Neprilysin, also known as membrane metallo-endopeptidase, neutral endopeptidase (NEP), CD

Cluster of differentiation

The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...

10, and common acute lymphoblastic leukemia

Acute lymphoblastic leukemia

Acute lymphoblastic leukemia is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts.Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone...

 antigen (CALLA), is a zinc

Zinc

Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...

-dependent metalloprotease 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 degrades a number of small secreted peptides, most notably the amyloid beta

Amyloid beta

Amyloid beta is a peptide of 36–43 amino acids that is processed from the Amyloid precursor protein. While it is most commonly known in association with Alzheimer's disease, it does not exist specifically to cause disease...

 peptide whose abnormal misfolding

Protein folding

Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....

 and aggregation in neural tissue has been implicated as a cause of Alzheimer's disease

Alzheimer's disease

Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

. Synthesized as a membrane-bound protein

Membrane protein

A membrane protein is a protein molecule that is attached to, or associated with the membrane of a cell or an organelle. More than half of all proteins interact with membranes.-Function:...

, the neprilysin ectodomain is released into the extracellular domain after it has been transported from the Golgi apparatus

Golgi apparatus

The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....

 to the cell surface. In neuron

Neuron

A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

s, neprilysin is regulated by the protein nicastrin

Nicastrin

Nicastrin, also known as NCSTN, is a protein which in humans is encoded by the NCSTN gene.Nicastrin is a protein that is part of the gamma secretase protein complex, which is one of the proteases involved in processing amyloid precursor protein to the short Alzheimer's disease-associated peptide...

, a component of the gamma secretase

Gamma secretase

Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases...

 complex that performs a necessary step in processing amyloid precursor protein

Amyloid precursor protein

Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...

 to amyloid beta.

Amyloid beta regulation

Mutations in the neprilysin gene have been associated with familial forms of Alzheimer's disease, and neprilysin-deficient knockout mice

Knockout mouse

A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...

 show both Alzheimer's-like behavioral impairment and amyloid-beta deposition in the brain, providing strong evidence for the protein's association with the Alzheimer's disease process. Because neprilysin is thought to be the rate-limiting step in amyloid beta degradation, it has been considered a potential therapeutic target; compounds such as the peptide hormone

Peptide hormone

Peptide hormones are a class of peptides that are secreted into the blood stream and have endocrine functions in living animals.Like other proteins, peptide hormones are synthesized in cells from amino acids according to an mRNA template, which is itself synthesized from a DNA template inside the...

 somatostatin

Somatostatin

Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...

 have been identified that increase the enzyme's activity level. One hypothesis for the strong dependence of Alzheimer's incidence on age focuses on the declining production of somatostatin in the brains of elderly people, which thus depresses the activity of neprilysin and promotes aggregation of unprocessed amyloid beta. Declining neprilysin activity with increasing age may also be explained by oxidative damage, known to be a causative factor in Alzheimer's disease; higher levels of inappropriately oxidized neprilysin have been found in Alzheimer's patients compared to cognitively normal elderly people.

Signaling peptides

Neprilysin is also associated with other biochemical processes, and is particularly highly expressed in kidney

Kidney

The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

 and lung

Lung

The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...

 tissues. Inhibitors have been designed with the aim of developing analgesic

Analgesic

An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

 and antihypertensive

Antihypertensive

The antihypertensives are a class of drugs that are used to treat hypertension . Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from...

 agents that act by preventing neprilysin's activity against signaling peptides such as enkephalin

Enkephalin

An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, or specifically endorphins, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin were revealed, one...

s, substance P

Substance P

In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...

, endothelin

Endothelin

Endothelins are proteins that constrict blood vessels and raise blood pressure. They are normally kept in balance by other mechanisms, but when they are over-expressed, they contribute to high blood pressure and heart disease....

, and atrial natriuretic factor.

Associations have been observed between neprilysin expression and various types of cancer

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...

; however, the relationship between neprilysin expression and carcinogenesis remains obscure. In cancer biomarker studies, the neprilysin gene is often referred to as CD10 or CALLA. In some types of cancer, such as metastatic carcinoma

Carcinoma

Carcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...

 and some advanced melanoma

Melanoma

Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...

s, neprilysin is overexpressed; in other types, most notably lung cancer

Lung cancer

Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...

s, neprilysin is downregulated, and thus unable to modulate the pro-growth autocrine signaling of cancer cells via secreted peptides such as mammalian homologs

Homology (biology)

Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...

 related to bombesin

Bombesin

Bombesin is a 14-amino acid peptide originally isolated from the skin of a frog. It has two known homologs in mammals called neuromedin B and gastrin-releasing peptide. It stimulates gastrin release from G cells. It activates three different G-protein-coupled receptors known as BBR1, -2, and -3. It...

.
Some plant extracts extracts (methanol extracts of Ceropegia

Ceropegia

Ceropegia is a genus of plants within the family Apocynaceae. It was named by Carl Linnaeus, who first described this genus in volume 1 of his Species plantarum, which appeared in 1753. Linnaeus thought that the flowers looked like a fountain of wax. From this the scientific name was derived:...

 rupicola, Kniphofia

Kniphofia

Kniphofia , also called Tritoma, Red hot poker, Torch lily or Poker plant, is a genus of plants in the family Xanthorrhoeaceae, subfamily Asphodeloideae, that includes 70 or more species native to Africa...

 sumarae, Plectranthus

Plectranthus

Plectranthus, with some 350 species, is a genus of warm-climate plants occurring largely in the southern hemisphere, in sub-Saharan Africa, Madagascar, India and the Indonesian archipelago down to Australia and some Pacific islands. It is closely related to Solenostemon, sometimes known as the...

 cf barbatus, and an aqueous extract of Pavetta

Pavetta

Pavetta is a genus of flowering plants in the Rubiaceae family. It comprises about 350 species of trees, evergreen shrubs and sub-shrubs. It is found in woodlands, grasslands and thickets in sub-tropical and tropical Africa and Asia. The plants are cultivated for their simple but variable leaves,...

 longiflora) were found able to inhibit the enzymatic activity of neutral endopeptidase.

External links

• The MEROPS
  Merops
  Merops may refer to:* Merops , a genus of bee-eaters.* MEROPS, an on-line database for peptidases.It may also refer to several figures from Greek mythology:* King of Ethiopia, husband of Clymene, who lay with Helios and bore Phaethon...
  
  online database for peptidases and their inhibitors: M13.001