| ENPP7 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | ENPP7 , ALK-SMase, E-NPP 7, NPP-7, NPP7, ectonucleotide pyrophosphatase/phosphodiesterase 7 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 616997; MGI: 3027917; HomoloGene: 110852; GeneCards: ENPP7; OMA:ENPP7 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 (E-NPP 7) also known as alkaline sphingomyelin phosphodiesterase (Alk-SMase) or intestinal alkaline sphingomyelinase is an enzyme that in humans is encoded by the ENPP7 gene. [5] [6]
ENPP7 is a new name for an old enzyme whose activity was originally identified in 1969 by Nilsson as a type of sphingomyelinase that hydrolyses sphingomyelin to ceramide in the intestinal tract. [7] The enzyme was then purified and characterized by Duan et al. and named alkaline sphingomyelinase (alk-SMase), as the optimal pH of the enzyme was 9.0 and its main substrate is sphingomyelin. [8] [9] Most previous studies used the name of alk-SMase for this protein. The name of ENPP7 was created based on the results of cloning studies which show that alk-SMase shares no structural similarities with either acid or neutral SMase but belongs to the family of ecto nucleotide pyrophosphatase/phosphodiesterase (ENPP). [5] [10] As a new addition to the family it is therefore called ENPP7 or NPP7. A 3D homology model of ENPP7 was recently constructed using the crystal structural of an NPP member in bacteria as a template. [11] [12] [ unreliable source? ]
Differing from other ENPP members, ENPP7 seems only expressed in the intestinal mucosa in many species and additionally in human liver. In the intestinal tract, ENPP7 activity is low in the duodenum and colon but high in the middle of the jejunum. [13] As an ecto enzyme, ENPP7 is located on the surface of the intestinal mucosa and is released in the lumen by bile salt and pancreatic trypsin. [14] [15] The enzyme expressed in human liver is released in the bile and delivered to the intestine.
The activity of ENPP7 depends specifically on two types of primary bile salts, taurocholate (TC) and taurochenodeoxycholate (TCDC) at critical micelle concentrations. [16] Other detergents, such as CHAPS and Triton X-100 have no stimulatory effects rather inhibitory effects, indicating a biologic interaction between bile salts and the enzyme. Unlike acid and neutral SMases in the intestinal tract that are rapidly inactivated by pancreatic trypsin, [13] alk-SMase is resistant to trypsin digestion. [15] Thus ENPP7 is active in the intestinal lumen and is transported along the intestinal tract. Significant activity can be detected in the faeces.
The substrates of ENPP family vary greatly. Some have activity against nucleotides, some have activity against phospholipid and lysophospholipids. [17] ENPP7 is the only enzyme that has a type of phospholipase C activity against sphingomyelin.
ENPP7 is the key enzyme in the gut that digests sphingomyelin. Sphingomyelin is a lipid constituent of cell membrane, and a dietary component being particularly abundant in milk, cheese, egg, and meat. [18] Digestion of sphingomyelin mainly occurs in the middle part of the small intestine, where ENPP7 is abundant, indicating a role of the enzyme in sphingomyelin digestion. [19] Recent studies on ENPP7 knockout mice clearly showed that digestion of sphingomyelin and generation of ceramide is severely affected in ENPP7 deficiency mice. ENPP7 is fully developed in the intestine before birth, [20] [21] which gives the infant ability to digest sphingomyelin in the milk.
The daily intake of sphingomyelin for human with Western diet is about 300 mg. Under physiological conditions, only part of the sphingomyelin can be digested and absorbed. [22] The limitation is thought to be caused by several factors that are present in the intestine such as cholesterol, phospholipids, fat and high concentrations of bile salts. [23] It is thus understandable why SM digestion occurs most effectively in the low part of the small intestine, where most fat, phospholipids, and bile salt have been absorbed or up taken. It is also understandable that considerable amount of dietary sphingomyelin is delivered into the colon and excreted in the feces. [19] [24] [25]
ENPP7 may have important roles in preventing tumorigenesis in the intestinal tract, as ceramide, the product of sphingomyelin hydrolysis, can inhibit cell proliferation and stimulate cell differentiation and apoptosis. Animal studies showed that supplement of SM or ceramide in the diet may inhibit the development of colon cancer. [26] Of particular interest is that the activity of ENPP7 is significantly decreased in human colorectal adenoma and carcinoma as well as in the feces of the cancer patients. [27] [28] [29] The decrease is caused by expression of a few mutant forms of ENPP7, which lack exon 4, resulting in total inactivation of the enzyme, as found in human colon and liver cancer cells. [16] [30] [31]
Besides sphingomyelin, ENPP7 can also degrade and inactivate platelet-activating factor (PAF), which is proinflammatory, indicating that ENPP7 may also have antiinflammatory effects. [32] Rectal administration of recombinant ENPP7 has been shown to improve ulcerative colitis in an animal study, [33] and patients with chronic ulcerative colitis are associated with a reduced ENPP7 activity. [34]
ENPP7 may also affect cholesterol absorption. In the intestinal tract cholesterol and sphingomyelin are co-exiting in plasma membrane and in lipid vesicles, liposomes and micelles. The two molecules form a stable complex via van der Waals forces. Cholesterol absorption can be inhibited by supplementation of sphingomyelin in the diet. [35] Milk sphingomyelin seems more potent than egg sphingomyelin, indicating that the inhibition is related to the degree of the saturation and the length of sphingomyelin. [36] Recent studies further showed that formation of ceramide by ENPP7 in the gut enhanced sphingomyelin-induced inhibition of cholesterol, [37] indicating regulatory roles of ENPP7 in cholesterol absorption.
The expression of ENPP7 can be modified by dietary factors. High fat diet (53% energy) greatly reduces ENPP7 activities and enzyme protein in the intestinal mucosa by 50%. [38] On the other hand, water-soluble fiber psyllium was shown to increase both the activities and protein of ENPP7 in the colon of mice. [38] Sphingomyelin can also increase the levels of ENPP7 after a long term of administration. [39] Besides, ursodeoxycholic acid and probiotic VSL#3 may stimulate the expression of ENPP7 in the intestine. [40] [41]
Dietary fiber or roughage is the portion of plant-derived food that cannot be completely broken down by human digestive enzymes. Dietary fibers are diverse in chemical composition and can be grouped generally by their solubility, viscosity and fermentability which affect how fibers are processed in the body. Dietary fiber has two main subtypes: soluble fiber and insoluble fiber which are components of plant-based foods such as legumes, whole grains, cereals, vegetables, fruits, and nuts or seeds. A diet high in regular fiber consumption is generally associated with supporting health and lowering the risk of several diseases. Dietary fiber consists of non-starch polysaccharides and other plant components such as cellulose, resistant starch, resistant dextrins, inulin, lignins, chitins, pectins, beta-glucans, and oligosaccharides.
The gastrointestinal tract is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and other animals, including the esophagus, stomach, and intestines. Food taken in through the mouth is digested to extract nutrients and absorb energy, and the waste expelled at the anus as faeces. Gastrointestinal is an adjective meaning of or pertaining to the stomach and intestines.
The enzyme alkaline phosphatase is a phosphatase with the physiological role of dephosphorylating compounds. The enzyme is found across a multitude of organisms, prokaryotes and eukaryotes alike, with the same general function, but in different structural forms suitable to the environment they function in. Alkaline phosphatase is found in the periplasmic space of E. coli bacteria. This enzyme is heat stable and has its maximum activity at high pH. In humans, it is found in many forms depending on its origin within the body – it plays an integral role in metabolism within the liver and development within the skeleton. Due to its widespread prevalence in these areas, its concentration in the bloodstream is used by diagnosticians as a biomarker in helping determine diagnoses such as hepatitis or osteomalacia.
Sphingolipids are a class of lipids containing a backbone of sphingoid bases, which are a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sphinx because of their enigmatic nature. These compounds play important roles in signal transduction and cell recognition. Sphingolipidoses, or disorders of sphingolipid metabolism, have particular impact on neural tissue. A sphingolipid with a terminal hydroxyl group is a ceramide. Other common groups bonded to the terminal oxygen atom include phosphocholine, yielding a sphingomyelin, and various sugar monomers or dimers, yielding cerebrosides and globosides, respectively. Cerebrosides and globosides are collectively known as glycosphingolipids.
Sphingomyelin is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphocholine and ceramide, or a phosphoethanolamine head group; therefore, sphingomyelins can also be classified as sphingophospholipids. In humans, SPH represents ~85% of all sphingolipids, and typically make up 10–20 mol % of plasma membrane lipids.
Prebiotics are compounds in food that foster growth or activity of beneficial microorganisms such as bacteria and fungi. The most common environment considered is the gastrointestinal tract, where prebiotics can alter the composition of organisms in the gut microbiome.
Ceramides are a family of waxy lipid molecules. A ceramide is composed of sphingosine and a fatty acid joined by an amide bond. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer. Contrary to previous assumptions that ceramides and other sphingolipids found in cell membrane were purely supporting structural elements, ceramide can participate in a variety of cellular signaling: examples include regulating differentiation, proliferation, and programmed cell death (PCD) of cells.
Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts.
Lipid signaling, broadly defined, refers to any biological cell signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.
Sphingomyelin phosphodiesterase is a hydrolase enzyme that is involved in sphingolipid metabolism reactions. SMase is a member of the DNase I superfamily of enzymes and is responsible for breaking sphingomyelin (SM) down into phosphocholine and ceramide. The activation of SMase has been suggested as a major route for the production of ceramide in response to cellular stresses.
Sphingomyelin phosphodiesterase D (EC 3.1.4.41, sphingomyelinase D) is an enzyme of the sphingomyelin phosphodiesterase family with systematic name sphingomyelin ceramide-phosphohydrolase. These enzymes catalyse the hydrolysis of sphingomyelin, resulting in the formation of ceramide 1-phosphate and choline:
Ceramidase is an enzyme which cleaves fatty acids from ceramide, producing sphingosine (SPH) which in turn is phosphorylated by a sphingosine kinase to form sphingosine-1-phosphate (S1P).
In enzymology, a sphingomyelin synthase is an enzyme that catalyzes the chemical reaction
Neutral ceramidase is an enzyme that in humans is encoded by the ASAH2 gene.
Phosphatidylcholine:ceramide cholinephosphotransferase 1 is an enzyme that in humans is encoded by the SGMS1 gene.
SMPD1-associated Niemann–Pick disease refers to two different types of Niemann–Pick disease, type A (NPA) and type B (NPB), which are associated with the SMPD1 gene.
Functional inhibitors of acid sphingomyelinase, or FIASMA, is a large group of pharmacological compounds inhibiting the enzyme acid sphingomyelinase. This enzyme is mainly located within the lysosome, where it cleaves sphingomyelin to ceramide and sphingosine, the latter of which is then phosphorylated to sphingosine-1-phosphate. These metabolites, and subsequent inhibition of the enzyme, influence the balance between cell death (apoptosis) and cell growth (proliferation). A lack of regulation of this sensitive equilibrium can lead to serious clinical consequences.
Acid sphingomyelinase is one of the enzymes that make up the sphingomyelinase (SMase) family, responsible for catalyzing the breakdown of sphingomyelin to ceramide and phosphorylcholine. They are organized into alkaline, neutral, and acidic SMase depending on the pH in which their enzymatic activity is optimal. Acid sphingomyelinases' (aSMases) enzymatic activity can be influenced by drugs, lipids, cations, pH, redox and other proteins in the environment. Specifically aSMases have been shown to have increased enzymatic activity in lysobisphosphatidic acid (LBPA) or phosphatidylinositol (PI) enriched environments, and inhibited activity when phosphorylated derivatives of PI are present.
Ceramide synthase 5 (CerS5) is the enzyme encoded in humans by the CERS5 gene.
Lipase inhibitors belong to a drug class that is used as an antiobesity agent. Their mode of action is to inhibit gastric and pancreatic lipases, enzymes that play an important role in the digestion of dietary fat. Lipase inhibitors are classified in the ATC-classification system as A08AB . Numerous compounds have been either isolated from nature, semi-synthesized, or fully synthesized and then screened for their lipase inhibitory activity but the only lipase inhibitor on the market is orlistat . Lipase inhibitors have also shown anticancer activity, by inhibiting fatty acid synthase.
