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

Abstract

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.

Beneficial Impact of Semicarbazide-Sensitive Amine Oxidase Inhibition on the Potential Cytotoxicity of Creatine Supplementation in Type 2 Diabetes Mellitus

“…Along with the referred substances, zinc-α2-glycoprotein (ZAG) —a major plasma protein is found to owe SSAO inhibitive capacity via binding the enzyme at the non-catalytic site and reducing its activity non-competitively [ 119 ]. In the body, it is a responsible factor in stimulating lipolysis [ 120 ].…”

Attenuation of Weight Gain and Prevention of Associated Pathologies by Inhibiting SSAO

“…In addition, SSAO inhibition can have a positive influence not only on diabetes [48] but for some other pathologies, e.g., inflammation diseases [37]. Interestingly, Zinc-α2-glycoprotein (ZAG), a plasma protein with SSAO-inhibitive capacity [49], is found to reduce body weight drastically [50]. There are researches showing that SSAO substrate benzylamine ameliorates insulin secretion and glucose uptake in Goto-Kakizaki rats [24], dependent on the hydrogen-peroxide which is produced alongside SSAO activity.…”

Increased monoamine oxidase activity and imidazoline binding sites in insulin-resistant adipocytes from obese Zucker rats

“…SSAO-mediated deamination reactions generate hydrogen peroxide, which also induces antilipolytic and lipogenic effects[ 54 ], especially in the presence of vanadate, by forming pervanadate, a potent insulin-like agent[ 38 , 55 ]. More recently, it has been proposed that SSAO interplays with Zinc-α2-glycoprotein[ 56 ] and with lipid metabolism in adipocytes[ 57 ]. In addition, SSAO is identical to vascular adhesion protein-1 (VAP-1), which supports leukocyte extravasation[ 58 ].…”