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

Elovaara, Heli; Parkash, Vimal; Fair-Mäkelä, Ruth; Salo‐Ahen, Outi M. H.; Guédez, Gabriela; Bligt-Lindén, Eva; Grönholm, Janne; Jalkanen, Sirpa; Salminen, Tiina A.

doi:10.1371/journal.pone.0166935

Cited by 9 publications

(18 citation statements)

References 51 publications

(96 reference statements)

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“…The lower Ki for theobromine relative to caffeine may be due to the formation of hydrogen bonds between the nitrogen in position 1 and amino acid side chains on PrAO. Imidazole was reported to be an inhibitor of PrAO at high concentrations (Elovaara et al, ) but at the highest level used herein (1.0 mM) showed only mild inhibition (Figure ).…”

Section: Discussionmentioning

confidence: 72%

Theobromine and related methylxanthines as inhibitors of Primary Amine Oxidase

Shanahan¹,

O'Sullivan

Tipton

et al. 2018

J Food Biochem

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Methylxanthines are among the most widely consumed drugs in the world and evidence of their health benefits has been growing in recent years. Primary Amine Oxidase (PrAO) has been recognized as a therapeutic target for the amelioration of inflammatory, vascular, and neurodegenerative diseases. Previous work in our laboratories showed that caffeine inhibited Bovine PrAO with a Ki of 1.0 mM using benzylamine as substrate. This study aimed to extend our previous work and explore the possibility that related methylxanthines might influence PrAO activity. While paraxanthine, theophylline, and 7‐methylxanthine had little effect on PrAO, theobromine was a noncompetitive inhibitor with a Ki of 276 ± 44 µM. The specific structural elements of methylxanthines that are required for inhibition allow us to suggest that their binding site on PrAO may be a target for therapeutics. The health benefits associated with dietary methylxanthine consumption could involve PrAO inhibition. Practical applications Inhibition of PrAO by methylxanthines may be significant in conferring health benefits. The design of PrAO inhibitors based on the structural motifs identified in this study (N‐methylation at specific locations) is indicated. Existing therapeutics based on a core xanthine structure can be evaluated for their effects on PrAO. PrAO inhibition must be considered as a potential mediator of the beneficial health effects of some methylxanthines. If inhibition in human tissues is comparable to, or greater than, that found in these studies it points to an important role for these compounds in human health.

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Section: Discussionmentioning

confidence: 72%

Theobromine and related methylxanthines as inhibitors of Primary Amine Oxidase

Shanahan¹,

O'Sullivan

Tipton

et al. 2018

J Food Biochem

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“…Such an explanation might also account for the complex kinetics observed. As with the bovine enzyme, it is possible that the methylxanthines in this study were binding to one or more imidazole binding site(s) identified in structural studies [40,45]. If blocking both of these binding sites caused inhibition of activity, then the complex kinetics we observed might be expected.…”

Section: Nature Of the Prao Inhibition Induced By Methylxanthines In mentioning

confidence: 82%

Methylxanthines Inhibit Primary Amine Oxidase and Monoamine Oxidase Activities of Human Adipose Tissue

et al. 2020

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Background: Methylxanthines including caffeine and theobromine are widely consumed compounds and were recently shown to interact with bovine copper-containing amine oxidase. To the best of our knowledge, no direct demonstration of any interplay between these phytochemicals and human primary amine oxidase (PrAO) has been reported to date. We took advantage of the coexistence of PrAO and monoamine oxidase (MAO) activities in human subcutaneous adipose tissue (hScAT) to test the interaction between several methylxanthines and these enzymes, which are involved in many key pathophysiological processes. Methods: Benzylamine, methylamine, and tyramine were used as substrates for PrAO and MAO in homogenates of subcutaneous adipose depots obtained from overweight women undergoing plastic surgery. Methylxanthines were tested as substrates or inhibitors by fluorimetric determination of hydrogen peroxide, an end-product of amine oxidation. Results: Semicarbazide-sensitive PrAO activity was inhibited by theobromine, caffeine, and isobutylmethylxanthine (IBMX) while theophylline, paraxanthine, and 7-methylxanthine had little effect. Theobromine inhibited PrAO activity by 54% at 2.5 mM. Overall, the relationship between methylxanthine structure and the degree of inhibition was similar to that seen with bovine PrAO, although higher concentrations (mM) were required for inhibition. Theobromine also inhibited oxidation of tyramine by MAO, at the limits of its solubility in a DMSO vehicle. At doses higher than 12 % v/v, DMSO impaired MAO activity. MAO was also inhibited by millimolar doses of IBMX, caffeine and by other methylxanthines to a lesser extent. Conclusions: This preclinical study extrapolates previous findings with bovine PrAO to human tissues. Given that PrAO is a potential target for anti-inflammatory drugs, it indicates that alongside phosphodiesterase inhibition and adenosine receptor antagonism, PrAO and MAO inhibition could contribute to the health benefits of methylxanthines, especially their anti-inflammatory effects.

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“…Moreover, Siglec-9 peptides targeted to hAOC3 have been used for PET (Positron Emission Tomography) imaging of inflammation and cancer using different animal models 9 – 12 and it was originally proposed that the Siglec-9 peptide binds covalently to the TPQ cofactor of hAOC3 8 . According to the recent data obtained using the full Siglec-9 extracellular domain, Siglec-9 is neither a substrate nor inhibitor for hAOC3 but it enhances the catalytic activity of hAOC3 towards the monoamine substrate benzylamine 13 . The interactions between Siglec-9 and the enzymatic groove of hAOC3 are mediated by two arginines located at the C2 2 domain of Siglec-9, Arg284 and Arg290 (R3 and R9 in the peptide, respectively) 8 , 13 .…”

Section: Introductionmentioning

confidence: 99%

Mapping the interaction site and effect of the Siglec-9 inflammatory biomarker on human primary amine oxidase

Carvalho

Elovaara

Ruyck

et al. 2018

Sci Rep

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Human primary amine oxidase (hAOC3), also known as vascular adhesion protein 1, mediates leukocyte rolling and trafficking to sites of inflammation by a multistep adhesion cascade. hAOC3 is absent on the endothelium of normal tissues and is kept upregulated during inflammatory conditions, which is an applicable advantage for imaging inflammatory diseases. Sialic acid binding immunoglobulin like-lectin 9 (Siglec-9) is a leukocyte ligand for hAOC3. The peptide (CARLSLSWRGLTLCPSK) based on the region of Siglec-9 that interacts with hAOC3, can be used as a specific tracer for hAOC3-targeted imaging of inflammation using Positron Emission Tomography (PET). In the present study, we show that the Siglec-9 peptide binds to hAOC3 and triggers its amine oxidase activity towards benzylamine. Furthermore, the hAOC3 inhibitors semicarbazide and imidazole reduce the binding of wild type and Arg/Ala mutated Siglec-9 peptides to hAOC3. Molecular docking of the Siglec-9 peptide is in accordance with the experimental results and predicts that the R3 residue in the peptide interacts in the catalytic site of hAOC3 when the topaquinone cofactor is in the non-catalytic on-copper conformation. The predicted binding mode of Siglec-9 peptide to hAOC3 is supported by the PET studies using rodent, rabbit and pig AOC3 proteins.

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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

Cited by 9 publications

References 51 publications

Theobromine and related methylxanthines as inhibitors of Primary Amine Oxidase

Theobromine and related methylxanthines as inhibitors of Primary Amine Oxidase

Methylxanthines Inhibit Primary Amine Oxidase and Monoamine Oxidase Activities of Human Adipose Tissue

Mapping the interaction site and effect of the Siglec-9 inflammatory biomarker on human primary amine oxidase

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