Ceramide synthase 5 (CerS5) is the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

encoded in humans by the CERS5 gene.

Function

CerS5 robustly synthesizes C16-

ceramide Ceramides are a family of waxy lipid molecules. A ceramide is composed of N-acetyl sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane The cell membrane (also known as the plasma membrane (PM) o ...

, which is often considered to be an important pro-

apoptotic Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes inc ...

ceramide. De novo ceramide synthesis is an essential trigger for Bax activation in

hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...

/reoxygenation. Following hypoxia/reoxygenation, CerS5 expression is elevated. Upon knocking down

acid sphingomyelinase 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 de ...

and CerS5 in

NTERA-2 The NTERA-2 (also designated NTERA2/D1, NTERA2, or NT2) cell line is a clonally derived, pluripotent human embryonal carcinoma cell line. Characteristics NTERA-2 cells exhibit biochemical and developmental properties similar to the cells of the ea ...

cells, Bax localization to mitochondria was reduced, indicating the importance of CerS5 activity in the apoptosis pathway.

Tissue distribution

CerS5 (TRH4) mRNA is found in all tissues and is strongly expressed in muscle and brain. CerS5 is the major

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 ...

detected in lung epithelia. Knock-down research in respiratory epithelium using CerS5

siRNA Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20-24 (normally 21) base pairs in length, similar to miRNA, and operating ...

fumonisin B1 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. Fumonis ...

reduced total CerS activity by 45% or 78%, respectively, indicating that CerS5 indeed contributes significantly to ceramide synthesis in lung. In the

brain The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head ( cephalization), usually near organs for special ...

, CerS5

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

is detected in most cells within the

gray Grey (more common in British English) or gray (more common in American English) is an intermediate color between black and white. It is a neutral or achromatic color, meaning literally that it is "without color", because it can be composed ...

and

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 ...

tissues.

Clinical significance

CerS5 sensitizes cells to the

chemotherapeutic Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...

drugs

doxorubicin Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used tog ...

and

vincristine Vincristine, also known as leurocristine and marketed under the brand name Oncovin among others, is a chemotherapy medication used to treat a number of types of cancer. This includes acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin' ...

, but not to

cisplatin Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelio ...

carboplatin Carboplatin, sold under the trade name Paraplatin among others, is a chemotherapy medication used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It is used ...

. A

splice variant Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be i ...

of CerS5 is expressed in

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enl ...

and other tumor cells and contribute to tumor recognition by the immune system. In response to

upregulation In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pr ...

of tumor suppressor protein

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

, C16-ceramide levels were increased in

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...

and

colon cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel ...

cells, as were levels of CerS5 mRNA in the leukemia cells, but not in the colon cancer cells. For this reason, CerS5 looks like a promising target for the regulation of cancer and of cell death pathways.

References

{{reflist Enzymes Human proteins Integral membrane proteins