Amine oxidase, copper containing 3 (AOC3), also known as vascular adhesion protein (VAP-1) and HPAO is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that in humans is encoded by the AOC3
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
on
chromosome 17
Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 83 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total D ...
. This
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
is a member of the
semicarbazide-sensitive amine oxidase (SSAO; aka primary amine oxidase) family of enzymes and is associated with many vascular diseases.
Structure
VAP-1 is a type 1 membrane-bound
glycoprotein that has a
distal adhesion domain and an enzymatically active
amine oxidase An amine oxidase is an enzyme that catalyzes the oxidative cleavage of alkylamines into aldehydes and ammonia
Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictoge ...
site outside of the membrane.
The AOC3 gene is mapped onto 17q21 and has an
exon count of 6.
Function
Amine oxidases are a family of
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s that catalyze the oxidation of various
endogenous amines, including
histamine
Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered ...
or
dopamine. VAP-1 constitutes the copper dependent class of amine oxidases, such as
lysyl oxidase
Lysyl oxidase (LOX), also known as protein-lysine 6-oxidase, is an enzyme that, in humans, is encoded by the ''LOX'' gene. It catalyzes the conversion of lysine molecules into highly reactive aldehydes that form cross-links in extracellular matr ...
or
lysine demethylase, and is one of the four known in humans. The other class is
flavin dependent such as
monoamine oxidase (MAO)
A and
B.
VAP-1, in particular, catalyzes the oxidative conversion of primary amines (
methylamine and
aminoacetone) to
aldehyde
In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...
s (
formaldehyde
Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section ...
and
methylglyoxal
Methylglyoxal (MGO) is the organic compound with the formula CH3C(O)CHO. It is a reduced derivative of pyruvic acid. It is a reactive compound that is implicated in the biology of diabetes. Methylglyoxal is produced industrially by degradation ...
) ammonium and
hydrogen peroxide
Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3%â ...
in the presence of copper and
quinone cofactor.
VAP-1 is primarily localized on the cell surface on the
adipocyte plasma membrane.
However, circulating VAP-1 has been shown to be the main source of SSAO in human serum. Serum VAP-1 originates from many tissues.
VAP-1 has adhesive properties, functional monoamine oxidase activity, and possibly plays a role in glucose handling, leukocyte trafficking, and migration during
inflammation
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
.
This rise in metabolic products contributes to generating advanced glycation end-products and oxidative stress along with the monoamine detoxification in the organism.
Like monoamine oxidase (MAO), VAP-1 can deaminate short-chain primary amines, but SSAO enzymes, including VAP-1, can tolerate several selective flavin-dependent MAO-A and MAO-B inhibitors like clorgiline, pargyline, and deprenyl, but are still sensitive to semicarbazide and other hydrazines, hydroxylamine and propargylamine.
VAP-1 is found in the smooth muscle of blood vessels and various other tissues, and can mostly be found in two forms: tissue-bound and soluble isoforms.
The tissue-bound SSAO is primarily located in the leukocytes, adipocytes, and the endothelium of highly vascularized tissues, including the kidney, liver, and gonads.
Thus, this form participates in cellular differentiation, deposition of the ECM (extracellular matrix) in smooth muscle cells, lipid trafficking in adipocytes and control of muscular tone, by mechanisms that are not completely understood.
The soluble form, which is commonly known as VAP-1, is a proinflammatory protein derived from shedding of the transmembrane protein. It is highly expressed on the endothelium of the lung and trachea, and absent from leukocytes and epithelial cells. It moderates leukocyte recruitment, is both an adhesion molecule and a primary amine oxidase, and plays a role in clinical disease.
Clinical significance
Membrane-bound VAP-1 releases an active, soluble form of the protein, which may be conducive to increased inflammation and the progression of many vascular disorders. In particular, elevation of VAP-1 activity and the increased enzymatic-mediated deamination is proposed to play a role in
renal
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...
and
vascular
The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away f ...
disease,
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
, acute and chronic
hyperglycemia, and
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
complications.
In diabetic patients, the amine oxidase activity stimulates
glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...
uptake via translocation of transporters to the cell membrane in adipocytes and smooth muscle cells. This modifies hepatic glucose homeostasis and may contribute to patterns of
GLUT expression in chronic disease, as insulin resistance in humans have been linked to altered expression of GLUT isoforms by granulosa cells and adipose tissues.
In particular, hydrogen peroxide, released during the
deamination
Deamination is the removal of an amino group from a molecule. Enzymes that catalyse this reaction are called deaminases.
In the human body, deamination takes place primarily in the liver, however it can also occur in the kidney. In situations of ...
of SSAO, acts as a signal-transducing molecule, affecting GLUT1 and GLUT4 translocation to the plasma membrane by granulosa cells and adipose tissue.
This mimics
insulin and interferes with cell processes in diabetic patients. Additionally, hydrogen peroxide, along with aldehydes and glucose, is involved in generating advanced glycation end-products and oxidative stress, which leads to the development of atherosclerosis, a disease in which plaque builds up inside arteries.
Cell processes involved in insulin resistance are often associated with elevated VAP-1 expression and modified GLUT expression in patients with liver diseases.
Accordingly, subjects with diabetes are often at an increased risk for the development of and mortality from various cancers, including colorectal cancer hepatocellular carcinoma. Because of hyperinsulinemia - the increased bioavailability of insulin-like growth factors-1 and hypoadiponectinemia - diabetic patients have a greater chance of developing oncogenesis and tumor progression. In one study, serum VAP-1 was shown to independently predict 10-year all-cause mortality, cardiovascular mortality, and cancer-related mortality in subjects with type 2 diabetes.
This may be because VAP-1 is involved in binding TIL, lymphokine-activated killer cells, and natural killer cells to the vasculature of cancer tissue.
Hence, increased serum VAP-1 activity has been repeatedly found to be associated with various vascular disorders, such as the complications of diabetes mellitus, acute and chronic hyperglycemia, congestive heart failure,
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...
, and
Alzheimer's disease.
The same elevation is seen in kidney disease, even when accounted for factors of age, gender, and smoking. Studies have established a strong correlation between serum VAP-1 levels and urinary albumin excretion, which supports the idea that VAP-1 may be involved in the pathogenesis of kidney damage in humans.
In renal pathology, the aldehydes produced by SSAO are highly reactive and lead to the formation of protein cross-linking and oxidative stress. Additionally, VAP-1 mediates leukocyte migration and, eventually, can lead to chronic inflammatory cell accumulation and the development of kidney fibrosis.
As for stroke patients, the products from deamination induce cytotoxicity protein cross-linking and amyloid-beta (Aβ) aggregation along with oxidative stress and thus are considered a potential risk factor for stress-related angiopathy. In these patients, VAP-1 may be involved in increasing vascular damage due to increased susceptibility of endothelial cells to oxygen-glucose deprivation (OGD).
In hemorrhagic stroke patients, plasmatic VAP-1 activity is increase, and in ischemic stroke patients, it can predict the appearance of parenchymal hemorrhages after tissue plasminogen activator treatment due to the transmigration of inflammatory cells into ischaemic brain. VAP-1-expression is increased in blood vessels of ischemic areas where it may be mediating neutrophil adhesion to vascular endothelium in ischemic heart. The presence of diminished expression of vascular VAP-1 in infarcted brain areas and the increased concentration of VAP-1 in serum suggests that acute cerebral ischaemia triggers early release of endothelial VAP-1 from brain vasculature.
Lastly, during pulmonary infection and airway hyper-activity, VAP-1 may also contribute to the recruitment of inflammatory cells and the transfer of neutrophils from the microvasculature.
Inhibitors of VAP-1 may be effective in reducing inflammation in various vascular diseases, but more studies are needed to understand to what extent.
Whether serum VAP-1 is a good biomarker for these diseases requires further investigation.
Although many studies concerning VAP-1 as a therapeutic target are becoming more frequent, it is difficult to study VAP-1 in cell or tissue systems, since the enzyme progressively loses its expression, and immortalized cell lines do not show any expression at all.
Interactions
VAP-1 has been shown to
interact
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with:
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MAO
References
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{{PDB Gallery, geneid=8639
Copper enzymes