Carbohydrates located on the top of the “cap” contribute to the adhesive and enzymatic functions of vascular adhesion protein‐1

Maula, Sanna-Mari; Salminen, Tiina A.; Kaitaniemi, Sam; Nymalm, Yvonne; Smith, David J.; Jalkanen, Sirpa

doi:10.1002/eji.200526351

Cited by 24 publications

(26 citation statements)

References 33 publications

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“…Furthermore, the R120S mutant, almost incapable of binding to hAOC3 under flow conditions (Fig 6C), modulated the amine oxidase activity like the WT protein (Fig 7C), but the R120S/R284S and R120S/R290S double mutants had lost this capacity (Fig 7C). This result explains our previous data according to which the removal of six N-glycosylation sites from the hAOC3 dimer could simultaneously reduce lymphocyte binding and increase enzymatic activity [14]. Consequently, in this study we have discovered a biological role for the binding of R284 and R290 to the active site of hAOC3: upon binding they modulate the amine oxidase activity of hAOC3.…”

Section: Discussionsupporting

confidence: 83%

“…The two functions of hAOC3 are interlinked since inhibition of the enzymatic activity of hAOC3 increases rolling velocity but reduces adhesion and transmigration steps of leukocyte extravasation in vivo [12]. Additionally, sialic acids of the hAOC3-attached glycans are crucial for adhesion [13] and the hAOC3 glycosylation is important in the initial recognition but also regulates the enzymatic activity [14]. Since the small molecular inhibitors of hAOC3 oxidase activity are shown to prevent the inflammatory function of hAOC3 in vivo , the hAOC3 inhibitors could be used in treating acute and chronic inflammatory conditions as well as tumor progression and metastatic spread of cancer (reviewed in [15]).…”

Section: Introductionmentioning

confidence: 99%

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Multivalent Interactions of Human Primary Amine Oxidase with the V and C22 Domains of Sialic Acid-Binding Immunoglobulin-Like Lectin-9 Regulate Its Binding and Amine Oxidase Activity

et al. 2016

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Sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on leukocyte surface is a counter-receptor for endothelial cell surface adhesin, human primary amine oxidase (hAOC3), a target protein for anti-inflammatory agents. This interaction can be used to detect inflammation and cancer in vivo, since the labeled peptides derived from the second C2 domain (C22) of Siglec-9 specifically bind to the inflammation-inducible hAOC3. As limited knowledge on the interaction between Siglec-9 and hAOC3 has hampered both hAOC3-targeted drug design and in vivo imaging applications, we have now produced and purified the extracellular region of Siglec-9 (Siglec-9-EC) consisting of the V, C21 and C22 domains, modeled its 3D structure and characterized the hAOC3–Siglec-9 interactions using biophysical methods and activity/inhibition assays. Our results assign individual, previously unknown roles for the V and C22 domains. The V domain is responsible for the unusually tight Siglec-9–hAOC3 interactions whereas the intact C22 domain of Siglec-9 is required for modulating the enzymatic activity of hAOC3, crucial for the hAOC3-mediated leukocyte trafficking. By characterizing the Siglec-9-EC mutants, we could conclude that R120 in the V domain likely interacts with the terminal sialic acids of hAOC3 attached glycans whereas residues R284 and R290 in C22 are involved in the interactions with the active site channel of hAOC3. Furthermore, the C22 domain binding enhances the enzymatic activity of hAOC3 although the sialic acid-binding capacity of the V domain of Siglec-9 is abolished by the R120S mutation. To conclude, our results prove that the V and C22 domains of Siglec-9-EC interact with hAOC3 in a multifaceted and unique way, forming both glycan-mediated and direct protein-protein interactions, respectively. The reported results on the mechanism of the Siglec-9–hAOC3 interaction are valuable for the development of hAOC3-targeted therapeutics and diagnostic tools.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Multivalent Interactions of Human Primary Amine Oxidase with the V and C22 Domains of Sialic Acid-Binding Immunoglobulin-Like Lectin-9 Regulate Its Binding and Amine Oxidase Activity

et al. 2016

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“…This result has consistently been noted with our SSAO inhibitors from several distinct chemical series and thus may reflect species-specific sequence differences at the enzyme active site or cell-and tissue-specific alterations in SSAO glycosylation patterns. Consistent with this possibility, modification of SSAO glycosylation has been shown to directly influence the enzymatic activity, as well as the ability of SSAO to support leukocyte adhesion (Maula et al, 2005). The specificity of LJP 1586 for inhibition of SSAO was demonstrated against a large panel of receptors and enzymes.…”

Section: Aoc3/ssao Inhibition By Ljp 1586 873mentioning

confidence: 75%

Anti-Inflammatory Effects of LJP 1586 [Z-3-Fluoro-2-(4-methoxybenzyl)allylamine Hydrochloride], an Amine-Based Inhibitor of Semicarbazide-Sensitive Amine Oxidase Activity

O’Rourke¹,

Wang²,

Miller³

et al. 2007

J Pharmacol Exp Ther

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Semicarbazide-sensitive amine oxidase (SSAO, amine oxidase, copper-containing 3, and vascular adhesion protein-1) is a copper-containing enzyme that catalyzes the oxidative deamination of primary amines to an aldehyde, ammonia, and hydrogen peroxide. SSAO is also involved in leukocyte migration to sites of inflammation, and the enzymatic activity of SSAO is essential to this role. Thus, inhibition of SSAO enzyme activity represents a target for the development of small molecule anti-inflammatory compounds. Here, we have characterized the novel SSAO inhibitor, Z-3-fluoro-2-(4-methoxybenzyl)allylamine hydrochloride (LJP 1586), and assessed its anti-inflammatory activity. LJP 1586 is a potent inhibitor of rodent and human SSAO activity, with IC 50 values between 4 and 43 nM. The selectivity of LJP 1586 was confirmed with a broad panel of receptors and enzymes that included the monoamine oxidases A and B. Oral administration of LJP 1586 resulted in complete inhibition of rat lung SSAO, with an ED 50 between 0.1 and 1 mg/kg, and a pharmacodynamic half-life of greater than 24 h. In a mouse model of inflammatory leukocyte trafficking oral dosing with LJP 1586 resulted in significant dose-dependent inhibition of neutrophil accumulation, with an effect comparable to that of anti-leukocyte function-associated antigen-1 antibody. In a rat model of LPS-induced lung inflammation, administration of 10 mg/kg LJP 1586 resulted in a 55% significant reduction in transmigrated cells recovered by bronchoalveolar lavage. The results demonstrate that a selective, orally active small molecule inhibitor of SSAO is an effective anti-inflammatory compound in vivo and provide further support for SSAO as a therapeutic anti-inflammatory target.Semicarbazide-sensitive amine oxidase [SSAO, AOC3, and vascular adhesion protein-1 (VAP-1)] is a copper-and topaquinone (TPQ) cofactor-containing enzyme that performs the oxidative deamination of primary amines. Endogenous substrates for SSAO include methylamine, formed from adrenaline and creatine metabolism, and aminoacetone, a product of amino acid catabolism. The active enzyme is a dimer and exists as both a type II transmembrane protein and in soluble form in plasma (for reviews see Boomsma et al

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“…20,21 On the top of the molecule there are multiple O-and N-linked oligosaccharides, which may be important for its adhesive function. 22 There is also a groove on the surface of VAP-1 which opens into narrow and deep substrate channel leading to the catalytic center of the molecule buried relatively deep inside each monomer. The amino acids guarding the entry into the channel differ between different SSAO and are likely to serve a key role in conferring the substrate specificity of these molecules.…”

Section: Figurementioning

confidence: 99%

VAP-1 and CD73, Endothelial Cell Surface Enzymes in Leukocyte Extravasation

Jalkanen

Salmi

2008

ATVB

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112

104

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Abstract-Leukocyte extravasation from the blood into tissues is crucial for normal immune surveillance and in inflammation. Traditionally molecules belonging to selectin, chemokine, integrin, and immunoglobulin super families are thought to mediate the multiple adhesive and activation events needed for a successful emigration cascade. Recently, emerging evidence suggests that enzymes expressed on the surface of endothelial cells and leukocytes also contribute to the leukocyte extravasation cascade. Here we briefly review the role of vascular adhesion protein-1 (VAP-1) and CD73, 2 cell surface enzymes, in leukocyte migration form the blood into the tissues. Importantly, specific enzyme inhibitors, gene-deficient mice, and recombinant enzymes have recently unambiguously shown that the catalytic activity of these enzymes regulates the leukocyte traffic.

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Carbohydrates located on the top of the “cap” contribute to the adhesive and enzymatic functions of vascular adhesion protein‐1

Cited by 24 publications

References 33 publications

Multivalent Interactions of Human Primary Amine Oxidase with the V and C22 Domains of Sialic Acid-Binding Immunoglobulin-Like Lectin-9 Regulate Its Binding and Amine Oxidase Activity

Multivalent Interactions of Human Primary Amine Oxidase with the V and C22 Domains of Sialic Acid-Binding Immunoglobulin-Like Lectin-9 Regulate Its Binding and Amine Oxidase Activity

Anti-Inflammatory Effects of LJP 1586 [Z-3-Fluoro-2-(4-methoxybenzyl)allylamine Hydrochloride], an Amine-Based Inhibitor of Semicarbazide-Sensitive Amine Oxidase Activity

VAP-1 and CD73, Endothelial Cell Surface Enzymes in Leukocyte Extravasation

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