Evolution and functional classification of mammalian copper amine oxidases

Carvalho, Leonor Lopes de; Bligt-Lindén, Eva; Ramaiah, Arunachalam; Johnson, Mark S.; Salminen, Tiina A.

doi:10.1016/j.ympev.2019.106571

Cited by 19 publications

(21 citation statements)

References 72 publications

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“…The recent demonstration of an inhibitory effect of methylxanthines on bovine amine oxidase [12] is in agreement with such anti-inflammatory actions. Bovine plasma amine oxidase is a copper-containing amine oxidase, an ortholog to the product of the human AOC3 gene (Amine Oxidase, Copper-Containing 3) [13,14]. This enzyme, also called semicarbazide-sensitive amine oxidase or vascular adhesion protein-1 (SSAO/VAP-1) is involved in mediating lymphocyte extravasation at sites of inflammation [15].…”

Section: Introductionmentioning

confidence: 99%

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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Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…Despite BTT2052 being a potent inhibitor of hVAP-1 and not inhibiting MAO, it was an effective inhibitor of hDAO and hRAO [74]. This is understandable in light of our current knowledge of human CAO active site channels [1], showing that the residues in the catalytic site are highly conserved and residues in the active site channel contribute to the subtype specificity. As a small inhibitor, BTT2052 does not interact with these residues in the active site channel.…”

Section: Indanolsmentioning

confidence: 98%

“…In addition to species-specific binding properties (Table S2), differences in the expression profile of the CAO sub-families should be considered when model organisms are selected for in vivo studies [1]. As an example, the pyridazinone inhibitors had a similar in vitro potency against VAP-1 from human and cynomolgus monkey [10], but cynomolgus monkey is not a good model organism for in vivo studies since it also has soluble plasma amine oxidase (SAO; AOC4), the closest CAO family member to VAP-1 [1]. In fact, of all studied primates, only human and gorilla lacked SAO [1].…”

Section: The Risk For Interaction With Other Cao Sub-family Membersmentioning

confidence: 99%

“…As a summary of the previous studies on species-specific binding properties of hVAP-1 inhibitors, it is clear that computational methods should be used to predict the species-specific binding properties in hVAP-1-targeted ligand design. In general, the likelihood of species-specificity increases with enlarged ligand size and is most prominent for those ligands that interact with the active site channel farther away from the catalytic site [1].…”

Section: The Risk For Interaction With Other Cao Sub-family Membersmentioning

confidence: 99%

“…In humans, the copper-containing amine oxidase (CAO) family consists of three proteins [1]. Diamine oxidase (hDAO; AOC1) prefers diamines and is involved in the degradation of histamine [2], while retina-specific amine oxidase (hRAO; AOC2) is a monoamine oxidase with enzymatic activity in retina [3], and vascular adhesion protein-1 (hVAP-1; AOC3) is a multifunctional cell-surface receptor and an enzyme with preference for monoamines [4].…”

Section: Introductionmentioning

confidence: 99%

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Human Copper-Containing Amine Oxidases in Drug Design and Development

et al. 2020

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Two members of the copper-containing amine oxidase family are physiologically important proteins: (1) Diamine oxidase (hDAO; AOC1) with a preference for diamines is involved in degradation of histamine and (2) Vascular adhesion protein-1 (hVAP-1; AOC3) with a preference for monoamines is a multifunctional cell-surface receptor and an enzyme. hVAP-1-targeted inhibitors are designed to treat inflammatory diseases and cancer, whereas the off-target binding of the designed inhibitors to hDAO might result in adverse drug reactions. The X-ray structures for both human enzymes are solved and provide the basis for computer-aided inhibitor design, which has been reported by several research groups. Although the putative off-target effect of hDAO is less studied, computational methods could be easily utilized to avoid the binding of VAP-1-targeted inhibitors to hDAO. The choice of the model organism for preclinical testing of hVAP-1 inhibitors is not either trivial due to species-specific binding properties of designed inhibitors and different repertoire of copper-containing amine oxidase family members in mammalian species. Thus, the facts that should be considered in hVAP-1-targeted inhibitor design are discussed in light of the applied structural bioinformatics and structural biology approaches.

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Evolutionary and structural constraints influencing apolipoprotein A‐I amyloid behavior

et al. 2021

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Aggregation-prone region 1 (APR1), comprising residues 14-19, is consistently conserved during the evolutionary history of Apolipoprotein A-I. • APR1 contributes to thermal stability of the ɑ-helix bundle in the full-length Apolipoprotein A-I model. • Amyloid variants introduce a destabilizing effect on the monomer structure of Apolipoprotein A-I, in contrast to HDL-deficiency and naturally-occurring variants, which are nearly neutral. • During molecular dynamics simulations, G26R amyloidogenic mutant lead to the partial unfolding of ɑ-helix bundle and exposure of APR1..

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Evolution and functional classification of mammalian copper amine oxidases

Cited by 19 publications

References 72 publications

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

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

Human Copper-Containing Amine Oxidases in Drug Design and Development

Evolutionary and structural constraints influencing apolipoprotein A‐I amyloid behavior

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