Sphingosine N-acyltransferase

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sphingosine N-acyltransferase
Identifiers
EC no. 2.3.1.24
CAS no. 37257-09-3
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In enzymology, sphingosine N-acyltransferases (ceramide synthases (CerS), EC 2.3.1.24) are enzymes that catalyze the chemical reaction of synthesis of ceramide:

Contents

acyl-CoA + sphingosine CoA + N-acylsphingosine

Thus, the two substrates of this enzyme are acyl-CoA and sphingosine, whereas its two products are CoA and N-acylsphingosine.

Ceramide synthases are integral membrane proteins of the endoplasmic reticulum.

This enzyme belongs to the family of transferases, specifically those acyltransferases transferring groups other than aminoacyl groups. The systematic name of this enzyme class is acyl-CoA:sphingosine N-acyltransferase. Other names in common use include ceramide synthetase, and sphingosine acyltransferase. This enzyme participates in sphingolipid metabolism.

History

CerS were originally called Lass (Longevity assurance) genes because of their homology to the yeast protein, longevity assurance gene-1 (LAG1p), and they were later renamed due to the discovery of their biological function. [1]

LAG1 in yeast was discovered in 1994 and named for the discovery that its deletion prolonged life span of Saccharomyces cerevisiae by almost 50%. [2] In the following years, it and its homologs were shown to be required for the syntheses of ceramides found in yeast. Three years previously, the mammalian gene upstream of growth and differentiation factor-1 (UOG-1) was discovered, but it wasn't until 2005 that it was defined as the first mammalian CerS, when Sujoy Lahiri and Tony Futerman from the Weizmann Institute of Science found that LASS5 is a bona fide mammalian ceramide synthase that specifically synthesizes palmitoyl (C16) ceramide. [1] [3]

Function

CerS are involved in the de novo synthesis pathway of ceramides. Their role is acylation coupling of sphinganine to a long-chain fatty acid to form a dihydroceramide, before the double bond is introduced to position 4 of the sphingoid base. [4]

Genetic Characteristics

CerS contain a unique C-terminal domain called the TLC domain and both mammalian and yeast CerS have 5–8 transmembrane domains. All mammalian CerS, aside from CerS1, contain a Hox-like domain shared by transcription factors important in development, although the first 15 amino acids of this domain are missing in CerS, indicating that this domain likely does not function as a genuine transcription factor. [1]

Mammalian CerS

Six mammalian CerS have been described, with each utilizing fatty acyl CoAs of relatively defined chain lengths for N‑acylation of the sphingoid long chain base. Mammals contain six distinct CerS, whereas most other enzymes in the sphingolipid biosynthetic pathway only occur in one or two isoforms. [5]

Ceramide synthases include:

Related Research Articles

<span class="mw-page-title-main">Sphingolipid</span> Family of chemical compounds

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.

<span class="mw-page-title-main">Sphingomyelin</span>

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.

<span class="mw-page-title-main">Fumonisin B1</span> Chemical compound

Fumonisin B1 is the most prevalent member of a family of toxins, known as fumonisins, produced by several species of Fusarium molds, such as Fusarium verticillioides, which occur mainly in maize (corn), wheat and other cereals. Fumonisin B1 contamination of maize has been reported worldwide at mg/kg levels. Human exposure occurs at levels of micrograms to milligrams per day and is greatest in regions where maize products are the dietary staple.

<span class="mw-page-title-main">Ceramide</span> Family of waxy lipid molecules

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.

<span class="mw-page-title-main">Sphingosine kinase</span> Class of enzymes

Sphingosine kinase (SphK) is a conserved lipid kinase that catalyzes formation sphingosine-1-phosphate (S1P) from the precursor sphingolipid sphingosine. Sphingolipid metabolites, such as ceramide, sphingosine and sphingosine-1-phosphate, are lipid second messengers involved in diverse cellular processes. There are two forms of SphK, SphK1 and SphK2. SphK1 is found in the cytosol of eukaryotic cells, and migrates to the plasma membrane upon activation. SphK2 is localized to the nucleus.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

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.

<span class="mw-page-title-main">Fatty-acyl-CoA synthase</span>

Fatty-acyl-CoA Synthase, or more commonly known as yeast fatty acid synthase, is an enzyme complex responsible for fatty acid biosynthesis, and is of Type I Fatty Acid Synthesis (FAS). Yeast fatty acid synthase plays a pivotal role in fatty acid synthesis. It is a 2.6 MDa barrel shaped complex and is composed of two, unique multi-functional subunits: alpha and beta. Together, the alpha and beta units are arranged in an α6β6 structure. The catalytic activities of this enzyme complex involves a coordination system of enzymatic reactions between the alpha and beta subunits. The enzyme complex therefore consists of six functional centers for fatty acid synthesis.

In enzymology, a long-chain-alcohol O-fatty-acyltransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Serine C-palmitoyltransferase</span>

In enzymology, a serine C-palmitoyltransferase (EC 2.3.1.50) is an enzyme that catalyzes the chemical reaction:

Sterol O-acyltransferase is an intracellular protein located in the endoplasmic reticulum that forms cholesteryl esters from cholesterol.

In enzymology, a ceramide kinase, also abbreviated as CERK, is an enzyme that catalyzes the chemical reaction:

<span class="mw-page-title-main">SPTLC2</span> Protein-coding gene in the species Homo sapiens

Serine palmitoyltransferase, long chain base subunit 2, also known as SPTLC2, is a protein which in humans is encoded by the SPTLC2 gene. SPTLC2 belongs to the class-II pyridoxal-phosphate-dependent aminotransferase family.

<span class="mw-page-title-main">ACOT11</span> Protein-coding gene in the species Homo sapiens

Acyl-coenzyme A thioesterase 11 also known as StAR-related lipid transfer protein 14 (STARD14) is an enzyme that in humans is encoded by the ACOT11 gene. This gene encodes a protein with acyl-CoA thioesterase activity towards medium (C12) and long-chain (C18) fatty acyl-CoA substrates which relies on its StAR-related lipid transfer domain. Expression of a similar murine protein in brown adipose tissue is induced by cold exposure and repressed by warmth. Expression of the mouse protein has been associated with obesity, with higher expression found in obesity-resistant mice compared with obesity-prone mice. Alternative splicing results in two transcript variants encoding different isoforms.

Very-long-chain 3-oxoacyl-CoA synthase (EC 2.3.1.199, very-long-chain 3-ketoacyl-CoA synthase, very-long-chain beta-ketoacyl-CoA synthase, condensing enzyme, CUT1 (gene), CERS6 (gene), FAE1 (gene), KCS (gene), ELO (gene)) is an enzyme with systematic name malonyl-CoA:very-long-chain acyl-CoA malonyltransferase (decarboxylating and thioester-hydrolysing). This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Ceramide synthase 1</span> Protein-coding gene in the species Homo sapiens

Ceramide synthase 1 also known as LAG1 longevity assurance homolog 1 is an enzyme that in humans is encoded by the CERS1 gene.

<span class="mw-page-title-main">Ceramide synthase 2</span> Protein-coding gene in the species Homo sapiens

Ceramide synthase 2, also known as LAG1 longevity assurance homolog 2 or Tumor metastasis-suppressor gene 1 protein is an enzyme that in humans is encoded by the CERS2 gene.

<span class="mw-page-title-main">Ceramide synthase 3</span> Protein-coding gene in the species Homo sapiens

Ceramide synthase 3 (CersS3), also known as longevity assurance homologue 3, is an enzyme that is encoded in humans by the CERS3 gene.

Ceramide synthase 4 (CerS4) is an enzyme that in humans is encoded by the CERS4 gene and is one of the least studied of the ceramide synthases.

Ceramide synthase 5 (CerS5) is the enzyme encoded in humans by the CERS5 gene.

<span class="mw-page-title-main">ACOT1</span> Protein-coding gene in the species Homo sapiens

Acyl-CoA thioesterase 1 is a protein that in humans is encoded by the ACOT1 gene.

References

  1. 1 2 3 Levy, Michal; Futerman, Anthony H. (2010). "Mammalian ceramide synthases". IUBMB Life. 62 (5): 347–56. doi:10.1002/iub.319. ISSN   1521-6543. PMC   2858252 . PMID   20222015.
  2. D'mello NP, Childress AM, Franklin DS, Kale SP, Pinswasdi C, Jazwinski SM (June 1994). "Cloning and characterization of LAG1, a longevity-assurance gene in yeast". The Journal of Biological Chemistry . 269 (22): 15451–9. PMID   8195187.
  3. Sujoy Lahiri; Anthony H Futerman (2005). "LASS5 is a bona fide dihydroceramide synthase that selectively utilizes palmitoyl-CoA as acyl donor". J Biol Chem. 280 (40): 33735–8. doi: 10.1074/jbc.m506485200 . PMID   16100120.
  4. Christie, William (30 January 2014). "Ceramides". LipidLibrary.aocs.org. AOCS. Archived from the original on 22 February 2014. Retrieved 14 February 2014.
  5. Stiban J, Tidhar R, Futerman AH (2010) Ceramide synthases: roles in cell physiology and signaling. Adv Exp Med Biol 688: 60-71.