ACADS

Last updated
ACADS
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases ACADS , acyl-CoA dehydrogenase, C-2 to C-3 short chain, ACAD3, SCAD, acyl-CoA dehydrogenase short chain
External IDs OMIM: 606885 MGI: 87868 HomoloGene: 20057 GeneCards: ACADS
Orthologs
SpeciesHumanMouse
Entrez

35

11409

Ensembl

ENSG00000122971

ENSMUSG00000029545

UniProt

P16219

Q07417

RefSeq (mRNA)

NM_001302554
NM_000017

NM_007383

RefSeq (protein)

NP_000008
NP_001289483
NP_001289483.1

NP_031409

Location (UCSC) Chr 12: 120.73 – 120.74 Mb Chr 5: 115.25 – 115.26 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Acyl-CoA dehydrogenase, C-2 to C-3 short chain is an enzyme that in humans is encoded by the ACADS gene. [5] This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. The ACADS gene is associated with short-chain acyl-coenzyme A dehydrogenase deficiency. [6] [5]

Contents

Structure

The ACADS gene is approximately 13 kb in length and has 10 exons. The coding sequence of this gene is 1239 bp long. [7] The encoded protein has 412 amino acids, and its size is 44.3 kDa (Human) or 44.9 KDa (Mouse). [8] [9]

Function

The SCAD enzyme catalyzes the first part of fatty acid beta-oxidation by forming a C2-C3 trans-double bond in the fatty acid through dehydrogenation of the flavoenzyme. SCAD is specific to short-chain fatty acids, between C2 and C3-acylCoA. The final result of beta-oxidation is acetyl-CoA. [10] When there are defects that result in SCAD being misfolded, there is an increased production of reactive oxygen species (ROS); the increased ROS forces the mitochondria to undergo fission, and the mitochondrial reticulum takes on a grain-like structure. [11]

Clinical significance

Mutations of the ACADS gene are associated with deficiency of the short-chain acyl-coenzyme A dehydrogenase protein (SCADD); this is also known as butyryl-CoA dehydrogenase deficiency. Many mutations have been identified in specific populations, and large-scale studies have been performed to determine the allelic and genotypic frequency for the defective gene. [12] [13] As short-chain acyl-CoA dehydrogenase is involved in beta-oxidation, a deficiency in this enzyme is marked by an increased amount of fatty acids. This deficiency is characterized by the presence of increased butyrylcarnitine (C4) in blood plasma, and increased ethylmalonic acid (EMA) concentrations in urine. Genotypes of individuals with this deficiency have it as a result of a mutation, variant, or a combination of the two. [14] Among one population with the disease, three subgroups have been identified: one group has a failure to thrive, feeding difficulties, and hypotonia; another group had seizures; finally, one group had hypotonia and no seizures. [15] Other studies showed that the deficiency may be asymptomatic in some individuals under normal conditions, with symptoms presenting under physiological stress conditions such as fasting or illness. [16] The treatment of this deficiency can sometimes be unclear, because it can sometimes be asymptomatic. The treatment for this disease is similar to treatment of other fatty acid oxidation disorders, by trying to restore biochemical and physiologic homeostasis, by promoting anabolism and providing alternative sources of energy. [14] Flavin adenine dinucleotide supplementation has also been identified as a therapy for this deficiency, because it is an essential cofactor for proper function of SCAD. [17] SCAD deficiency is inherited in an autosomal recessive manner. Carrier testing can be performed for at-risk family members, and prenatal testing is also a possibility. [14]

The ACADS gene has also been implicated in delaying the onset of Prader-Willi Syndrome, which is characterized by hypotonia, growth failure, and neurodevelopmental delays in the first years of life, and hyperphagia and obesity much later. [18]

In a genome-wide association study (GWAS), a single-nucleotide polymorphism in ACADS has been associated with a reduced amount of insulin release shown by an oral glucose tolerance test, or OGTT. [19]

See also

Related Research Articles

<span class="mw-page-title-main">Medium-chain acyl-coenzyme A dehydrogenase deficiency</span> Medical condition

Medium-chain acyl-CoA dehydrogenase deficiency is a disorder of fatty acid oxidation that impairs the body's ability to break down medium-chain fatty acids into acetyl-CoA. The disorder is characterized by hypoglycemia and sudden death without timely intervention, most often brought on by periods of fasting or vomiting.

<span class="mw-page-title-main">Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency</span> Medical condition

Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency is a rare autosomal recessive fatty acid oxidation disorder that prevents the body from converting certain fats into energy. This can become life-threatening, particularly during periods of fasting.

<span class="mw-page-title-main">Inborn error of lipid metabolism</span> Medical condition

Numerous genetic disorders are caused by errors in fatty acid metabolism. These disorders may be described as fatty oxidation disorders or as a lipid storage disorders, and are any one of several inborn errors of metabolism that result from enzyme defects affecting the ability of the body to oxidize fatty acids in order to produce energy within muscles, liver, and other cell types.

<span class="mw-page-title-main">Mitochondrial trifunctional protein deficiency</span> Medical condition

Mitochondrial trifunctional protein deficiency is an autosomal recessive fatty acid oxidation disorder that prevents the body from converting certain fats to energy, particularly during periods without food. People with this disorder have inadequate levels of an enzyme that breaks down a certain group of fats called long-chain fatty acids.

<span class="mw-page-title-main">ACADVL</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">ACADM</span> Mammalian protein found in Homo sapiens

ACADM is a gene that provides instructions for making an enzyme called acyl-coenzyme A dehydrogenase that is important for breaking down (degrading) a certain group of fats called medium-chain fatty acids.

<span class="mw-page-title-main">Malonyl-CoA decarboxylase deficiency</span> Medical condition

Malonyl-CoA decarboxylase deficiency (MCD) is an autosomal-recessive metabolic disorder caused by a genetic mutation that disrupts the activity of Malonyl-CoA decarboxylase. This enzyme breaks down Malonyl-CoA into acetyl-CoA and carbon dioxide.

<span class="mw-page-title-main">Short-chain acyl-coenzyme A dehydrogenase deficiency</span> Medical condition

Short-chain acyl-coenzyme A dehydrogenase deficiency (SCADD) is an autosomal recessive fatty acid oxidation disorder which affects enzymes required to break down a certain group of fats called short chain fatty acids.

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) and C3 (β) of the acyl-CoA thioester substrate. Flavin adenine dinucleotide (FAD) is a required co-factor in addition to the presence of an active site glutamate in order for the enzyme to function.

<span class="mw-page-title-main">ACADL</span> Protein-coding gene in the species Homo sapiens

Acyl-CoA dehydrogenase, long chain is a protein that in humans is encoded by the ACADL gene.

<span class="mw-page-title-main">Mitochondrial trifunctional protein</span> Inner mitochondrial membrane protein

Mitochondrial trifunctional protein (MTP) is a protein attached to the inner mitochondrial membrane which catalyzes three out of the four steps in beta oxidation. MTP is a hetero-octamer composed of four alpha and four beta subunits:

<span class="mw-page-title-main">HADHA</span> Protein-coding gene in the species Homo sapiens

Trifunctional enzyme subunit alpha, mitochondrial also known as hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit is a protein that in humans is encoded by the HADHA gene. Mutations in HADHA have been associated with trifunctional protein deficiency or long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.

<span class="mw-page-title-main">HADHB</span> Protein-coding gene in the species Homo sapiens

Trifunctional enzyme subunit beta, mitochondrial (TP-beta) also known as 3-ketoacyl-CoA thiolase, acetyl-CoA acyltransferase, or beta-ketothiolase is an enzyme that in humans is encoded by the HADHB gene.

<span class="mw-page-title-main">ACADSB</span> Protein-coding gene in the species Homo sapiens

ACADSB is a human gene that encodes short/branched chain specific acyl-CoA dehydrogenase (SBCAD), an enzyme in the acyl CoA dehydrogenase family.

<span class="mw-page-title-main">ETFA</span> Protein-coding gene in humans

The human ETFA gene encodes the Electron-transfer-flavoprotein, alpha subunit, also known as ETF-α. Together with Electron-transfer-flavoprotein, beta subunit, encoded by the 'ETFB' gene, it forms the heterodimeric electron transfer flavoprotein (ETF). The native ETF protein contains one molecule of FAD and one molecule of AMP, respectively.

<span class="mw-page-title-main">ETFB</span> Protein-coding gene in humans

The human ETFB gene encodes the Electron-transfer-flavoprotein, beta subunit, also known as ETF-β. Together with Electron-transfer-flavoprotein, alpha subunit, encoded by the 'ETFA' gene, it forms the heterodimeric Electron transfer flavoprotein (ETF). The native ETF protein contains one molecule of FAD and one molecule of AMP, respectively.

<span class="mw-page-title-main">ACAD8</span> Protein-coding gene in the species Homo sapiens

Isobutyryl-CoA dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ACAD8 gene on chromosome 11.

<span class="mw-page-title-main">ACAD9</span> Protein-coding gene in the species Homo sapiens

Acyl-CoA dehydrogenase family member 9, mitochondrial is an enzyme that in humans is encoded by the ACAD9 gene. Mitochondrial Complex I Deficiency with varying clinical manifestations has been associated with mutations in ACAD9.

<span class="mw-page-title-main">Fatty-acid metabolism disorder</span> Medical condition

A broad classification for genetic disorders that result from an inability of the body to produce or utilize an enzyme or transport protein that is required to oxidize fatty acids. They are an inborn error of lipid metabolism, and when it affects the muscles also a metabolic myopathy.

<span class="mw-page-title-main">Hydroxyacyl-Coenzyme A dehydrogenase</span> Protein-coding gene in the species Homo sapiens

Hydroxyacyl-Coenzyme A dehydrogenase (HADH) is an enzyme which in humans is encoded by the HADH gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000122971 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000029545 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 "Entrez Gene: Acyl-CoA dehydrogenase, C-2 to C-3 short chain".
  6. ↑ Tein I, Elpeleg O, Ben-Zeev B, Korman SH, Lossos A, Lev D, et al. (February 2008). "Short-chain acyl-CoA dehydrogenase gene mutation (c.319C>T) presents with clinical heterogeneity and is candidate founder mutation in individuals of Ashkenazi Jewish origin". Molecular Genetics and Metabolism. 93 (2): 179–189. doi:10.1016/j.ymgme.2007.09.021. PMID   18054510.
  7. ↑ Corydon MJ, Andresen BS, Bross P, Kjeldsen M, Andreasen PH, Eiberg H, et al. (December 1997). "Structural organization of the human short-chain acyl-CoA dehydrogenase gene". Mammalian Genome. 8 (12): 922–926. doi:10.1007/s003359900612. PMID   9383286. S2CID   9157185.
  8. ↑ "Protein Information: P16219". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 14 August 2016. Retrieved 23 July 2016.
  9. ↑ "Protein Information: Q07417". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 14 August 2016. Retrieved 23 July 2016.
  10. ↑ Voet DJ, Voet JG, Pratt CW (2010). "Chapter 18, Mitochondrial ATP synthesis". Principles of Biochemistry (4th ed.). Wiley. p. 667. ISBN   978-0-470-23396-2.
  11. ↑ Schmidt SP, Corydon TJ, Pedersen CB, Bross P, Gregersen N (June 2010). "Misfolding of short-chain acyl-CoA dehydrogenase leads to mitochondrial fission and oxidative stress". Molecular Genetics and Metabolism. 100 (2): 155–162. doi:10.1016/j.ymgme.2010.03.009. PMID   20371198.
  12. ↑ Jethva R, Bennett MJ, Vockley J (December 2008). "Short-chain acyl-coenzyme A dehydrogenase deficiency". Molecular Genetics and Metabolism. 95 (4): 195–200. doi:10.1016/j.ymgme.2008.09.007. PMC   2720545 . PMID   18977676.
  13. ↑ Okuyaz C, Ezgü FS, Biberoglu G, Zeviani M, Tiranti V, Yilgör E (June 2008). "Severe infantile hypotonia with ethylmalonic aciduria: case report". Journal of Child Neurology. 23 (6): 703–705. doi:10.1177/0883073807313048. PMID   18539996. S2CID   46624539.
  14. 1 2 3 Wolfe L, Jethva R, Oglesbee D, Vockley J (1993). "Short-Chain Acyl-CoA Dehydrogenase Deficiency". In Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A (eds.). GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle. PMID   21938826.
  15. ↑ Pedersen CB, Kølvraa S, Kølvraa A, Stenbroen V, Kjeldsen M, Ensenauer R, et al. (August 2008). "The ACADS gene variation spectrum in 114 patients with short-chain acyl-CoA dehydrogenase (SCAD) deficiency is dominated by missense variations leading to protein misfolding at the cellular level". Human Genetics. 124 (1): 43–56. doi:10.1007/s00439-008-0521-9. PMID   18523805. S2CID   25491212.
  16. ↑ Bok LA, Vreken P, Wijburg FA, Wanders RJ, Gregersen N, Corydon MJ, et al. (November 2003). "Short-chain Acyl-CoA dehydrogenase deficiency: studies in a large family adding to the complexity of the disorder" (PDF). Pediatrics. 112 (5): 1152–1155. doi:10.1542/peds.112.5.1152. PMID   14595061.
  17. ↑ van Maldegem BT, Duran M, Wanders RJ, Waterham HR, Wijburg FA (March 2010). "Flavin adenine dinucleotide status and the effects of high-dose riboflavin treatment in short-chain acyl-CoA dehydrogenase deficiency". Pediatric Research. 67 (3): 304–308. doi: 10.1203/PDR.0b013e3181cbd57b . PMID   19952864.
  18. ↑ Giurgiutiu DV, Espinoza LM, Wood TC, DuPont BR, Holden KR (January 2008). "Persistent growth failure in Prader-Willi syndrome associated with short-chain acyl-CoA dehydrogenase gene variant". Journal of Child Neurology. 23 (1): 112–117. doi:10.1177/0883073807307979. PMID   18184946. S2CID   31888136.
  19. ↑ Hornbak M, Banasik K, Justesen JM, Krarup NT, Sandholt CH, Andersson Å, et al. (January 2011). "The minor C-allele of rs2014355 in ACADS is associated with reduced insulin release following an oral glucose load". BMC Medical Genetics. 12: 4. doi: 10.1186/1471-2350-12-4 . PMC   3022800 . PMID   21211036.

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