Ceramide phosphoethanolamine synthase

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In enzymology, a ceramide phosphoethanolamine synthase (EC 2.7.8.-) is an enzyme that catalyzes the chemical reaction

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a ceramide + a phosphoethanolamine head group donor a ceramide-phosphoethanolamine + side product

Ceramide phosphoethanolamine (CPE) is a sphingolipid consisted of a ceramide and a phosphoethanolamine head group. Thus, this class of enzymes uses ceramide and a donor molecule for phosphoethanolamine as substrates to produce a ceramide phosphoethanolamine and a side product. The head group donor for phosphoethanolamine can be either phosphatidylethanolamine or CDP-ethanolamine, thus the side product is either a 1,2-diacylglycerol or a CMP, respectively.

This enzyme belongs to the family of transferases, specifically those transferring non-standard substituted phosphate groups.

Mammalian Ceramide Phosphoethanolamine Synthases

In mammalian cells, two CPE synthase activities have been described, one resides in the endoplasmic reticulum, and the other one is associated with the plasma membrane. [1] [2] [3] [4] [5] The endoplasmic reticulum-resident CPE synthase, SMSr, is identified as a monofunctional CPE synthase produces trace amounts of CPE. [4] [5] On the other hand, mammalian CPE synthase that is on the plasma membrane, SMS2, is a bifunctional enzyme that produces both CPE and sphingomyelin, thus also functioning as a sphingomyelin synthase. [4] Both mammalian CPE synthases, SMS2 and SMSr, use phosphatidylethanolamine (PE) as head group donor and catalyzes the reaction

a ceramide + a phosphatidylethanolamine a ceramide-phosphoethanolamine + 1,2-diacylglycerol

Invertebrate Ceramide Phosphoethanolamine Synthases

SMSr protein is found in all organisms throughout the animal kingdom as a CPE synthase, yet it produces trace amounts of CPE. [5] [6] Drosophila and a group of invertebrates lack SMS2 homologues. [5] [6] This group of invertebrates synthesizes CPE using a particular enzyme called CPES. [6] CPES uses CDP-ethanolamine rather than phosphatidylethanolamine as head group donor, thus catalyzes the reaction [6]

a ceramide + a CDP-ethanolamine a ceramide-phosphoethanolamine + CMP

CPES uses a different reaction mechanism than the one sphingomyelin synthase uses, but very similar to that of enzymes involved in synthesis of phosphatidyl ethanolamine (EC 2.7.8.1) via the Kennedy pathway. [7]

Related Research Articles

Phospholipid

Phospholipids (PL) are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group, and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue. The phosphate group can be modified with simple organic molecules such as choline, ethanolamine or serine.

Sphingolipid

Sphingolipids are a class of lipids containing a backbone of sphingoid bases, 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 an R group consisting of a hydrogen atom only is a ceramide. Other common R groups 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

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.

Glycerophospholipid

Glycerophospholipids or phosphoglycerides are glycerol-based phospholipids. They are the main component of biological membranes.

Ceramide

Ceramides are a family of waxy lipid molecules. A ceramide is composed of sphingosine and a fatty acid. 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.

Lipid signaling

Lipid signaling, broadly defined, refers to any biological 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.

Phospholipase D (PLD) is an enzyme of the phospholipase superfamily. Phospholipases occur widely, and can be found in a wide range of organisms, including bacteria, yeast, plants, animals, and viruses. Phospholipase D's principal substrate is phosphatidylcholine, which it hydrolyzes to produce the signal molecule phosphatidic acid (PA), and soluble choline. Plants contain numerous genes that encode various PLD isoenzymes, with molecular weights ranging from 90 to 125 kDa. Mammalian cells encode two isoforms of phospholipase D: PLD1 and PLD2. Phospholipase D is an important player in many physiological processes, including membrane trafficking, cytoskeletal reorganization, receptor-mediated endocytosis, exocytosis, and cell migration. Through these processes, it has been further implicated in the pathophysiology of multiple diseases: in particular the progression of Parkinson's and Alzheimer's, as well as various cancers. PLD may also help set the threshold for sensitivity to anesthetia and mechanical force.

Phosphatidylethanolamine

Phosphatidylethanolamines are a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. S-Adenosyl methionine can subsequently methylate the amine of phosphatidylethanolamines to yield phosphatidylcholines. It can mainly be found in the inner (cytoplasmic) leaflet of the lipid bilayer.

Phosphatidate phosphatase

Phosphatidate phosphatase (PAP) (EC 3.1.3.4) is a key regulatory enzyme in lipid metabolism, catalyzing the conversion of phosphatidate to diacylglycerol. The two substrates of PAP are phosphatidate and H2O, and its two products are diacylglycerol and phosphate, as shown here.

In enzymology, sphingosine N-acyltransferases are enzymes that catalyze the chemical reaction of synthesis of ceramide:

In enzymology, a ceramide cholinephosphotransferase is an enzyme that catalyzes the chemical reaction

In enzymology, an ethanolaminephosphotransferase is an enzyme that catalyzes the chemical reaction

Phosphatidate cytidylyltransferase (CDS) is the enzyme that catalyzes the synthesis of CDP-diacylglycerol from cytidine triphosphate and phosphatidate.

In enzymology, a phosphatidylcholine synthase is an enzyme that catalyzes the chemical reaction

In enzymology, a serine-phosphoethanolamine synthase is an enzyme that catalyzes the chemical reaction

In enzymology, a sphingomyelin synthase is an enzyme that catalyzes the chemical reaction

Phospholipase C

Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role in eukaryotic cell physiology, in particular signal transduction pathways. There are thirteen kinds of mammalian phospholipase C that are classified into six isotypes (β, γ, δ, ε, ζ, η) according to structure. Each PLC has unique and overlapping controls over expression and subcellular distribution. Activators of each PLC vary, but typically include heterotrimeric G protein subunits, protein tyrosine kinases, small G proteins, Ca2+, and phospholipids.

SGMS1

Phosphatidylcholine:ceramide cholinephosphotransferase 1 is an enzyme that in humans is encoded by the SGMS1 gene.

Glypiation is the addition by covalent bonding of a glycosylphosphatidylinositol (GPI) anchor and is a common post-translational modification that localizes proteins to cell membranes. This special kind of glycosylation is widely detected on surface glycoproteins in eukaryotes and some Archaea.

CDP-choline pathway

The CDP-choline pathway, first identified by Eugene Kennedy in 1956, is the predominant mechanism by which mammalian cells synthesize phosphatidylcholine (PC) for incorporation into membranes or lipid-derived signalling molecules. The CDP-choline pathway represents one half of what is known as the Kennedy pathway. The other half is the CDP-ethanolamine pathway which is responsible for the biosynthesis of the phospholipid phosphatidylethanolamine (PE).

References

  1. Malgat, M., Maurice, A., and Baraud, J. (1986) Sphingomyelin and ceramide-phosphoethanolamine synthesis by microsomes and plasma membranes from rat liver and brain. J. Lipid Res. 27, 251–260
  2. Malgat, M., Maurice, A., and Baraud, J. (1987) Sidedness of ceramidephosphoethanolamine synthesis on rat liver and brain microsomal membranes. J. Lipid Res. 28, 138–143
  3. Maurice, A., Malgat, M., and Baraud, J. (1989) Sidedness of ceramidephosphoethanolamine synthesis on rat liver plasma membrane. Biochimie 71, 373–378
  4. 1 2 3 Ternes, P., Brouwers, J. F., van den Dikkenberg, J., and Holthuis, J. C. (2009) Sphingomyelin synthase SMS2 displays dual activity as ceramide phosphoethanolamine synthase. J. Lipid Res. 50, 2270–2277
  5. 1 2 3 4 Vacaru, A. M., Tafesse, F. G., Ternes, P., Kondylis, V., Hermansson, M., Browers, J. F. H. M., Somerharju, P., Rabouille, C., and Holthuis, J. C. (2009) Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER. J. Cell Biol. 185, 1013–1027
  6. 1 2 3 4 Vacaru AM, van den Dikkenberg J, Ternes P, Holthuis JC. Ceramide phosphoethanolamine biosynthesis in Drosophila is mediated by a unique ethanolamine phosphotransferase in the Golgi lumen. J Biol Chem. 2013 Apr 19;288(16):11520-30. doi : 10.1074/jbc.M113.460972. Epub 2013 Feb 28. PMID   23449981; PMC   3630839
  7. KENNEDY EP, WEISS SB. The function of cytidine coenzymes in the biosynthesis of phospholipides. J Biol Chem. 1956 Sep;222(1):193-214. PMID   13366993.