Lysyl oxidase
Encyclopedia
Lysyl oxidase also known as protein-lysine 6-oxidase is a protein
that, in humans, is encoded by the LOX gene
. Its inhibition can cause lathyrism
, but, at the same time, its upregulation by tumor
cells may promote metastasis
of the existing tumor, causing it to become malignant and cancerous
.
is an extracellular copper enzyme
that catalyzes formation of aldehydes from lysine
residues in collagen
and elastin
precursors. These aldehydes are highly reactive, and undergo spontaneous chemical reactions with other lysyl oxidase-derived aldehyde residues, or with unmodified lysine residues. This results in cross-linking collagen and elastin, which is essential for stabilization of collagen fibrils and for the integrity and elasticity of mature elastin.
Complex cross-links are formed in collagen (pyridinoline
s derived from three lysine residues) and in elastin (desmosine
s derived from four lysine residues) that differ in structure.
The importance of lysyl oxidase-derived cross-linking was established from animal studies in which lysyl oxidase was inhibited either by nutritional copper-deficiency or by supplementation of diets with β-aminopropionitrile (BAPN), an inhibitor of lysyl oxidase. This resulted in lathyrism
, characterized by poor bone formation and strength, hyperextensible skin, weak ligaments, and increased occurrence of aortic aneurysms. These abnormalities correlated well with decreased cross-linking of collagen and elastin.
breast and head and neck tumors. Patients with high LOX-expressing tumors have poor overall survival. Furthermore, inhibition of LOX has been demonstrated to eliminate metastases in mice. Secreted LOX is responsible for the invasive properties of hypoxic cancer cells through focal adhesion kinase
activity and cell-to-matrix adhesion. LOX may be required to create a niche permissive for metastatic growth and, thus, may be required for hypoxia-induced metastasis.
In a rodent model of breast cancer, a small-molecule or antibody inhibitors of LOX abolished metastasis. LOX secreted by hypoxic breast tumor cells crosslinks collagen
in the basement membrane
and is essential for CD11b+
myeloid cell recruitment. CD11b+ cells in turn adhere to crosslinked collagen and produce matrix metalloproteinase-2
, which cleaves collagen, enhancing the invasion of metastasizing tumor cells. In contrast, LOX inhibition prevents CD11b+ cell recruitment and metastatic growth.
Hence, inhibitors of the LOX enzyme may be useful in preventing tumor progression and metastasis as well as treating other fibrotic disease involving remodeling of the extracellular matrix
, including neurodegenerative and cardiovascular diseases.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that, in humans, is encoded by the LOX gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. Its inhibition can cause lathyrism
Lathyrism
Lathyrism or Neurolathyrism is a neurological disease of humans and domestic animals, caused by eating certain legumes of the genus Lathyrus...
, but, at the same time, its upregulation by tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
cells may promote metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
of the existing tumor, causing it to become malignant and cancerous
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
.
Function
Lysyl oxidaseOxidase
An oxidase is any enzyme that catalyzes an oxidation-reduction reaction involving molecular oxygen as the electron acceptor. In these reactions, oxygen is reduced to water or hydrogen peroxide ....
is an extracellular copper enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that catalyzes formation of aldehydes from lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
residues in collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
and elastin
Elastin
Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched. Elastin is also an important load-bearing tissue in the bodies of...
precursors. These aldehydes are highly reactive, and undergo spontaneous chemical reactions with other lysyl oxidase-derived aldehyde residues, or with unmodified lysine residues. This results in cross-linking collagen and elastin, which is essential for stabilization of collagen fibrils and for the integrity and elasticity of mature elastin.
Complex cross-links are formed in collagen (pyridinoline
Pyridinoline
Pyridinoline is a fluorescent cross-linking compound of collagen fibers. Crosslinks in collagen andelastin are derived from lysyl and hydroxylysyl residues, a process catalyzed by lysyl oxidase. Fujimoto and colleagues first described the isolation and characterization of a fluorescent material in...
s derived from three lysine residues) and in elastin (desmosine
Desmosine
A desmosine cross-link is formed from three allysyl side chains plus one unaltered lysyl side chain from the same or neighbouring polypeptides.It is found in elastin. Desmosine causes a yellow color....
s derived from four lysine residues) that differ in structure.
The importance of lysyl oxidase-derived cross-linking was established from animal studies in which lysyl oxidase was inhibited either by nutritional copper-deficiency or by supplementation of diets with β-aminopropionitrile (BAPN), an inhibitor of lysyl oxidase. This resulted in lathyrism
Lathyrism
Lathyrism or Neurolathyrism is a neurological disease of humans and domestic animals, caused by eating certain legumes of the genus Lathyrus...
, characterized by poor bone formation and strength, hyperextensible skin, weak ligaments, and increased occurrence of aortic aneurysms. These abnormalities correlated well with decreased cross-linking of collagen and elastin.
Clinical significance
LOX expression is regulated by hypoxia-inducible factors (HIFs), and, hence, LOX expression is often upregulated in hypoxicHypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
breast and head and neck tumors. Patients with high LOX-expressing tumors have poor overall survival. Furthermore, inhibition of LOX has been demonstrated to eliminate metastases in mice. Secreted LOX is responsible for the invasive properties of hypoxic cancer cells through focal adhesion kinase
PTK2
PTK2 protein tyrosine kinase 2 , also known as Focal Adhesion Kinase , is a protein that, in humans, is encoded by the PTK2 gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion and spreading processes...
activity and cell-to-matrix adhesion. LOX may be required to create a niche permissive for metastatic growth and, thus, may be required for hypoxia-induced metastasis.
In a rodent model of breast cancer, a small-molecule or antibody inhibitors of LOX abolished metastasis. LOX secreted by hypoxic breast tumor cells crosslinks collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
in the basement membrane
Basement membrane
The basement membrane is a thin sheet of fibers that underlies the epithelium, which lines the cavities and surfaces of organs including skin, or the endothelium, which lines the interior surface of blood vessels.- Composition :...
and is essential for CD11b+
Integrin alpha M
Integrin alpha M is one protein subunit that forms the heterodimeric integrin alpha-M beta-2 molecule, also known as macrophage-1 antigen or complement receptor 3 . ITGAM is also known as CR3A, and cluster of differentiation molecule 11B...
myeloid cell recruitment. CD11b+ cells in turn adhere to crosslinked collagen and produce matrix metalloproteinase-2
MMP2
72 kDa type IV collagenase also known as matrix metalloproteinase-2 and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene....
, which cleaves collagen, enhancing the invasion of metastasizing tumor cells. In contrast, LOX inhibition prevents CD11b+ cell recruitment and metastatic growth.
Hence, inhibitors of the LOX enzyme may be useful in preventing tumor progression and metastasis as well as treating other fibrotic disease involving remodeling of the extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
, including neurodegenerative and cardiovascular diseases.