Protein Domain : IPR015937

Type:  Family Name:  Aconitase/isopropylmalate dehydratase
Description:  Aconitase (aconitate hydratase; ) 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 [, ]. 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) []. 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 []. 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) [, ]. 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 [].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 []. 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 []. 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 coliand Salmonella enterica[, ]. 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.This entry represents the core four domains that make up aconitase, as well as the structurally similar core domains of homoaconitase, 3-isopropylmalate dehydratase small and large subunits, 2-methylisocitrate dehydratase (AcnD), and iron regulatory protein 2 (IRP2). Short Name:  Acoase/IPM_deHydtase
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7 Child Features

DB identifier Type Name
IPR006249 Family Aconitate/Iron-responsive element-binding protein 2
IPR006248 Family Aconitase, mitochondrial-like
IPR004430 Family 3-isopropylmalate dehydratase, large subunit
IPR004431 Family 3-isopropylmalate dehydratase, small subunit
IPR004406 Family Aconitase B
IPR015934 Family Aconitase/2-methylisocitrate dehydratase
IPR004418 Family Homoaconitase, mitochondrial

6 Contains

DB identifier Type Name
IPR015931 Domain Aconitase/3-isopropylmalate dehydratase large subunit, alpha/beta/alpha, subdomain 1/3
IPR000573 Domain Aconitase A/isopropylmalate dehydratase small subunit, swivel domain
IPR001030 Domain Aconitase/3-isopropylmalate dehydratase large subunit, alpha/beta/alpha domain
IPR015928 Domain Aconitase/3-isopropylmalate dehydratase, swivel
IPR015932 Domain Aconitase/3-isopropylmalate dehydratase large subunit, alpha/beta/alpha, subdomain 2
IPR018136 Binding_site Aconitase family, 4Fe-4S cluster binding site

1 Cross References

Identifier
PTHR11670

0 Found In

1 GO Annotation

GO Term Gene Name
GO:0008152 IPR015937

1 Ontology Annotations

GO Term Gene Name
GO:0008152 IPR015937

0 Parent Features

3256 Proteins

DB identifier UniProt Accession Secondary Identifier Organism Name Length
443331 D8S0I5 PAC:15412963 Selaginella moellendorffii 949  
421784 D8SGC5 PAC:15418200 Selaginella moellendorffii 336  
119930 D8SLS4 PAC:15415349 Selaginella moellendorffii 187  
439578 D8R661 PAC:15402528 Selaginella moellendorffii 507  
132907 D8T624 PAC:15409123 Selaginella moellendorffii 907  
evm.model.supercontig_12.301 PAC:16406861 Carica papaya 806  
evm.model.supercontig_29.188 PAC:16416219 Carica papaya 256  
evm.model.supercontig_59.7 PAC:16423210 Carica papaya 462  
evm.model.supercontig_6.311 PAC:16423500 Carica papaya 891  
evm.model.supercontig_87.76 PAC:16427747 Carica papaya 996  
29784.m000362 B9SXB6 PAC:16808465 Ricinus communis 900  
30008.m000797 B9SQS5 PAC:16815567 Ricinus communis 510  
30008.m000798 B9SQS6 PAC:16815568 Ricinus communis 621  
27777.m000279 PAC:16799168 Ricinus communis 997  
27625.m000051 B9TA26 PAC:16798841 Ricinus communis 757  
29600.m000550 B9SDW5 PAC:16803491 Ricinus communis 997  
Cucsa.313660.2 PAC:16977033 Cucumis sativus 392  
Cucsa.313660.1 A0A0A0LEJ4 PAC:16977032 Cucumis sativus 510  
Cucsa.043950.2 PAC:16953124 Cucumis sativus 811  
Cucsa.043950.4 PAC:16953126 Cucumis sativus 797  
Cucsa.043950.3 PAC:16953125 Cucumis sativus 797  
Cucsa.043950.1 PAC:16953123 Cucumis sativus 900  
Cucsa.129780.1 PAC:16962336 Cucumis sativus 253  
Cucsa.148530.1 PAC:16964165 Cucumis sativus 989  
orange1.1g013574m A0A067DPR9 PAC:18110775 Citrus sinensis 440  
orange1.1g019862m A0A067DNL3 PAC:18110776 Citrus sinensis 334  
orange1.1g012009m A0A067DGC2 PAC:18110773 Citrus sinensis 473  
orange1.1g013449m A0A067DC59 PAC:18110774 Citrus sinensis 443  
orange1.1g010403m A0A067DCL7 PAC:18110772 Citrus sinensis 511  
orange1.1g002785m A0A067FVC5 PAC:18098894 Citrus sinensis 881  

11 Publications

First Author Title Year Journal Volume Pages PubMed ID
            9020582
            10087914
            15877277
            16850017
            17513696
            15882410
            15009904
            15543948
            15604397
            16407072
            17185597