ACADVL
Very long-chain specific acyl-CoA dehydrogenase, mitochondrial (VLCAD) is an enzyme that in humans is encoded by the ACADVL gene.
Mutations in the ACADVL are associated with very long-chain acyl-coenzyme A dehydrogenase deficiency. The protein encoded by this gene is targeted to the inner mitochondrial membrane, where it catalyzes the first step of the mitochondrial fatty acid beta-oxidation 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. Alternative splicing results in multiple transcript variants encoding different isoforms.[1]
Structure
The ACADVL gene contains 20 exons,[2] and is about 5.4 kb long.[3] VLCAD has interesting gene structure in humans, in that is located in a head-to-head structure with the DLG4 gene on Chromosome 17, and that the transcribed regions of these genes overlap. It has been shown that treatment with DEHP results in upregulation by the minimal promoter.[4] 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.[3]
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.[5] 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.[6]
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. 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, which is triggered by exercise or fasting.[7] The disease is typically diagnosed by first performing tandem mass spectrometry 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, myocardial irritation, dehydration, and high fat diets are avoided in attempt to prevent secondary complications.[8]
See also
References
- ↑ "acyl-CoA dehydrogenase, very long chain".
- ↑ Strauss AW, Powell CK, Hale DE, Anderson MM, Ahuja A, Brackett JC, Sims HF (Nov 1995). "Molecular basis of human mitochondrial very-long-chain acyl-CoA dehydrogenase deficiency causing cardiomyopathy and sudden death in childhood". Proceedings of the National Academy of Sciences of the United States of America 92 (23): 10496–500. doi:10.1073/pnas.92.23.10496. PMC: 40638. PMID 7479827.
- 1 2 Zhou C, Blumberg B (Feb 2003). "Overlapping gene structure of human VLCAD and DLG4". Gene 305 (2): 161–6. doi:10.1016/s0378-1119(02)01235-0. PMID 12609736.
- ↑ Zhang LF, Ding JH, Yang BZ, He GC, Roe C (Dec 2003). "Characterization of the bidirectional promoter region between the human genes encoding VLCAD and PSD-95". Genomics 82 (6): 660–8. doi:10.1016/s0888-7543(03)00211-8. PMID 14611808.
- ↑ Aoyama T, Souri M, Ushikubo S, Kamijo T, Yamaguchi S, Kelley RI, Rhead WJ, Uetake K, Tanaka K, Hashimoto T (Jun 1995). "Purification of human very-long-chain acyl-coenzyme A dehydrogenase and characterization of its deficiency in seven patients". The Journal of Clinical Investigation 95 (6): 2465–73. doi:10.1172/JCI117947. PMC: 295925. PMID 7769092.
- ↑ Pougovkina O, te Brinke H, Ofman R, van Cruchten AG, Kulik W, Wanders RJ, Houten SM, de Boer VC (Jul 2014). "Mitochondrial protein acetylation is driven by acetyl-CoA from fatty acid oxidation". Human Molecular Genetics 23 (13): 3513–22. doi:10.1093/hmg/ddu059. PMID 24516071.
- ↑ Andresen BS, Olpin S, Poorthuis BJ, Scholte HR, Vianey-Saban C, Wanders R, Ijlst L, Morris A, Pourfarzam M, Bartlett K, Baumgartner ER, deKlerk JB, Schroeder LD, Corydon TJ, Lund H, Winter V, Bross P, Bolund L, Gregersen N (Feb 1999). "Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency". American Journal of Human Genetics 64 (2): 479–94. doi:10.1086/302261. PMC: 1377757. PMID 9973285.
- ↑ "Very Long-Chain Acyl-Coenzyme a Dehydrogenase Deficiency". 1993. PMID 20301763.
External links
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.