The ASAH1
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 ...
encodes in humans the ''acid
ceramidase
Ceramidase (, ''acylsphingosine deacylase'', ''glycosphingolipid ceramide deacylase'') is an enzyme which cleaves fatty acids from ceramide, producing sphingosine (SPH) which in turn is phosphorylated by a sphingosine kinase to form sphingosine- ...
''
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 ...
.
Function
This gene encodes a
heterodimeric
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
protein consisting of a nonglycosylated alpha subunit and a
glycosylated
Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
beta subunit that is cleaved to the mature enzyme
posttranslationally. The encoded protein catalyzes the synthesis and degradation of
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 of eukaryotic cells, since they are component lipids that make ...
into
sphingosine
Sphingosine (2-amino-4-trans-octadecene-1,3-diol) is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phos ...
and fatty acid. Mutations in this gene have been associated with a
lysosomal storage disorder
Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other ...
known as
Farber disease
Farber disease (also known as Farber's lipogranulomatosis, acid ceramidase deficiency, "Lipogranulomatosis", and ''ASAH1''-related disorders) is an extremely rare, progressive, autosomal recessive lysosomal storage disease caused by a deficiency ...
and, recently, with a rare neurodegenerative condition known as
spinal muscular atrophy with progressive myoclonic epilepsy
Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), sometimes called Jankovic–Rivera syndrome, is a very rare neurodegenerative disease whose symptoms include slowly progressive muscle (atrophy), predominantly affecting proxi ...
. Two transcript variants encoding distinct isoforms have been identified for this gene.
In
melanocytic cells ASAH1 gene expression may be regulated by
MITF
Microphthalmia-associated transcription factor also known as class E basic helix-loop-helix protein 32 or bHLHe32 is a protein that in humans is encoded by the ''MITF'' gene.
MITF is a basic helix-loop-helix leucine zipper transcription factor ...
.
As a glioblastoma drug target
ASAH1 expression is upregulated following radiation, suggesting it plays a role in conferring radioresistance to
glioblastoma
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ...
and in the development of recurrent glioblastoma. Inhibiting the activity of ASAH1 with
carmofur, a drug that has been approved for clinical treatment of
colorectal cancers in several countries, leads to substantial cell deaths and as a result has been proposed as a drug target in the treatment of glioblastoma. It has also been suggested to be a novel drug target against pediatric brain tumors as well.
References
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