Very long-chain specific acyl-CoA dehydrogenase, mitochondrial (VLCAD) is an enzyme that in humans is encoded by the ACADVL

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. Mutations in the ACADVL are associated with very long-chain acyl-coenzyme A dehydrogenase deficiency. The

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

encoded by this gene is targeted to the

inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...

, where it catalyzes the first step of the mitochondrial fatty acid

beta-oxidation In biochemistry and metabolism, beta oxidation (also β-oxidation) is the Catabolism, catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl ...

pathway. This acyl-Coenzyme A dehydrogenase is specific to long-chain and very-long-chain fatty acids. A deficiency in this gene product reduces myocardial fatty acid beta-oxidation and is associated with

cardiomyopathy Cardiomyopathy is a group of primary diseases of the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...

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

results in multiple transcript variants encoding different isoforms.

Structure

The ACADVL gene contains 20

exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence i ...

, and is about 5.4 kb long. VLCAD has interesting gene structure in humans, in that is located in a head-to-head structure with the

DLG4 PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a protein that in humans is encoded by the ''DLG4'' (discs large homolog 4) gene. PSD-95 is a member of the membrane-associated guanylate kinase (MA ...

gene on

Chromosome 17 Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 84 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total DN ...

, and that the transcribed regions of these genes overlap. It has been shown that treatment with DEHP results in upregulation by the minimal promoter. While DLG4 and VLCAD share common regulatory elements, they each have separate and distinct tissue-specific elements that confer their function. In mice, these two genes are in a head-to-head orientation, but they do not overlap.

Function

The VLCAD enzyme catalyzes most of fatty acid beta-oxidation by forming a C2-C3

trans Trans- is a Latin prefix meaning "across", "beyond", or "on the other side of". Used alone, trans may refer to: Sociology * Trans, a sociological term which may refer to: ** Transgender, people who identify themselves with a gender that di ...

double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...

in the fatty acid. VLCAD is specific to very long-chain fatty acids, typically C16-

acyl-CoA Acyl-CoA is a group of coenzyme A, CoA-based coenzymes that metabolize carboxylic acids. Fatty acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several e ...

and longer. In mice that have VLCAD deficiency, there is little to no protein hyperacetylation in the liver; this implies that the VLCAD protein is also necessary for

protein acetylation Protein acetylation (and deacetylation) are acetylation reactions that occur within living cells as drug metabolism, by enzymes in the liver and other organs (e. g., the brain). Pharmaceuticals frequently employ acetylation to enable such esters to ...

in this biological system.

Clinical significance

ACADVL is linked with very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD), which has many symptoms, and typically presents as one of three

phenotypes In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological properti ...

. The first is severe, with an early childhood onset and high mortality rate; the most common symptom is this form is

. The second is a late onset childhood form, with milder symptoms that present most commonly as hypoketotic hypoglycemia. The final form presents in adulthood, and presents as isolated skeletal muscle involvement,

rhabdomyolysis Rhabdomyolysis (shortened as rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some o ...

, and

myoglobinuria Myoglobinuria is the presence of myoglobin in the urine, which usually results from rhabdomyolysis or muscle injury. Myoglobin is present in muscle cells as a reserve of oxygen. Signs and symptoms Signs and symptoms of myoglobinuria are usua ...

, which is triggered by exercise or fasting. The disease is typically diagnosed by first performing

tandem mass spectrometry Tandem mass spectrometry, also known as MS/MS or MS2, is a technique in instrumental analysis where two or more stages of analysis using one or more mass analyzer are performed with an additional reaction step in between these analyses to increa ...

on a blood sample of the patient during a period of stress, and then performing molecular

genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

for the presence of the ACADVL gene. The deficiency is treated systematically, but certain conditions such as

fasting Fasting is the act of refraining from eating, and sometimes drinking. However, from a purely physiological context, "fasting" may refer to the metabolic status of a person who has not eaten overnight (before "breakfast"), or to the metabolic sta ...

, myocardial irritation,

dehydration In physiology, dehydration is a lack of total body water that disrupts metabolic processes. It occurs when free water loss exceeds intake, often resulting from excessive sweating, health conditions, or inadequate consumption of water. Mild deh ...

, and high fat diets are avoided in an attempt to prevent secondary complications.

Interactions

ACADVL has been shown to have 75 binary protein-protein interactions including 73 co-complex interactions. ACADVL appears to interact with RPSA and

GPHN Gephyrin is a protein that in humans is encoded by the ''GPHN'' gene. This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subu ...

References

External links

GeneReviews/NCBI/NIH/UW entry on Very long-chain acyl-coenzyme A dehydrogenase deficiency
* {{DEFAULTSORT:Acadvl