Neprilysin (), also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10), and common acute lymphoblastic leukemia antigen (CALLA) 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 ''MME'' gene. Neprilysin is a

zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...

-dependent

metalloprotease A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myo ...

that cleaves

peptides Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

at the amino side of hydrophobic residues and inactivates several peptide hormones including

glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a medication to tre ...

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

substance P Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) and a member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its clo ...

neurotensin Neurotensin is a 13 amino acid neuropeptide that is implicated in the regulation of luteinizing hormone and prolactin release and has significant interaction with the dopaminergic system. Neurotensin was first isolated from extracts of bovine ...

oxytocin Oxytocin (Oxt or OT) is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. It plays a role in social bonding, reproduction, childbirth, and the period after childbirth. Oxytoc ...

, and

bradykinin Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor an ...

. It also degrades the

amyloid beta Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is ...

peptide whose abnormal folding and aggregation in neural tissue has been implicated as a cause of

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...

. Synthesized as a membrane-bound protein, the neprilysin ectodomain is released into the extracellular domain after it has been transported from the

Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...

to the cell surface. Neprilysin is expressed in a wide variety of tissues and is particularly abundant in kidney. It is also a common

acute lymphocytic leukemia Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruisin ...

antigen that is an important cell surface marker in the diagnosis of human acute lymphocytic leukemia (ALL). This protein is present on leukemic cells of pre-B phenotype, which represent 85% of cases of ALL. Hematopoietic progenitors expressing CD10 are considered "common lymphoid progenitors", which means they can differentiate into T, B or natural killer cells. CD10 is of use in hematological diagnosis since it is expressed by early B, pro-B and pre-B lymphocytes, and by lymph node

germinal centers Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, prolifer ...

. Hematologic diseases in which it is positive include ALL,

angioimmunoblastic T cell lymphoma Angioimmunoblastic T-cell lymphoma (AITL, sometimes misspelled AILT, formerly known as "angioimmunoblastic lymphadenopathy with dysproteinemia") is a mature T-cell lymphoma of blood or lymph vessel immunoblasts characterized by a polymorphous lym ...

Burkitt lymphoma Burkitt lymphoma is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Afric ...

chronic myelogenous leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumul ...

in blast crisis (90%),

diffuse large B-cell lymphoma Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,00 ...

(variable), follicular center cells (70%),

hairy cell leukemia Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes. It is usually classified as a subtype of chronic lymphocytic leukemia (CLL). Hairy cell leukemia makes up about 2% of all leu ...

(10%), and myeloma (some). It tends to be negative in

acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may inclu ...

chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever ...

mantle cell lymphoma Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma (NHL), comprising about 6% of NHL cases. There are only about 15,000 patients presently in the United States with mantle cell lymphoma. It is named for the mantle zone of the lymph n ...

, and

marginal zone lymphoma Marginal zone B-cell lymphomas, also known as marginal zone lymphomas (MZLs), are a heterogeneous group of lymphomas that derive from the malignant transformation of marginal zone B-cells. Marginal zone B cells are innate lymphoid cells that no ...

. CD10 is found on non-T ALL cells, which derive from pre-B lymphocytes, and in germinal center-related non-Hodgkin lymphoma such as Burkitt lymphoma and follicular lymphoma, but not on leukemia cells or lymphomas, which originate in more mature B cells.

Amyloid beta regulation

Neprilysin-deficient

knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

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 chemical kinetics, the overall rate of a reaction is often approximately determined by the slowest step, known as the rate-determining step (RDS or RD-step or r/d step) or rate-limiting step. For a given reaction mechanism, the prediction of the ...

in amyloid beta degradation, it has been considered a potential therapeutic target; compounds such as the

peptide hormone Peptide hormones or protein hormones are hormones whose molecules are peptide, or proteins, respectively. The latter have longer amino acid chain lengths than the former. These hormones have an effect on the endocrine system of animals, including h ...

somatostatin Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-cou ...

have been identified that increase the enzyme's activity level. Declining neprilysin activity with increasing age may also be explained by

oxidative Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...

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 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; blo ...

and

lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of ...

tissues. Inhibitors have been designed with the aim of developing

analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...

and

antihypertensive Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests th ...

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

endothelin Endothelins are peptides with receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute ...

, and

atrial natriuretic peptide Atrial natriuretic peptide (ANP) or atrial natriuretic factor (ANF) is a natriuretic peptide hormone secreted from the cardiac atria that in humans is encoded by the NPPA gene. Natriuretic peptides (ANP, BNP, and CNP) are a family of hormone/p ...

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

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

; however, the relationship between neprilysin expression and carcinogenesis remains obscure. In cancer

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...

studies, the neprilysin gene is often referred to as CD10 or CALLA. In some types of cancer, such as

metastatic Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

carcinoma Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesoderm ...

and some advanced

melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...

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

lung cancer Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. Lung carcinomas derive from transformed, mali ...

s, neprilysin is downregulated, and thus unable to modulate the pro-growth

autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with p ...

signaling of cancer cells via secreted peptides such as mammalian

homologs A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci where they provide points alon ...

related to

bombesin Bombesin is a 14-amino acid peptide originally isolated from the skin of the European fire-bellied toad (''Bombina bombina'') by Vittorio Erspamer ''et al.'' and named after its source. NIHMSID 45053. It has two known homologs in mammals called ...

. Some plant extracts (methanol extracts of ''

Ceropegia ''Ceropegia'' is a genus of plants within the family Apocynaceae, native to Africa, southern Asia, and Australia. It was named by Carl Linnaeus, who first described this genus in his ''Genera plantarum'', which appeared in 1737. Linnaeus referr ...

rupicola'', ''

Kniphofia ''Kniphofia'' is a genus of perennial flowering plants in the family Asphodelaceae, first described as a genus in 1794. Species are native to Africa. Common names include tritoma, red hot poker, torch lily and poker plant. Description Herbaceou ...

sumarae'', '' Plectranthus cf barbatus'', and an aqueous extract of ''

Pavetta ''Pavetta'' is a genus of flowering plants in the family Rubiaceae. It comprises about 360 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 plan ...

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

Inhibitors

Inhibitors have been designed with the aim of developing

and

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

, and

. Some are intended to treat

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...

. *

Sacubitril/valsartan Sacubitril/valsartan, sold under the brand name Entresto, is a fixed-dose combination medication for use in heart failure. It consists of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan. The combination is s ...

(Entresto/LCZ696), which has been tested against

enalapril Enalapril, sold under the brand name Vasotec among others, is an ACE inhibitor medication used to treat high blood pressure, diabetic kidney disease, and heart failure. For heart failure, it is generally used with a diuretic, such as furose ...

in patients with heart failure. *

Sacubitril Sacubitril (; INN) is an antihypertensive drug used in combination with valsartan. The combination drug sacubitril/valsartan, known during trials as ''LCZ696'' and marketed under the brand name ''Entresto'', is a treatment for heart failure. It ...

(AHU-377), a

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the dru ...

which is a component of

sacubitril/valsartan Sacubitril/valsartan, sold under the brand name Entresto, is a fixed-dose combination medication for use in heart failure. It consists of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan. The combination is s ...

Sacubitrilat Sacubitrilat ( INN; or LBQ657) is the active metabolite of the antihypertensive drug sacubitril, which is used in the treatment of heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of s ...

(LBQ657), the active form of sacubitril *

RB-101 RB-101 is a drug that acts as an enkephalinase inhibitor, which is used in scientific research. RB-101 is a prodrug which acts by splitting at the disulfide bond once inside the brain, to form two selective enzyme inhibitors and blocking both ty ...

, an enkephalinase inhibitor, used in scientific research. *

UK-414,495 UK-414,495 is a drug developed by Pfizer for the treatment of female sexual arousal disorder. UK-414,495 acts as a potent, selective inhibitor of the enzyme neutral endopeptidase, which normally serves to break down the neuropeptide VIP. The c ...

Omapatrilat Omapatrilat ( INN, proposed trade name Vanlev) is an experimental antihypertensive agent that was never marketed. It inhibits both neprilysin (neutral endopeptidase, NEP) and angiotensin-converting enzyme (ACE). NEP inhibition results in elevat ...

(dual inhibitor of NEP and

angiotensin-converting enzyme Angiotensin-converting enzyme (), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconst ...

) developed by BMS did not receive FDA approval due to

angioedema Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are ...

safety concerns. *

Ecadotril Ecadotril is a neutral endopeptidase inhibitor ((NEP) EC 3.4.24.11) and determined by the presence of peptidase family M13 as a neutral endopeptidase inhibited by phosphoramidon. Ecadotril is the (''S'')-enantiomer of racecadotril. NEP-like enzy ...

Candoxatril Candoxatril is the orally active prodrug of candoxatrilat (UK-73967). Human neutral endopeptidase Human neutral endopeptidase ( neprilysin) as the neutral endopeptidase 24.11 complexed (RB-101) with phosphoramidon degrades and inactivates a numb ...

Other dual inhibitors of NEP with ACE/angiotensin receptor are (in 2003) being developed by pharmaceutical companies.

Immunochemistry

CD10 is used in clinical pathology for diagnostic purpose.

In lymphomas and leukemias

Acute lymphoblastic leukemia Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruis ...

(ALL) cells are CD10⁺. *

Follicular lymphoma Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells norma ...

(follicle centre cell lymphoma) are CD10⁺. * Burkitt Lymphoma cells are CD10⁺. * CD10⁺ diffuse large B cell lymphoma (CD10⁺ DLBCL) ** Marker for germinal center phenotype (CD10, HGAL, BCL6, CD38) are considered a favorable prognostic factor, but CD10⁺,

BCL2 Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis ...

⁺tumors could have poorer survival. For some authors, CD10 expression in DLBCL does not influence survival. *

Angioimmunoblastic T cell lymphoma Angioimmunoblastic T-cell lymphoma (AITL, sometimes misspelled AILT, formerly known as "angioimmunoblastic lymphadenopathy with dysproteinemia") is a mature T-cell lymphoma of blood or lymph vessel immunoblasts characterized by a polymorphous lym ...

(AITL) are CD10⁺ and distinguishes AITL from other T cell lymphomas (CD10⁻) ** Some benign T cells can be CD10⁺

In epithelial tumors

* Clear cell renal cell carcinoma (Clear cell RCC) ** CD10⁺ distinguishes renal cell carcinoma, conventional type with eosinophilic morphology from its mimickers. Chromophobe carcinoma and oncocytoma are CD10⁻. *

Pancreatic tumor Pancreatic tumors ( Pancreatic cancer) are often broken down into exocrine or endocrine tumors. Each different type of pancreatic tumor has a different appearance when examined under a microscope. These unique microscopic features and genetic marker ...

s **

Solid pseudopapillary tumour A solid pseudopapillary tumour is a low-grade malignant neoplasm of the pancreas of papillary architecture that typically afflicts young women. Signs and symptoms Solid pseudopapillary tumours are often asymptomatic and are identified incidentall ...

s are CD10⁺. ** CD10⁺ differentiates mucinous cystic neoplasms (CD10⁺/CK20+) from

intraductal papillary mucinous neoplasm Intraductal papillary mucinous neoplasm (IPMN) is a type of tumor that can occur within the cells of the pancreatic duct. IPMN tumors produce mucus, and this mucus can form pancreatic cysts. Although intraductal papillary mucinous neoplasms are b ...

of branch duct type (CD10⁻/CK20-). * Cutaneous tumors ** CD10 may differentiate

basal cell carcinoma Basal-cell carcinoma (BCC), also known as basal-cell cancer, is the most common type of skin cancer. It often appears as a painless raised area of skin, which may be shiny with small blood vessels running over it. It may also present as a raise ...

(CD10 epithelial staining) from

trichoblastoma Trichoblastomas are a skin condition characterized by benign neoplasms of the follicular germinative cells known as ''trichoblasts''. ''Trichoblastic fibroma'' is a term used to describe small nodular trichoblastomas that contain a conspicuous ...

(CD10 peritumoral stromal staining), basal cell carcinoma with follicular differentiation (CD10 stromal and epithelial staining) and

squamous cell carcinoma Squamous-cell carcinomas (SCCs), also known as epidermoid carcinomas, comprise a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...

(strong stromal staining). ** CD10 differentiates CD10⁺

atypical fibroxanthoma Atypical fibroxanthoma of the skin is a low-grade malignancy related to malignant fibrous histiocytoma, which it resembles histologically.James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology'' ...

from CD10⁻ spindle cell

and sarcomatoid

. *

Urothelial tumor Transitional epithelium also known as urothelium is a type of stratified epithelium. Transitional epithelium is a type of tissue that changes shape in response to stretching (stretchable epithelium). The transitional epithelium usually appears ...

s express CD10 (42-67%). ** CD10 expression is strongly correlated with high tumor grade and stage in urothelial carcinoma of the bladder. CD10 may be associated with tumor progression in bladder cancer pathogenesis.

In other tumors

* CD10 expression might be one of the characteristics of müllerian system-derived neoplastic mesenchymal cells. ** Normal endometrial stroma ** Endometrial stromal sarcoma (ESS) are CD10⁺ (

Smooth muscle tumor Smooth muscle tumours show a smooth muscle differentiation. There are two main types of smooth muscle tumour: the benign leiomyoma and the malignant leiomyosarcoma Leiomyosarcoma is a malignant (cancerous) smooth muscle tumor. A benign tumor orig ...

s are usually CD10⁻, but can be CD10⁺ ** Malignant müllerian mixed tumor (MMMT) ** Müllerian adenosarcoma ** Uterine high-grade leiomyosarcoma ** Uterine rhabdomyosarcoma * Vascular tumors ** Epithelioid hemangioendothelioma are mostly CD10⁺. **

Hemangioblastoma Hemangioblastomas, or haemangioblastomas, are vascular tumors of the central nervous system that originate from the vascular system, usually during middle age. Sometimes, these tumors occur in other sites such as the spinal cord and retina. They ma ...

is usually CD10⁻ (metastatic

renal cell carcinoma Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, re ...

is CD10⁺)

References

External links

* The

MEROPS MEROPS is an online database for peptidases (also known as proteases, proteinases and proteolytic enzymes) and their inhibitors. The classification scheme for peptidases was published by Rawlings & Barrett in 1993, and that for protein inhibitors ...

online database for peptidases and their inhibitors
M13.001
* * {{Portal bar, Biology, border=no Alzheimer's disease EC 3.4.24 Tumor markers

Amyloid beta regulation

Signaling peptides

Inhibitors

Immunochemistry

In lymphomas and leukemias

In epithelial tumors

In other tumors

See also

References

External links