Ceramide synthase 2, also known as LAG1 longevity assurance homolog 2 or Tumor metastasis-suppressor gene 1 protein 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 CERS2

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. Ceramide synthase 2 is a

ceramide synthase In enzymology, sphingosine N-acyltransferases (ceramide synthases (CerS), ) are enzymes that catalyze the chemical reaction of synthesis of ceramide: :acyl-CoA + sphingosine \rightleftharpoons CoA + N-acylsphingosine Thus, the two substrates of ...

that catalyses the synthesis of very long acyl chain

ceramides Ceramides are a family of waxy lipid molecules. A ceramide is composed of N-acetylsphingosine 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 ...

, including C20 and C26 ceramides. It is the most ubiquitously expressed of all CerS and has the broadest distribution in the human body. CerS2 was first identified in 2001. It contains the conserved TLC domain and Hox-like domain common to almost all CerS.

Distribution

CerS2 mRNA (TRH3) has been found in most tissues and it is strongly expressed in liver, intestine and brain. CerS2 is much more widely distributed than Ceramide synthase 1 (CerS1) and is found in at least 12 tissues in the human body, with high expression in the

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

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

, and moderate expression in the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

and other organs. In the

mouse brain The mouse brain refers to the brain of Mus musculus. Various brain atlases exist. For reasons of reproducibility, genetically characterized, stable strains like C57BL/6 were chosen to produce high-resolution images and databases. Well known onl ...

, CerS2 is mainly expressed

white matter White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distributi ...

tracts, specifically in

oligodendrocytes Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...

and

Schwann cells Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory en ...

Function

Expression of CerS2 is transiently increased during periods of active myelination, suggesting that it is important for the synthesis of

myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...

sphingolipids. The lack of CerS2, as shown in knockout mice, induces the autophagy and activation of the

unfolded protein response The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between all mammalian species, as well as yeast and worm organisms. The UPR is activated in resp ...

(UPR). These mice showed no decrease in overall ceramide level, but levels of

sphinganine Safingol is a lyso-sphingolipid protein kinase inhibitor. It has the molecular formula C18H39NO2 and is a colorless solid. Medicinally, safingol has demonstrated promising anticancer potential as a modulator of multi-drug resistance and as an i ...

were elevated. They also developed severe liver disease, but there was no observable change in the kidneys. The ''CerS2'' gene is compact in size and is located in a

chromosomal A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

region that is replicated early in the

cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...

. CerS2 activity is regulated by

sphingosine-1-phosphate Sphingosine-1-phosphate (S1P) is a signaling sphingolipid, also known as lysosphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcoho ...

(S1P) via two

sphingosine-1-phosphate receptor The sphingosine-1-phosphate receptors are a class of G protein-coupled receptors that are targets of the lipid signalling molecule Sphingosine-1-phosphate (S1P). They are divided into five subtypes: S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5. Disco ...

-like residues on CerS2 that operate independently.

Pathological significance

CerS2 levels are significantly elevated in

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...

tissue compared to normal tissue, along with increased levels of ceramide synthase 6 ( CerS6). CerS2 was also implicated in the control of body weight. The administration of leptin to rats induced a decrease in CerS2 was observed in

white adipose tissue White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind is brown adipose tissue. White adipose tissue is composed of monolocular adipocytes. In humans, the healthy amount of white adipose t ...

Distribution

Function

Pathological significance

References

Further reading