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| Aliases | ACO2 , ACONM, ICRD, OCA8, HEL-S-284, OPA9, aconitase 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 100850 MGI: 87880 HomoloGene: 856 GeneCards: ACO2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Aconitase 2, mitochondrial is a protein that in humans is encoded by the ACO2 gene. [5]
| ACO2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | ACO2 , ACONM, ICRD, OCA8, HEL-S-284, OPA9, aconitase 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 100850 MGI: 87880 HomoloGene: 856 GeneCards: ACO2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Aconitase 2, mitochondrial is a protein that in humans is encoded by the ACO2 gene. [5]
The secondary structure of ACO2 consists of numerous alternating alpha helices and beta sheets (SCOP classification: α/β alternating). The tertiary structure reveals that the active site is buried in the middle of the enzyme, and, since there is only one subunit, there is no quaternary structure. Aconitase consists of four domains: three of the domains are tightly compact, and the fourth domain is more flexible, allowing for conformational changes. [6] The ACO2 protein contains a 4Fe-4S iron-sulfur cluster. This iron sulfur cluster does not have the typical function of participating in oxidation-reduction reactions, but rather facilitates the elimination of the citrate hydroxyl group by holding the group in a certain conformation and orientation. [7] It is at this 4Fe-4S site that citrate or isocitrate binds to initiate catalysis. The rest of the active site is made up of the following residues: Gln72, Asp100, His101, Asp165, Ser166, His167, His147, Glu262, Asn258, Cys358, Cys421, Cys424, Cys358, Cys421, Asn446, Arg447, Arg452, Asp568, Ser642, Ser643, Arg644, Arg580. Their functions have yet to be elucidated. [8]
The protein encoded by this gene belongs to the aconitase/IPM isomerase family. It is an enzyme that catalyzes the interconversion of citrate to isocitrate via cis-aconitate in the second step of the TCA cycle. This protein is encoded in the nucleus and functions in the mitochondrion. It was found to be one of the mitochondrial matrix proteins that are preferentially degraded by the serine protease 15 (PRSS15), also known as Lon protease, after oxidative modification.
While both forms of aconitases have similar functions, most studies focus on ACO2. The iron-sulfur (4Fe-4S) cofactor is held in place by the sulfur atoms on Cys385, Cys448, and Cys451, which are bind to three of the four available iron atoms. A fourth iron atom is included in the cluster together with a water molecule when the enzyme is activated. This fourth iron atom binds to either one, two, or three partners; in this reaction, oxygen atoms belonging to outside metabolites are always involved. [8] When ACO2 is not bound to a substrate, the iron-sulfur cluster is bound to a hydroxyl group through an interaction with one of the iron molecules. When the substrate binds, the bound hydroxyl becomes protonated. A hydrogen bond forms between His101 and the protonated hydroxyl, which allows the hydroxyl to form a water molecule. Alternatively, the proton could be donated by His167 as this histidine is hydrogen bonded to a H2O molecule. His167 is also hydrogen bonded to the bound H2O in the cluster. Both His101 and His167 are paired with carboxylates Asp100 and Glu262, respectively, and are likely to be protonated. The conformational change associated with substrate binding reorients the cluster. The residue that removes a proton from citrate or isocitrate is Ser642. This causes the cis-Aconitate intermediate, which is a direct result of the deprotonation. Then, there is a rehydration of the double bond of cis-aconitate to form the product. [9]
A serious ailment associated with aconitase is known as aconitase deficiency. [10] It is caused by a mutation in the gene for iron-sulfur cluster scaffold protein (ISCU), which helps build the Fe-S cluster on which the activity of aconitase depends. [10] The main symptoms are myopathy and exercise intolerance; physical strain is lethal for some patients because it can lead to circulatory shock. [10] [11] There are no known treatments for aconitase deficiency. [10]
Another disease associated with aconitase is Friedreich's ataxia (FRDA), which is caused when the Fe-S proteins in aconitase and succinate dehydrogenase have decreased activity. [12] A proposed mechanism for this connection is that decreased Fe-S activity in aconitase and succinate dehydrogenase is correlated with excess iron concentration in the mitochondria and insufficient iron in the cytoplasm, disrupting iron homeostasis. [12] This deviance from homeostasis causes FRDA, a neurodegenerative disease for which no effective treatments have been found. [12]
Finally, aconitase is thought to be associated with diabetes. [13] [14] Although the exact connection is still being determined, multiple theories exist. [13] [14] In a study of organs from mice with alloxan diabetes (experimentally induced diabetes [15] ) and genetic diabetes, lower aconitase activity was found to decrease the rates of metabolic reactions involving citrate, pyruvate, and malate. [13] In addition, citrate concentration was observed to be unusually high. [13] Since these abnormal data were found in diabetic mice, the study concluded that low aconitase activity is likely correlated with genetic and alloxan diabetes. [13] Another theory is that, in diabetic hearts, accelerated phosphorylation of heart aconitase by protein kinase C causes aconitase to speed up the final step of its reverse reaction relative to its forward reaction. [14] That is, it converts isocitrate back to cis-aconitate more rapidly than usual, but the forward reaction proceeds at the usual rate. [14] This imbalance may contribute to disrupted metabolism in diabetics. [14]
The mitochondrial form of aconitase, ACO2, is correlated with many diseases, as it is directly involved in the conversion of glucose into ATP, or the central metabolic pathway. Decreased expression of ACO2 in gastric cancer cells has been associated with a poor prognosis; [16] this effect has also been seen in prostate cancer cells. [17] [18] A few treatments have been identified in vitro to induce greater ACO2 expression, including exposing the cells to hypoxia and the element manganese. [19] [20]
In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribosomes, soluble enzymes, small organic molecules, nucleotide cofactors, and inorganic ions.[1] The enzymes in the matrix facilitate reactions responsible for the production of ATP, such as the citric acid cycle, oxidative phosphorylation, oxidation of pyruvate, and the beta oxidation of fatty acids.
Succinate dehydrogenase complex subunit C, also known as succinate dehydrogenase cytochrome b560 subunit, mitochondrial, is a protein that in humans is encoded by the SDHC gene. This gene encodes one of four nuclear-encoded subunits that comprise succinate dehydrogenase, also known as mitochondrial complex II, a key enzyme complex of the tricarboxylic acid cycle and aerobic respiratory chains of mitochondria. The encoded protein is one of two integral membrane proteins that anchor other subunits of the complex, which form the catalytic core, to the inner mitochondrial membrane. There are several related pseudogenes for this gene on different chromosomes. Mutations in this gene have been associated with pheochromocytomas and paragangliomas. Alternatively spliced transcript variants have been described.
Iron–sulfur proteins are proteins characterized by the presence of iron–sulfur clusters containing sulfide-linked di-, tri-, and tetrairon centers in variable oxidation states. Iron–sulfur clusters are found in a variety of metalloproteins, such as the ferredoxins, as well as NADH dehydrogenase, hydrogenases, coenzyme Q – cytochrome c reductase, succinate – coenzyme Q reductase and nitrogenase. Iron–sulfur clusters are best known for their role in the oxidation-reduction reactions of electron transport in mitochondria and chloroplasts. Both Complex I and Complex II of oxidative phosphorylation have multiple Fe–S clusters. They have many other functions including catalysis as illustrated by aconitase, generation of radicals as illustrated by SAM-dependent enzymes, and as sulfur donors in the biosynthesis of lipoic acid and biotin. Additionally, some Fe–S proteins regulate gene expression. Fe–S proteins are vulnerable to attack by biogenic nitric oxide, forming dinitrosyl iron complexes. In most Fe–S proteins, the terminal ligands on Fe are thiolate, but exceptions exist.
Aconitase is an enzyme that catalyses the stereo-specific isomerization of citrate to isocitrate via cis-aconitate in the tricarboxylic acid cycle, a non-redox-active process.
fChromosome 9 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome, as they normally do with all chromosomes. Chromosome 9 spans about 150 million base pairs of nucleic acids and represents between 4.0 and 4.5% of the total DNA in cells.
Fumarase is an enzyme that catalyzes the reversible hydration/dehydration of fumarate to malate. Fumarase comes in two forms: mitochondrial and cytosolic. The mitochondrial isoenzyme is involved in the Krebs cycle and the cytosolic isoenzyme is involved in the metabolism of amino acids and fumarate. Subcellular localization is established by the presence of a signal sequence on the amino terminus in the mitochondrial form, while subcellular localization in the cytosolic form is established by the absence of the signal sequence found in the mitochondrial variety.
Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial (SDHB) also known as iron-sulfur subunit of complex II (Ip) is a protein that in humans is encoded by the SDHB gene.
Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the SDHA gene. This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. SDHA contains the FAD binding site where succinate is deprotonated and converted to fumarate. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.
The iron-responsive element-binding proteins, also known as IRE-BP, IRBP, IRP and IFR , bind to iron-responsive elements (IREs) in the regulation of human iron metabolism.
NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial is an enzyme that in humans is encoded by the NDUFS3 gene on chromosome 11. This gene encodes one of the iron-sulfur protein (IP) components of mitochondrial NADH:ubiquinone oxidoreductase. Mutations in this gene are associated with Leigh syndrome resulting from mitochondrial complex I deficiency.
NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial also known as NADH-ubiquinone oxidoreductase 23 kDa subunit, Complex I-23kD (CI-23kD), or TYKY subunit is an enzyme that in humans is encoded by the NDUFS8 gene. The NDUFS8 protein is a subunit 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 Leigh syndrome.
Isocitrate dehydrogenase [NADP], mitochondrial is an enzyme that in humans is encoded by the IDH2 gene.
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.
NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial is an enzyme that in humans is encoded by the NDUFS6 gene.
Malate dehydrogenase, mitochondrial also known as malate dehydrogenase 2 is an enzyme that in humans is encoded by the MDH2 gene.
Iron-sulfur cluster assembly enzyme ISCU, mitochondrial is a protein that in humans is encoded by the ISCU gene. It encodes an iron-sulfur (Fe-S) cluster scaffold protein involved in [2Fe-2S] and [4Fe-4S] cluster synthesis and maturation. A deficiency of ISCU is associated with a mitochondrial myopathy with lifelong exercise intolerance where only minor exertion causes tachycardia, shortness of breath, muscle weakness and myalgia.
NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10 is an enzyme that in humans is encoded by the NDUFA10 gene. The NDUFA10 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in subunits of NADH dehydrogenase (ubiquinone), also known as Complex I, frequently lead to complex neurodegenerative diseases such as Leigh's syndrome. Furthermore, reduced NDUFA10 expression levels due to FOXM1-directed hypermethylation are associated with human squamous cell carcinoma and may be related to other forms of cancer.
Tricarboxylate transport protein, mitochondrial, also known as tricarboxylate carrier protein and citrate transport protein (CTP), is a protein that in humans is encoded by the SLC25A1 gene. SLC25A1 belongs to the mitochondrial carrier gene family SLC25. High levels of the tricarboxylate transport protein are found in the liver, pancreas and kidney. Lower or no levels are present in the brain, heart, skeletal muscle, placenta and lung.
Aconitase 1, soluble is a protein that in humans is encoded by the ACO1 gene.
Infantile cerebellar retinal degeneration is a rare hereditary neurological disorder which primarily affects the eyes and the brain.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
