Ceramide synthase 5 (CerS5) is the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

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 sphingosine and a fatty acid joined by an amide bond. Ceramides are found in high concentrations within the cell membrane of Eukaryote, eukaryotic cells, since they are co ...

, which is often considered to be an important pro-

apoptotic Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes ( morphology) and death. These ...

ceramide.

De novo De novo (Latin, , used in English to mean 'from the beginning', 'anew') may refer to: Science and computers * ''De novo'' mutation, a new germline mutation not inherited from either parent * ''De novo'' protein design, the creation of a protei ...

ceramide synthesis is an essential trigger for Bax activation in hypoxia/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 d ...

and CerS5 in NTERA-2 cells, Bax localization to

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

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 non-coding RNA molecules, typically 20–24 base pairs in length, similar to microRNA (miRNA), and operating within the RN ...

fumonisin B1 Fumonisin B1 is the most prevalent member of a family of toxins, known as fumonisins, produced by multiple species of ''Fusarium'' Mold (fungus), molds, such as ''Fusarium verticillioides'', which occur mainly in maize (corn), wheat and other cere ...

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 (biology), 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 ...

, 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 Protein biosynthesis, synthesizing a protein. mRNA is ...

is detected in most cells within the

gray Grey (more frequent in British English) or gray (more frequent in American English) is an intermediate color between black and white. It is a neutral or achromatic color, meaning that it has no chroma. It is the color of a cloud-covered s ...

and

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

tissues.

Clinical significance

CerS5 sensitizes cells to the

chemotherapeutic Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a curat ...

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 toge ...

and

vincristine Vincristine, also known as leurocristine and sold 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 lym ...

, but not to

cisplatin Cisplatin is a chemical compound with chemical formula, formula ''cis''-. It is a coordination complex of platinum that is used as a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, c ...

carboplatin Carboplatin, sold under the brand 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 a ...

. A

splice variant Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included ...

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). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...

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

upregulation In biochemistry, in the biological context of organisms' regulation of gene expression and production of gene products, downregulation is the process by which a cell decreases the production and quantities of its cellular components, such as R ...

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 transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...

, C16-ceramide levels were increased in

leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce 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