| ACAD9 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | ACAD9 , NPD002, acyl-CoA dehydrogenase family member 9, MC1DN20 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 611103 MGI: 1914272 HomoloGene: 8539 GeneCards: ACAD9 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Acyl-CoA dehydrogenase family member 9, mitochondrial is an enzyme that in humans is encoded by the ACAD9 gene. [5] [6] Mitochondrial Complex I Deficiency with varying clinical manifestations has been associated with mutations in ACAD9. [7]
The ACAD9 gene contains an open reading frame of 1866 base pairs; this gene encodes a protein with 621 amino acid residues. Alignment of the ACAD9 protein sequence with that of other human ACAD proteins showed that ACAD-9 protein displays 46–27% identity, and 56–38% similarity with the eight members of the ACAD family, including ACADVL, ACADS, ACADM, ACADL, IVD, GCD, ACADSB, and ACD8. The calculated molecular weight of the ACAD9 is 68.8 kDa. [5]
The ACAD9 enzyme catalyzes a crucial step in fatty acid beta-oxidation by forming a C2-C3 trans-double bond in the fatty acid. LVCAD is specific to very long-chain fatty acids, typically C16-acylCoA and longer. [8] It has been observed that ACAD9 can catalyze acyl-CoAs with very long chains. The specific activity of ACAD9 towards palmitoyl-CoA (C16:0) is three times higher than that towards stearoyl-CoA (C18:0). ACAD-9 has little activity on n-octanoyl-CoA (C8:0), n-butyryl-CoA (C4:0) or isovaleryl-CoA (C5:0). [5]
In contrast with ACADVL, ACAD9 is also involved in assembly of the oxidative phosphorylation complex I. ACAD9 binds complex I assembly factors NDUFAF1 and Ecsit and is specifically required for the assembly of complex I. Furthermore, ACAD9 mutations result in complex I deficiency and not in disturbed long-chain fatty acid oxidation. [9]
Mutations in the ACAD9 gene are associated with mitochondrial complex I deficiency type 20, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders. [10] [11] Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype–phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible. [12] However, the majority of cases are caused by mutations in nuclear-encoded genes. [13] [14] It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. [15]
A few cases specific to ACAD9 have been reported. Some cases presented with episodic liver dysfunction during otherwise mild illnesses or cardiomyopathy, along with chronic neurologic dysfunction. Brain findings were notable for generalized edema with diffuse ventricular compression, acute left tonsillar herniation, and diffuse multifocal acute damage in the hippocampus. In addition, some abnormalities consistent with nonacute changes were seen, including a subacute right cerebellar hemispheric infarct and reduction in the number of neurons in several areas. [16] In one patient, whose clinical manifestations of hypotonia, cardiomyopathy, and lactic acidosis, a vigorous treatment with riboflavin allowed the individual to have normal psychomotor development and no cognitive impairment at 5 years of age. [17] Exercise-induced rhabdomyolysis, mitochondrial encephalomyopathy, and hyperplasia in liver, cardiac myocytes, skeletal muscle, and renal tubules have also been observed in patients with ACAD9 mutations. [18] [19] [7]
ACAD9 is part of the mitochondrial complex I assembly (MCIA) complex. The complex comprises at least TMEM126B, NDUFAF1, ECSIT, and ACAD9, which interacts directly with NDUFAF1 and ECSIT. [9]
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.
Very long-chain specific acyl-CoA dehydrogenase, mitochondrial (VLCAD) is an enzyme that in humans is encoded by the ACADVL gene.
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.
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.
Acyl-CoA dehydrogenase, C-2 to C-3 short chain is an enzyme that in humans is encoded by the ACADS gene. 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 associated with short-chain acyl-coenzyme A dehydrogenase deficiency.
Acyl-CoA dehydrogenase, long chain is a protein that in humans is encoded by the ACADL gene.
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:
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.
ACADSB is a human gene that encodes short/branched chain specific acyl-CoA dehydrogenase (SBCAD), an enzyme in the acyl CoA dehydrogenase family.
Electron-transferring-flavoprotein dehydrogenase is an enzyme that transfers electrons from electron-transferring flavoprotein in the mitochondrial matrix, to the ubiquinone pool in the inner mitochondrial membrane. It is part of the electron transport chain. The enzyme is found in both prokaryotes and eukaryotes and contains a flavin and FE-S cluster. In humans, it is encoded by the ETFDH gene. Deficiency in ETF dehydrogenase causes the human genetic disease multiple acyl-CoA dehydrogenase deficiency.
Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial is an enzyme that in humans is encoded by the PDHA1 gene.The pyruvate dehydrogenase complex is a nuclear-encoded mitochondrial matrix multienzyme complex that provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle by catalyzing the irreversible conversion of pyruvate into acetyl-CoA. The PDH complex is composed of multiple copies of 3 enzymes: E1 (PDHA1); dihydrolipoyl transacetylase (DLAT) ; and dihydrolipoyl dehydrogenase (DLD). The E1 enzyme is a heterotetramer of 2 alpha and 2 beta subunits. The E1-alpha subunit contains the E1 active site and plays a key role in the function of the PDH complex.
NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial (NDUFS4) also known as NADH-ubiquinone oxidoreductase 18 kDa subunit is an enzyme that in humans is encoded by the NDUFS4 gene. This gene encodes a nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase. Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome.
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.
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.
NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1) is an enzyme that in humans is encoded by the NDUFS1 gene. The encoded protein, NDUFS1, is the largest subunit of complex I, located on the inner mitochondrial membrane, and is important for mitochondrial oxidative phosphorylation. Mutations in this gene are associated with complex I deficiency.
(See also: List of proteins in the human body)
Complex I intermediate-associated protein 30, mitochondrial (CIA30), or NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 1 (NDUFAF1), is a protein that in humans is encoded by the NDUFAF1 or CIA30 gene. The NDUFAF1 gene encodes a human homolog of a Neurospora crassa protein involved in the assembly of complex I. The NDUFAF1 protein is an assembly factor of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variants of the NDUFAF1 gene are associated with hypertrophic cardiomyopathy, leukodystrophy, and cardioencephalomyopathy.
NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3, also known as 2P1, E3-3, or C3orf60, is a protein that in humans is encoded by the NDUFAF3 gene. NDUFAF3 is a mitochondrial assembly protein involved in the assembly of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in this gene have been associated with severe complex I deficiency and Leigh syndrome.
NADH:ubiquinone oxidoreductase complex assembly factor 2 (NDUFAF2), also known as B17.2L or NDUFA12L is a protein that in humans is encoded by the NDUFAF2, or B17.2L, gene. The NDUFAF2 protein is a chaperone involved in the assembly of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in this gene have been associated with progressive encephalopathy and Leigh disease resulting from mitochondrial complex I deficiency.
