Summary: Aconitase family (aconitate hydratase)
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Aconitase Edit Wikipedia article
Illustration of pig aconitase in complex with the [Fe4S4] cluster. The protein is colored by secondary structure, and iron atoms are blue and the sulfur red.
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
Structure of aconitase.
Aconitase (aconitate hydratase; EC 220.127.116.11) 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.
In contrast with the majority of iron-sulfur proteins that function as electron carriers, the iron-sulfur cluster of aconitase reacts directly with an enzyme substrate. Aconitase has an active [Fe4S4]2+ cluster, which may convert to an inactive [Fe3S4]+ form. Three cysteine (Cys) residues have been shown to be ligands of the [Fe4S4] centre. In the active state, the labile iron ion of the [Fe4S4] cluster is not coordinated by Cys but by water molecules.
The iron-responsive element-binding protein (IRE-BP) and 3-isopropylmalate dehydratase (α-isopropylmalate isomerase; EC 18.104.22.168), an enzyme catalysing the second step in the biosynthesis of leucine, are known aconitase homologues. Iron regulatory elements (IREs) constitute a family of 28-nucleotide, non-coding, stem-loop structures that regulate iron storage, heme synthesis and iron uptake. They also participate in ribosome binding and control the mRNA turnover (degradation). The specific regulator protein, the IRE-BP, binds to IREs in both 5' and 3' regions, but only to RNA in the apo form, without the Fe-S cluster. Expression of IRE-BP in cultured cells has revealed that the protein functions either as an active aconitase, when cells are iron-replete, or as an active RNA-binding protein, when cells are iron-depleted. Mutant IRE-BPs, in which any or all of the three Cys residues involved in Fe-S formation are replaced by serine, have no aconitase activity, but retain RNA-binding properties.
Aconitase, displayed in the structures in the right margin of this page, has two slightly different structures, depending on whether it is activated or inactivated. In the inactive form, its structure is divided into four domains. Counting from the N-terminus, only the first three of these domains are involved in close interactions with the [3Fe-4S] cluster, but the active site consists of residues from all four domains, including the larger C-terminal domain. The Fe-S cluster and a SO42- anion also reside in the active site. When the enzyme is activated, it gains an additional iron atom, creating a [4Fe-4S] cluster. However, the structure of the rest of the enzyme is nearly unchanged; the conserved atoms between the two forms are in essentially the same positions, up to a difference of 0.1 angstroms.
Aconitase employs a dehydration-hydration mechanism. The catalytic residues involved are His-101 and Ser-642. His-101 protonates the hydroxyl group on C3 of citrate, allowing it to leave as water, and Ser-642 concurrently abstracts the proton on C2, forming a double bond between C2 and C3, forming a cis-aconitate intermediate. At this point, the intermediate is rotated 180°. This rotation is referred to as a "flip." Because of this flip, the intermediate is said to move from a "citrate mode" to a "isocitrate mode."
How exactly this flip occurs is debatable. One theory is that, in the rate-limiting step of the mechanism, the cis-aconitate is released from the enzyme, then reattached in the isocitrate mode to complete the reaction. This rate-liming step ensures that the right stereochemistry, specifically (2R,3S), is formed in the final product. Another hypothesis is that cis-aconitate stays bound to the enzyme while it flips from the citrate to the isocitrate mode.
In either case, flipping cis-aconitate allows the dehydration and hydration steps to occur on opposite faces of the intermediate. Aconitase catalyzes trans elimination/addition of water, and the flip guarantees that the correct stereochemistry is formed in the product. To complete the reaction, the serine and histidine residues reverse their original catalytic actions: the histidine, now basic, abstracts a proton from water, priming it as a nucleophile to attack at C2, and the protonated serine is deprotonated by the cis-aconitate double bond to complete the hydration, producing isocitrate.
A serious ailment associated with aconitase is known as aconitase deficiency. 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. The main symptoms are myopathy and exercise intolerance; physical strain is lethal for some patients because it can lead to circulatory shock. There are no known treatments for aconitase deficiency.
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. 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. This deviance from homeostasis causes FRDA, a neurodegenerative disease for which no effective treatments have been found.
Finally, aconitase is thought to be associated with diabetes. Although the exact connection is still being determined, multiple theories exist. In a study of organs from mice with alloxan diabetes (experimentally induced diabetes) and genetic diabetes, lower aconitase activity was found to decrease the rates of metabolic reactions involving citrate, pyruvate, and malate. In addition, citrate concentration was observed to be unusually high. Since these abnormal data were found in diabetic mice, the study concluded that low aconitase activity is likely correlated with genetic and alloxan diabetes. 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. That is, it converts isocitrate back to cis-aconitate more rapidly than usual, but the forward reaction proceeds at the usual rate. This imbalance may contribute to disrupted metabolism in diabetics.
Aconitases are expressed in bacteria to humans. Humans express the following two aconitase isozymes:
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78".
- PDB 7ACN; Lauble, H.; Kennedy, M. C.; Beinert, H.; Stout, C. D. (1992). "Crystal structures of aconitase with isocitrate and nitroisocitrate bound". Biochemistry 31 (10): 2735–48. doi:10.1021/bi00125a014. PMID 1547214.
- PDB 1ACO; Lauble, H; Kennedy, MC; Beinert, H; Stout, CD (1994). "Crystal Structures of Aconitase with Trans-aconitate and Nitrocitrate Bound". Journal of Molecular Biology 237 (4): 437–51. doi:10.1006/jmbi.1994.1246. PMID 8151704.
- Beinert, H; Kennedy, MC (1993). "Aconitase, a two-faced protein: Enzyme and iron regulatory factor". The FASEB Journal 7 (15): 1442–9. PMID 8262329.
- Flint, Dennis H.; Allen, Ronda M. (1996). "Iron−Sulfur Proteins with Nonredox Functions". Chemical Reviews 96 (7): 2315–34. doi:10.1021/cr950041r.
- Beinert, Helmut; Kennedy, Mary Claire; Stout, C. David (1996). "Aconitase as Iron−Sulfur Protein, Enzyme, and Iron-Regulatory Protein". Chemical Reviews 96 (7): 2335–74. doi:10.1021/cr950040z. PMID 11848830.
- Gardner, Paul R. (2002). "Aconitase: Sensitive target and measure of superoxide". Superoxide Dismutase. Methods in Enzymology 349. pp. 9–23. doi:10.1016/S0076-6879(02)49317-2. ISBN 978-0-12-182252-1.
- Robbins AH, Stout CD (1989). "The structure of aconitase". Proteins 5 (4): 289–312. doi:10.1002/prot.340050406. PMID 2798408.
- Robbins AH, Stout CD (May 1989). "Structure of activated aconitase: formation of the [4Fe-4S] cluster in the crystal". Proc. Natl. Acad. Sci. U.S.A. 86 (10): 3639–43. doi:10.1073/pnas.86.10.3639. PMC 287193. PMID 2726740.
- Lauble H, Kennedy MC, Beinert H, Stout CD (March 1992). "Crystal structures of aconitase with isocitrate and nitroisocitrate bound". Biochemistry 31 (10): 2735–48. doi:10.1021/bi00125a014. PMID 1547214.
- Takusagawa F. "Chapter 16: Citric Acid Cycle". Takusagawa’s Note. The University of Kansas. Retrieved 2011-07-10.
- Beinert H, Kennedy MC, Stout CD (November 1996). "Aconitase as Ironminus signSulfur Protein, Enzyme, and Iron-Regulatory Protein". Chem. Rev. 96 (7): 2335–2374. doi:10.1021/cr950040z. PMID 11848830.
- PDB 1C96; Lloyd SJ, Lauble H, Prasad GS, Stout CD (December 1999). "The mechanism of aconitase: 1.8 A resolution crystal structure of the S642a:citrate complex". Protein Sci. 8 (12): 2655–62. doi:10.1110/ps.8.12.2655. PMC 2144235. PMID 10631981.
- Han D, Canali R, Garcia J, Aguilera R, Gallaher TK, Cadenas E (September 2005). "Sites and mechanisms of aconitase inactivation by peroxynitrite: modulation by citrate and glutathione". Biochemistry 44 (36): 11986–96. doi:10.1021/bi0509393. PMID 16142896.
- Lauble H, Stout CD (May 1995). "Steric and conformational features of the aconitase mechanism". Proteins 22 (1): 1–11. doi:10.1002/prot.340220102. PMID 7675781.
- "Aconitase family". The Prosthetic groups and Metal Ions in Protein Active Sites Database Version 2.0. The University of Leeds. 1999-02-02. Archived from the original on 8 June 2011. Retrieved 2011-07-10.
- Orphanet, "Aconitase deficiency," April 2008, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=43115
- Hall, R E; Henriksson, K G; Lewis, S F; Haller, R G; Kennaway, N G (1993). "Mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency. Abnormalities of several iron-sulfur proteins". Journal of Clinical Investigation 92 (6): 2660–6. doi:10.1172/JCI116882. PMC 288463. PMID 8254022.
- Ye, Hong; Rouault, Tracey A. (2010). "Human Iron−Sulfur Cluster Assembly, Cellular Iron Homeostasis, and Disease". Biochemistry 49 (24): 4945–56. doi:10.1021/bi1004798. PMC 2885827. PMID 20481466.
- Boquist, L.; Ericsson, I.; Lorentzon, R.; Nelson, L. (1985). "Alterations in mitochondrial aconitase activity and respiration, and in concentration of citrate in some organs of mice with experimental or genetic diabetes". FEBS Letters 183 (1): 173–6. doi:10.1016/0014-5793(85)80979-0. PMID 3884379.
- Lin, G.; Brownsey, R. W.; MacLeod, K. M. (2009). "Regulation of mitochondrial aconitase by phosphorylation in diabetic rat heart". Cellular and Molecular Life Sciences 66 (5): 919–32. doi:10.1007/s00018-009-8696-3. PMID 19153662.
- "Alloxan Diabetes - Medical Definition," Stedman's Medical Dictionary, 2006 Lippincott Williams & Wilkins, http://www.medilexicon.com/medicaldictionary.php?t=24313
- Aconitase at the US National Library of Medicine Medical Subject Headings (MeSH)
- Proteopedia Aconitase - the Aconitase structure in interactive 3D
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Aconitase family (aconitate hydratase) Provide feedback
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This tab holds annotation information from the InterPro database.
InterPro entry IPR001030
Aconitase (aconitate hydratase; EC) is an iron-sulphur protein that contains a [4Fe-4S]-cluster and catalyses the interconversion of isocitrate and citrate via a cis-aconitate intermediate. Aconitase functions in both the TCA and glyoxylate cycles, however unlike the majority of iron-sulphur proteins that function as electron carriers, the [4Fe-4S]-cluster of aconitase reacts directly with an enzyme substrate. In eukaryotes there is a cytosolic form (cAcn) and a mitochondrial form (mAcn) of the enzyme. In bacteria there are also 2 forms, aconitase A (AcnA) and B (AcnB). Several aconitases are known to be multi-functional enzymes with a second non-catalytic, but essential function that arises when the cellular environment changes, such as when iron levels drop [PUBMED:10087914, PUBMED:15877277]. Eukaryotic cAcn and mAcn, and bacterial AcnA have the same domain organisation, consisting of three N-terminal alpha/beta/alpha domains, a linker region, followed by a C-terminal 'swivel' domain with a beta/beta/alpha structure (1-2-3-linker-4), although mAcn is small than cAcn. However, bacterial AcnB has a different organisation: it contains an N-terminal HEAT-like domain, followed by the 'swivel' domain, then the three alpha/beta/alpha domains (HEAT-4-1-2-3) [PUBMED:9020582]. Below is a description of some of the multi-functional activities associated with different aconitases.
- Eukaryotic mAcn catalyses the second step of the mitochondrial TCA cycle, which is important for energy production, providing high energy electrons in the form of NADH and FADH2 to the mitochondrial oxidative phosphorylation pathway [PUBMED:15543948]. The TCA cycle also provides precursors for haem and amino acid production. This enzyme has a second, non-catalytic but essential role in mitochondrial DNA (mtDNA) maintenance: mAcn acts to stabilise mtDNA, forming part of mtDNA protein-DNA complexes known as nucleoids. mAcn is thought to reversibly model nucleoids to directly influence mitochondrial gene expression in response to changes in the cellular environment. Therefore, mAcn can influence the expression of components of the oxidative phosphorylation pathway encoded in mtDNA.
- Eukaryotic cAcn enzyme balances the amount of citrate and isocitrate in the cytoplasm, which in turn creates a balance between the amount of NADPH generated from isocitrate by isocitrate dehydrogenase with the amount of acetyl-CoA generated from citrate by citrate lyase. Fatty acid synthesis requires both NADPH and acetyl-CoA, as do other metabolic processes, including the need for NADPH to combat oxidative stress. The enzymatic form of cAcn predominates when iron levels are normal, but if they drop sufficiently to cause the disassembly of the [4Fe-4S]-cluster, then cAcn undergoes a conformational change from a compact enzyme to a more open L-shaped protein known as iron regulatory protein 1 (IRP1; or IRE-binding protein 1, IREBP1) [PUBMED:17185597, PUBMED:16407072]. As IRP1, the catalytic site and the [4Fe-4S]-cluster are lost, and two new RNA-binding sites appear. IRP1 functions in the post-transcriptional regulation of genes involved in iron metabolism - it binds to mRNA iron-responsive elements (IRE), 30-nucleotide stem-loop structures at the 3' or 5' end of specific transcripts. Transcripts containing an IRE include ferritin L and H subunits (iron storage), transferrin (iron plasma chaperone), transferrin receptor (iron uptake into cells), ferroportin (iron exporter), mAcn, succinate dehydrogenase, erythroid aminolevulinic acid synthetase (tetrapyrrole biosynthesis), among others. If the IRE is in the 5'-UTR of the transcript (e.g. in ferritin mRNA), then IRP1-binding prevents its translation by blocking the transcript from binding to the ribosome. If the IRE is in the 3'-UTR of the transcript (e.g. transferrin receptor), then IRP1-binding protects it from endonuclease degradation, thereby prolonging the half-life of the transcript and enabling it to be translated [PUBMED:15604397].
- IRP2 is another IRE-binding protein that binds to the same transcripts as IRP1. However, since IRP1 is predominantly in the enzymatic cAcn form, it is IRP2 that acts as the major metabolic regulator that maintains iron homeostasis [PUBMED:16850017]. Although IRP2 is homologous to IRP1, IRP2 lacks aconitase activity, and is known only to have a single function in the post-transcriptional regulation of iron metabolism genes [PUBMED:17513696]. In iron-replete cells, IRP2 activity is regulated primarily by iron-dependent degradation through the ubiquitin-proteasomal system.
- Bacterial AcnB is also known to be multi-functional. In addition to its role in the TCA cycle, AcnB was shown to be a post-transcriptional regulator of gene expression in Escherichia coli and Salmonella enterica [PUBMED:15882410, PUBMED:15009904]. In S. enterica, AcnB initiates a regulatory cascade controlling flagella biosynthesis through an interaction with the ftsH transcript, an alternative RNA polymerase sigma factor. This binding lowers the intracellular concentration of FtsH protease, which in turn enhances the amount of RNA polymerase sigma32 factor (normally degraded by FtsH protease), and sigma32 then increases the synthesis of chaperone DnaK, which in turn promotes the synthesis of the flagellar protein FliC. AcnB regulates the synthesis of other proteins as well, such as superoxide dismutase (SodA) and other enzymes involved in oxidative stress.
3-isopropylmalate dehydratase (or isopropylmalate isomerase; EC) catalyses the stereo-specific isomerisation of 2-isopropylmalate and 3-isopropylmalate, via the formation of 2-isopropylmaleate. This enzyme performs the second step in the biosynthesis of leucine, and is present in most prokaryotes and many fungal species. The prokaryotic enzyme is a heterodimer composed of a large (LeuC) and small (LeuD) subunit, while the fungal form is a monomeric enzyme. Both forms of isopropylmalate are related and are part of the larger aconitase family [PUBMED:9020582]. Aconitases are mostly monomeric proteins which share four domains in common and contain a single, labile [4Fe-4S] cluster. Three structural domains (1, 2 and 3) are tightly packed around the iron-sulphur cluster, while a fourth domain (4) forms a deep active-site cleft. The prokaryotic enzyme is encoded by two adjacent genes, leuC and leuD, corresponding to aconitase domains 1-3 and 4 respectively [PUBMED:1400210, PUBMED:9813279]. LeuC does not bind an iron-sulphur cluster. It is thought that some prokaryotic isopropylamalate dehydrogenases can also function as homoaconitase EC, converting cis-homoaconitate to homoisocitric acid in lysine biosynthesis [PUBMED:15522288]. Homoaconitase has been identified in higher fungi (mitochondria) and several archaea and one thermophilic species of bacteria, Thermus thermophilus [PUBMED:16524361].
This entry represents a region containing 3 domains, each with a 3-layer alpha/beta/alpha topology. This regions represents the [4Fe-4S] cluster-binding region found at the N-terminal of eukaryotic mAcn, cAcn/IPR1 and IRP2, and bacterial AcnA, but in the C-terminal of bacterial AcnB. This domain is also found in the large subunit of isopropylmalate dehydratase (LeuC).
More information about these proteins can be found at Protein of the Month: Aconitase [PUBMED:].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Biological process||metabolic process (GO:0008152)|
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|Number in seed:||11|
|Number in full:||14106|
|Average length of the domain:||338.30 aa|
|Average identity of full alignment:||28 %|
|Average coverage of the sequence by the domain:||64.53 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||15|
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Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 3 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Aconitase domain has been found. There are 25 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
Loading structure mapping...