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 (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 ...

. Mutations in the ACADVL are associated with

very long-chain acyl-coenzyme A dehydrogenase deficiency Very long-chain acyl-coenzyme A dehydrogenase deficiency is a fatty-acid metabolism disorder which prevents the body from converting certain fats to energy, particularly during periods without food. Those affected by this disorder have inadequ ...

. The

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

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. ...

, where it catalyzes the first step of the mitochondrial fatty acid beta-oxidation pathway. This

acyl-Coenzyme A dehydrogenase Acyl-CoA dehydrogenases (ACADs) are a class of enzymes that function to catalyze the initial step in each cycle of fatty acid β-oxidation in the mitochondria of cells. Their action results in the introduction of a trans double-bond between C2 (α ...

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. Alternative splicing results in multiple transcript variants encoding different isoforms.

Structure

The ACADVL gene contains 20 exons, 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 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 83 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total D ...

, and that the transcribed regions of these genes overlap. It has been shown that treatment with

DEHP Bis(2-ethylhexyl) phthalate (di-2-ethylhexyl phthalate, diethylhexyl phthalate, diisooctyl phthalate, DEHP; incorrectly — dioctyl phthalate, DIOP) is an organic compound with the formula C6H4(CO2C8H17)2. DEHP is the most common member of the cl ...

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-double bond in the fatty acid. VLCAD is specific to very long-chain fatty acids, typically C16-acylCoA 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 in this biological system.

Clinical significance

ACADVL is linked with

(VLCADD), which has many symptoms, and typically presents as one of three

phenotypes In genetics, the phenotype () is the set of observable characteristics or phenotypic trait, traits of an organism. The term covers the organism's morphology (biology), morphology or physical form and structure, its Developmental biology, dev ...

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

, 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 mass analyzers are coupled together using an additional reaction step to increase their abilities to analyse chemical samples. A com ...

on a blood sample of the patient during a period of stress, and then performing molecular genetic testing for the presence of the ACADVL gene. The deficiency is treated systematically, but certain conditions such as

fasting Fasting is the abstention from eating and sometimes drinking. From a purely physiological context, "fasting" may refer to the metabolic status of a person who has not eaten overnight (see " Breakfast"), or to the metabolic state achieved after ...

, myocardial irritation,

dehydration In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...

, and high fat diets are avoided in 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 40S ribosomal protein SA is a ribosomal protein that in humans is encoded by the ''RPSA'' gene. It also acts as a cell surface receptor, in particular for laminin, and is involved in several pathogenic processes. Function Laminins, a family o ...

and GPHN.

References

External links

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