scholarly journals Zinc-α2-Glycoprotein Is An Inhibitor Of Amine Oxidase Copper-Containing 3

2019 ◽  
Author(s):  
Matthias Romauch
Keyword(s):  
Amine Oxidase ◽  
Current Knowledge ◽  
Primary Amines ◽  
Adhesion Protein ◽  
Diagnosis And Prognosis ◽  
Fat Mobilization ◽  
Clinical Biomarker ◽  
Progressive Weight Loss ◽  
Inhibitory Potential ◽  
Vascular Adhesion

AbstractZinc-alpha2-glycoprotein (ZAG) is a major plasma protein whose levels increase in chronic energy-demanding diseases and thus serves as an important clinical biomarker in the diagnosis and prognosis of the development of cachexia. Current knowledge suggests that ZAG mediates progressive weight loss through β-adrenergic signaling in adipocytes, resulting in the activation of lipolysis and fat mobilization. Here, through crosslinking experiments, amine oxidase copper-containing 3 (AOC3) is identified as a novel ZAG binding partner. AOC3 – also known as vascular adhesion protein 1 (VAP-1) and semicarbazide sensitive amine oxidase (SSAO) – deaminates primary amines, thereby generating the corresponding aldehyde, H2O2 and HN3. It is an ectoenzyme largely expressed by adipocytes and induced in endothelial cells during inflammation. Extravasation of immune cells depends on amine oxidase activity and AOC3-derived H2O2 has an insulinogenic effect. The observations described here suggest that ZAG acts as an allosteric inhibitor of AOC3 and interferes with the associated pro-inflammatory and anti-lipolytic functions. Thus, inhibition of the deamination of lipolytic hormone octopamine by AOC3 represents a novel mechanism by which ZAG might stimulate lipolysis. Furthermore, experiments involving overexpression of recombinant ZAG reveal that its glycosylation is co-regulated by oxygen availability and that the pattern of glycosylation affects its inhibitory potential. The newly identified protein interaction between AOC3 and ZAG highlights a previously unknown functional relationship, which may be relevant to inflammation, energy metabolism and the development of cachexia.

scholarly journals Zinc-α2-glycoprotein as an inhibitor of amine oxidase copper-containing 3

Open Biology ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 190035 ◽  
Author(s):  
Matthias Romauch
Keyword(s):  
Amine Oxidase ◽  
Current Knowledge ◽  
Primary Amines ◽  
Adhesion Protein ◽  
Diagnosis And Prognosis ◽  
Fat Mobilization ◽  
Clinical Biomarker ◽  
Progressive Weight Loss ◽  
Inhibitory Potential ◽  
Vascular Adhesion

Zinc-α2-glycoprotein (ZAG) is a major plasma protein whose levels increase in chronic energy-demanding diseases and thus serves as an important clinical biomarker in the diagnosis and prognosis of the development of cachexia. Current knowledge suggests that ZAG mediates progressive weight loss through β-adrenergic signalling in adipocytes, resulting in the activation of lipolysis and fat mobilization. Here, through cross-linking experiments, amine oxidase copper-containing 3 (AOC3) is identified as a novel ZAG binding partner. AOC3—also known as vascular adhesion protein 1 (VAP-1) and semicarbazide sensitive amine oxidase (SSAO)—deaminates primary amines, thereby generating the corresponding aldehyde, H 2 O 2 and NH 3 . It is an ectoenzyme largely expressed by adipocytes and induced in endothelial cells during inflammation. Extravasation of immune cells depends on amine oxidase activity and AOC3-derived H 2 O 2 has an insulinogenic effect. The observations described here suggest that ZAG acts as an allosteric inhibitor of AOC3 and interferes with the associated pro-inflammatory and anti-lipolytic functions. Thus, inhibition of the deamination of lipolytic hormone octopamine by AOC3 represents a novel mechanism by which ZAG might stimulate lipolysis. Furthermore, experiments involving overexpression of recombinant ZAG reveal that its glycosylation is co-regulated by oxygen availability and that the pattern of glycosylation affects its inhibitory potential. The newly identified protein interaction between AOC3 and ZAG highlights a previously unknown functional relationship, which may be relevant to inflammation, energy metabolism and the development of cachexia.

scholarly journals Comparison of Inhibitor and Substrate Selectivity between Rodent and Human Vascular Adhesion Protein-1

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Ryo Kubota ◽  
Michael J. Reid ◽  
Kuo Lee Lieu ◽  
Mark Orme ◽  
Christine Diamond ◽  
...  
Keyword(s):  
Amine Oxidase ◽  
Leukocyte Adhesion ◽  
Primary Amines ◽  
Oxidative Deamination ◽  
Adhesion Protein ◽  
Common Marker ◽  
Small Primary ◽  
Vascular Adhesion ◽  
Vascular Adhesion Protein 1

Vascular adhesion protein-1 (VAP-1) is an ectoenzyme that functions as a copper-containing amine oxidase and is involved in leukocyte adhesion at sites of inflammation. Inhibition of VAP-1 oxidative deamination has become an attractive target for anti-inflammatory therapy with demonstrated efficacy in rodent models of inflammation. A previous comparison of purified recombinant VAP-1 from mouse, rat, monkey, and human gene sequences predicted that rodent VAP-1 would have higher affinity for smaller hydrophilic substrates/inhibitors because of its narrower and more hydrophilic active site channel. An optimized in vitro oxidative deamination fluorescence assay with benzylamine (BA) was used to compare inhibition of five known inhibitors in recombinant mouse, rat, and human VAP-1. Human VAP-1 was more sensitive compared to rat or mouse VAP-1 (lowest IC50 concentration) to semicarbazide but was least sensitive to hydralazine and LJP-1207. Hydralazine had a lower IC50 in rats compared to humans, although not significant. However, the IC50 of hydralazine was significantly higher in the rat compared to mouse VAP-1. The larger hydrophobic compounds from Astellas (compound 35c) and Boehringer Ingelheim (PXS-4728A) were hypothesized to have higher binding affinity for human VAP-1 compared to rodent VAP-1 since the channel in human VAP-1 is larger and more hydrophobic than that in rodent VAP-1. Although the sensitivity of these two inhibitors was the lowest in the mouse enzyme, we found no significant differences between mouse, rat, and human VAP-1. Michaelis-Menten kinetics of the small primary amines phenylethylamine and tyramine were also compared to the common marker substrate BA demonstrating that BA had the highest affinity among the substrates. Rat VAP-1 had the highest affinity for all three substrates and mouse VAP-1 had intermediate affinity for BA and phenylethylamine, but tyramine was not a substrate for mouse VAP-1 under these assay conditions. These results suggest that comparing oxidative deamination in mouse and rat VAP-1 may be important if using these species for preclinical efficacy models.

scholarly journals Vascular Adhesion Protein-1 (VAP-1)/Semicarbazide-Sensitive Amine Oxidase (SSAO): A Potential Therapeutic Target for Atherosclerotic Cardiovascular Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Hui Li ◽  
Shiyu Du ◽  
Panpan Niu ◽  
Xiaosong Gu ◽  
Jun Wang ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Amine Oxidase ◽  
Vascular Inflammation ◽  
Adhesion Protein ◽  
Diagnosis And Prognosis ◽  
Atherosclerotic Lesions ◽  
Vascular Adhesion ◽  
Atherosclerotic Cardiovascular Diseases ◽  
Progression Of Atherosclerosis ◽  
Vascular Adhesion Protein 1

Vascular adhesion protein-1 (VAP-1) is a semicarbazide-sensitive amine oxidase (SSAO), whose enzymatic activity regulates the adhesion/exudation of leukocytes in/from blood vessels. Due to its abundant expressions in vascular systems and prominent roles in inflammations, increasing attentions have been paid to the roles of VAP-1/SSAO in atherosclerosis, a chronic vascular inflammation that eventually drives clinical cardiovascular events. Clinical studies have demonstrated a potential value of soluble VAP-1 (sVAP-1) for the diagnosis and prognosis of cardiovascular diseases. Recent findings revealed that VAP-1 is expressed in atherosclerotic plaques and treatment with VAP-1 inhibitors alleviates the progression of atherosclerosis. This review will focus on the roles of VAP-1/SSAO in the progression of atherosclerotic lesions and therapeutic potentials of VAP-1 inhibitors for cardiovascular diseases.

scholarly journals Human Siglec-10 can bind to vascular adhesion protein-1 and serves as its substrate

Blood ◽  
2009 ◽  
Vol 114 (26) ◽  
pp. 5385-5392 ◽  
Author(s):  
Elina Kivi ◽  
Kati Elima ◽  
Kristiina Aalto ◽  
Yvonne Nymalm ◽  
Kaisa Auvinen ◽  
...  
Keyword(s):  
Primary Amines ◽  
Leukocyte Trafficking ◽  
Hydrogen Peroxide Production ◽  
Lymphocyte Adhesion ◽  
Adhesion Protein ◽  
Inflammatory Microenvironment ◽  
Inflamed Endothelium ◽  
End Products ◽  
Vascular Adhesion ◽  
Vascular Adhesion Protein 1

Abstract Leukocytes migrate from the blood into areas of inflammation by interacting with various adhesion molecules on endothelial cells. Vascular adhesion protein-1 (VAP-1) is a glycoprotein expressed on inflamed endothelium where it plays a dual role: it is both an enzyme that oxidizes primary amines and an adhesin that is involved in leukocyte trafficking to sites of inflammation. Although VAP-1 was identified more than 15 years ago, the counterreceptor(s) for VAP-1 on leukocytes has remained unknown. Here we have identified Siglec-10 as a leukocyte ligand for VAP-1 using phage display screenings. The binding between Siglec-10 and VAP-1 was verified by different adhesion assays, and this interaction was also consistent with molecular modeling. Moreover, the interaction between Siglec-10 and VAP-1 led to increased hydrogen peroxide production, indicating that Siglec-10 serves as a substrate for VAP-1. Thus, the Siglec-10–VAP-1 interaction seems to mediate lymphocyte adhesion to endothelium and has the potential to modify the inflammatory microenvironment via the enzymatic end products.

It can be a complicated life being an enzyme

2003 ◽  
Vol 31 (3) ◽  
pp. 711-715 ◽  
Author(s):  
K.F. Tipton ◽  
M.I. O'Sullivan ◽  
G.P. Davey ◽  
J. O'Sullivan
Keyword(s):  
Amine Oxidase ◽  
Reaction Products ◽  
Functional Protein ◽  
Adhesion Protein ◽  
Protein Databases ◽  
Detoxifying Enzyme ◽  
Genetic Deletion ◽  
Vascular Adhesion ◽  
Catalytic Functions

It is becoming increasingly apparent that many well-known enzymes have alternative non-enzymic functions. Similarly, several proteins that were identified as having non-catalytic functions were subsequently found to have enzyme activities. Some examples are considered to illustrate the diversity of alternative functions. The semicarbazide-sensitive amine oxidase (EC 1.4.3.6) is considered in more depth as an example. It was originally believed to be a detoxifying enzyme, but the reaction products may have important signalling functions. Furthermore, this enzyme, from some sources, also behaves as a vascular-adhesion protein. Finally, the challenges posed by such multiplicity of functions for the interpretation of genetic deletion, in vivo inhibition and the development of functional protein databases are briefly considered.

Bioluminescent Method for Assaying Multiple Semicarbazide-Sensitive Amine Oxidase (SSAO) Family Members in Both 96- and 384-Well Formats

2011 ◽  
Vol 16 (9) ◽  
pp. 1106-1111 ◽  
Author(s):  
Gregory W. Peet ◽  
Susan Lukas ◽  
Melissa Hill-Drzewi ◽  
Leslie Martin ◽  
Irina V. Rybina ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Immune Cell ◽  
Amine Oxidase ◽  
Inflammatory Diseases ◽  
Live Cells ◽  
Primary Amines ◽  
Cell Trafficking ◽  
Vascular Adhesion

Vascular adhesion protein–1 (VAP-1), also known as semicarbazide-sensitive amine oxidase (SSAO) or copper-containing amine oxidase (AOC3, EC 1.4.3.6), catalyzes oxidative deamination of primary amines. One endogenous substrate has recently been described (Siglec 10), and although its mechanism of action in vivo is not completely understood, it is suggested to play a role in immune cell trafficking, making it a target of interest for autoimmune and inflammatory diseases. Much of the enzymology performed around this target has been conducted with absorbance, fluorescent, or radiometric formats that can have some limitations for high-throughput screening and subsequent compound profiling. The authors present the use of a bioluminescent assay, originally developed for monoamine oxidase enzymes, in a high-throughput format. It can be used for related SSAOs such as AOC1 given their substrate similarity with VAP-1. The authors also demonstrate that it is compatible with different sources of VAP-1, both purified recombinant and VAP-1 overexpressed on live cells.

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