binding strength of a cluster ligand depended mainly on two factors: (1) the maximum spatial inter-galactose distances and (2) the flexibility of the arm connecting galactosyl residues and the branch points. It has been postulated that the three galactose-combining sites of the lectin are arranged in space at the vertexes of a triangle whose sides are 15, 22, and 25 A [Lee, Y. C., Townsend, R. R., Hardy, M. R., Lönngren, J., & Bock, K. (1984) in Biochemical and Biophysical Studies of Proteins and Nucleic Acids (Lo, T. B., Liu, T. Y., & Li, C. H., Eds.) pp 349-360, Elsevier, New York]. Ligands having inter-galactose distances shorter than these lengths were invariably poor ligands at their respective level of valency.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 92%

New synthetic cluster ligands for galactose/N-acetylgalactosamine-specific lectin of mammalian liver

Lee¹,

Lin²,

Lee³

1984

Biochemistry

182

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“…The known heterogeneity of oligosaccharides linked to ASOR (Fournet et al, 1978;Schmid et al, 1979) could certainly account for the observed complexity of hepatic lectin-ASOR interaction, even if the hepatic lectin sites themselves were all identical. TRI, though simpler in structure, may still be heterogeneous with respect to fine details of its constituent oligosaccharide structures [for example, the attachment site of the third iV-acetyllactosamine branch has not been determined (Hodges et al, 1979;Mega et al, 1980)]. Also, a recent report (Bayard et al, 1982) indicates that some TRI preparations from human a-1 protease inhibitor may also contain biantennary structures with GlcNAc linked ß\-+4 to the ßlinked Man.…”

Section: Discussionmentioning

confidence: 99%

Different modes of ligand binding to the hepatic galactose/N-acetylgalactosamine lectin on the surface of rabbit hepatocytes

Hardy¹,

Townsend²,

Parkhurst³

et al. 1985

Biochemistry

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A study of the binding of three different 125I-labeled, galactose-terminated ligands to the hepatic galactose/N-acetylgalactosamine-specific lectin found on the surface of rabbit hepatocytes revealed that the different ligands manifest different physical parameters of binding. Asialoorosomucoid (125I-ASOR) binding was best described as involving two independent classes of binding sites on rabbit hepatocytes, with 161 000 sites/cell with a dissociation constant of 0.44 nM and 292 000 sites/cell with a Kd of 9.7 nM. Asialotriantennary glycopeptide purified from human alpha-1 protease inhibitor and modified with tyrosine at the N-terminus to permit radioiodination (TRI) [Lee, Y. C., Townsend, R. R., Hardy, M. R., Lönngren, J., Arnarp, J., Haraldsson, M., & Lönn, H. (1983) J. Biol. Chem. 258, 199-202] was also found to bind to two apparent classes of binding sites but with different binding parameters: 292 000 sites/cell of Kd = 1.47 nM and 982 000 sites/cell of Kd = 25.3 nM. A synthetic ligand, alpha,beta-diaspartamide of tris[(beta-lactosyloxy)methyl](6-aminohexanamido)methane (di-tris-lac) containing six nonreducing galactose residues [Lee, R. T., Lin, P., & Lee, Y. C. (1984) Biochemistry 23, 4255-4261], was found to bind to 817 000 sites/cell of Kd = 0.63 nM and 1.23 X 10(6) sites/cell of Kd = 25.3 nM. Thus, there were many more total binding sites for TRI or di-tris-lac on the surface of rabbit hepatocytes than there were for asialoorosomucoid, although the dissociation constants were similar for all three ligands.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…A number of these are associated with pronounced deficiency of AAT in the circulation; the most important is the Z mutation. 105 The most commonly found form of AAT in humans is the M phenotype which has normal levels of the protein and is at no increased risk of lung or liver disease. 22 Multiple isoforms of AAT are known to exist, and these differ according to the glycan groups found at these three sites (Figure 2).…”

Section: Glycosylation Of Acute Phase Proteinsmentioning

confidence: 99%

“…There are multiple genetic variations of AAT which differ according to their electrophoretic properties and in their concentration found in plasma. A number of these are associated with pronounced deficiency of AAT in the circulation; the most important is the Z mutation . The most commonly found form of AAT in humans is the M phenotype which has normal levels of the protein and is at no increased risk of lung or liver disease .…”

Section: Introductionmentioning

confidence: 99%

The Role and Importance of Glycosylation of Acute Phase Proteins with Focus on Alpha-1 Antitrypsin in Acute and Chronic Inflammatory Conditions

et al. 2014

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Acute phase proteins (APPs) are a group of circulating plasma proteins which undergo changes quantitatively or qualitatively at the time of inflammation. Many of these APPs are glycosylated, and it has been shown that alterations in glycosylation may occur in inflammatory and malignant conditions. Changes in glycosylation have been studied as potential biomarkers in cancer and also in chronic inflammatory conditions and have been shown to correlate with disease severity in certain conditions. Serine protease inhibitors (serpins), many of which are also APPs, are proteins involved in the control of proteases in numerous pathways. Alpha-1 Antitrypsin (AAT) is the most abundant serpin within the circulation and is an APP which has been shown to increase in response to inflammation. The primary role of AAT is maintaining the protease/antiprotease balance in the lung, but it also possesses important anti-inflammatory and immune-modulating properties. Several glycoforms of AAT exist, and they possess differing properties in regard to plasma half-life and stability. Glycosylation may also be important in determining the immune modulatory properties of AAT. The review will focus on the role and importance of glycosylation in acute phase proteins with particular attention to AAT and its use as a biomarker of disease. The review describes the processes involved in glycosylation, how glycosylation changes in differing disease states, and the alterations that occur to glycans of APPs with disease and inflammation. Finally, the review explores the importance of changes in glycosylation of AAT at times of inflammation and in malignant conditions and how this may impact upon the functions of AAT.

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Structure of the oligosaccharide chains in human alpha 1-protease inhibitor.

Cited by 70 publications

References 16 publications

New synthetic cluster ligands for galactose/N-acetylgalactosamine-specific lectin of mammalian liver

New synthetic cluster ligands for galactose/N-acetylgalactosamine-specific lectin of mammalian liver

Different modes of ligand binding to the hepatic galactose/N-acetylgalactosamine lectin on the surface of rabbit hepatocytes

The Role and Importance of Glycosylation of Acute Phase Proteins with Focus on Alpha-1 Antitrypsin in Acute and Chronic Inflammatory Conditions

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