Aconitase: Difference between revisions
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==Function== | ==Function== | ||
[[Aconitase]] (ACO, EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.3 4.2.1.3]) is an enzymatic domain that confers the ability to catalyse the equilibrium | [[Aconitase]] (ACO, EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.3 4.2.1.3]) is an enzymatic domain that confers the ability to catalyse the equilibrium | ||
:citrate = aconitate + H<sub>2</sub>O = L-isocitrate | :citrate = aconitate + H<sub>2</sub>O = L-isocitrate | ||
This reaction is part of the citrate (TCA-, Krebs-)cycle. | This reaction is part of the citrate (TCA-, Krebs-)cycle. | ||
In most organisms, there is a cytosolic enzyme with an ACO domain (cAc), and in eukaryotes, a second copy of it was introduced with mitochondria (mAc). Plants developed even more copies in mitochondria. | In most organisms, there is a cytosolic enzyme with an ACO domain (cAc), and in eukaryotes, a second copy of it was introduced with mitochondria (mAc). Plants developed even more copies in mitochondria. | ||
Aconitase contains a Fe4S4 cluster which converts to Fe3S4 when the enzyme is inactive. In humans, two types of ACO are expressed: the soluble '''ACO1''' and the mitochondrial '''ACO2'''. | Aconitase contains a Fe4S4 cluster which converts to Fe3S4 when the enzyme is inactive. In humans, two types of ACO are expressed: the soluble '''ACO1''' and the mitochondrial '''ACO2'''. Two types of '''ACO X''' were characterized as '''mevalonate 5-phosphate dehydratase''' and '''cis-3-hydroxy-L-proline dehydrates'''. | ||
Aconitase from pig (PDB [[7acn]]) is a single polypeptide (M<sub>r</sub> 83kD) that catalyzes the reversible isomerization of citrate and isocitrate.<ref name="Zheng">PMID 1313811</ref> It is the second enzyme in the Citric acid cycle, which is a series of enzyme-catalysed chemical reactions that is crucial to aerobic cellular respiration and the production of ATP. See also:<br /> | Aconitase from pig (PDB [[7acn]]) is a single polypeptide (M<sub>r</sub> 83kD) that catalyzes the reversible isomerization of citrate and isocitrate.<ref name="Zheng">PMID 1313811</ref> It is the second enzyme in the Citric acid cycle, which is a series of enzyme-catalysed chemical reactions that is crucial to aerobic cellular respiration and the production of ATP. See also:<br /> | ||
*[[Citric Acid Cycle]] | |||
*[[ | |||
*[[Krebs cycle step 2]] | *[[Krebs cycle step 2]] | ||
*[[Glyoxylate cycle]] | |||
==Structure== | ==Structure== | ||
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== Catalytic mechanism of mitochondrial ACO == | == Catalytic mechanism of mitochondrial ACO == | ||
Both mAc and cAc are quite similar in their ACO function. Studies, however, concentrated on <scene name='Aconitase/7acn-sf4/1'>the mitochondrial ACO</scene>. ACO is an excellent system for understanding the role of iron-sulfur-clusters in catalysis. The <scene name='Aconitase/7acn-sf4/2'>(4Fe-4S) cofactor is held in place</scene> by three sulfur atoms belonging to the cysteins-385, -448, and -451 <scene name=' | Both mAc and cAc are quite similar in their ACO function. Studies, however, concentrated on <scene name='Aconitase/7acn-sf4/1'>the mitochondrial ACO</scene>. ACO is an excellent system for understanding the role of iron-sulfur-clusters in catalysis. The <scene name='Aconitase/7acn-sf4/2'>(4Fe-4S) cofactor is held in place</scene> by three sulfur atoms belonging to the cysteins-385, -448, and -451 <scene name='33/338089/7acn-morph/5'>which are bound to three of the four</scene> cluster iron atoms. On activation of the enzyme, <scene name='33/338089/7acn-morph/8'>a fourth iron atom is included in the cluster</scene> together with a water molecule.This Fe4 is free to bind one, two, or three partners, in this reaction always oxygen atoms belonging to other molecules.<ref>PMID:8151704</ref> | ||
<!--It is clear that, in order to synthesize L-isocitrate, stereoselective catalysis must occur.--> | <!--It is clear that, in order to synthesize L-isocitrate, stereoselective catalysis must occur.--> | ||
Substrate-free aconitase contains a [4Fe-4S]<sup>2+</sup> cluster with hydroxyl bound to one of the Fe. Upon binding of substrate the bound hydroxyl is protonated. A hydrogen bond from <scene name='Anthony_Noles_Sandbox/His101/3'>His101</scene> to the isocitrate hydroxyl is donated to form water. Alternatively, the proton could be donated by <scene name='Anthony_Noles_Sandbox/His167/3'>His167</scene> as this histidine is hydrogen bonded to a H<sub>2</sub>O molecule. His167 is also hydrogen bonded to the bound H<sub>2</sub>O in the [4Fe-4S] cluster. Both <scene name='Anthony_Noles_Sandbox/His_101_and_167/4'>His101 and His167</scene> are paired with carboxylates (<scene name='Anthony_Noles_Sandbox/Asp100_and_glu262/3'>Asp100 and Glu262</scene>, respectively) and are likely to be protonated. The conformational change associated with substrate binding reorients the cluster. <ref name="Beinert" /> The residue which removes a proton from citrate or isocitrate is <scene name='Anthony_Noles_Sandbox/Ser642/4'>Ser642</scene>. <ref name="Beinert" /> This causes the cis-Aconitate intermediate (seen below), which consists of a double bond, which is a direct result of the deprotonation. Then, there is a rehydration of the double bond of cis-aconitate to form isocitrate (if the original substrate was citrate). To better understand this, consider this process as stages, seen below. | Substrate-free aconitase contains a [4Fe-4S]<sup>2+</sup> cluster with hydroxyl bound to one of the Fe. Upon binding of substrate the bound hydroxyl is protonated. A hydrogen bond from <scene name='Anthony_Noles_Sandbox/His101/3'>His101</scene> to the isocitrate hydroxyl is donated to form water. Alternatively, the proton could be donated by <scene name='Anthony_Noles_Sandbox/His167/3'>His167</scene> as this histidine is hydrogen bonded to a H<sub>2</sub>O molecule. His167 is also hydrogen bonded to the bound H<sub>2</sub>O in the [4Fe-4S] cluster. Both <scene name='Anthony_Noles_Sandbox/His_101_and_167/4'>His101 and His167</scene> are paired with carboxylates (<scene name='Anthony_Noles_Sandbox/Asp100_and_glu262/3'>Asp100 and Glu262</scene>, respectively) and are likely to be protonated. The conformational change associated with substrate binding reorients the cluster. <ref name="Beinert" /> The residue which removes a proton from citrate or isocitrate is <scene name='Anthony_Noles_Sandbox/Ser642/4'>Ser642</scene>. <ref name="Beinert" /> This causes the cis-Aconitate intermediate (seen below), which consists of a double bond, which is a direct result of the deprotonation. Then, there is a rehydration of the double bond of cis-aconitate to form isocitrate (if the original substrate was citrate). To better understand this, consider this process as stages, seen below. | ||
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{{Clear}} | {{Clear}} | ||
== Cytosolic aconitase and its other function == | == Cytosolic aconitase and its other function == | ||
A specialty of cAc is that in mammals it has developed a <scene name=' | A specialty of cAc is that in mammals it has developed a <scene name='33/338089/Cv/2'>second function</scene> as inhibitor of <scene name='33/338089/Cv/3'>those mRNA</scene> that carry an <scene name='33/338089/Cv/4'>iron-responsive element (IRE)</scene>. Therefore, the cytosolic cAc is named IREBP for IRE-binding protein when this function is talked about. Only one of the two functions is active, depending on whether <scene name='Aconitase/2b3x-cluster/1'>the (4Fe-4S) cofactor</scene> is present in the molecule: it's essential for <scene name='Aconitase/2b3x-total/1'>the ACO function</scene>. You can see, by <scene name='Aconitase/Morph/2'>looking at the morph</scene>, how much the enzyme structure differs between those two functions. | ||
Along with serving as a catalyst, aconitase is a member of the iron regulatory protien-1 (IRP-1) family. These enzymes have been found to play a role in regulatory RNA-binding proteins. This suggests a novel role for Fe-S clusters as post-translational regulatory switches.<ref name="Frishman" /> | Along with serving as a catalyst, aconitase is a member of the iron regulatory protien-1 (IRP-1) family. These enzymes have been found to play a role in regulatory RNA-binding proteins. This suggests a novel role for Fe-S clusters as post-translational regulatory switches.<ref name="Frishman" /> | ||
== 3D structures of Aconitase== | |||
[[Aconitase 3D structures]] | |||
</StructureSection> | </StructureSection> | ||
__NOTOC__ | __NOTOC__ | ||
== Literature == | == Literature == | ||
* M. Claire Kennedy and Helmut Beinert: ''IX.4. Aconitase.'' in Ivano Bertini, Harry B. Gray, Edward I. Stiefel, Joan Selverstone Valentine (eds.): ''Biological Inorganic Chemistry: Structure and Reactivity.'' University Science Books, Herndon 2006. ISBN 1891389432 pp.209-- | * M. Claire Kennedy and Helmut Beinert: ''IX.4. Aconitase.'' in Ivano Bertini, Harry B. Gray, Edward I. Stiefel, Joan Selverstone Valentine (eds.): ''Biological Inorganic Chemistry: Structure and Reactivity.'' University Science Books, Herndon 2006. ISBN 1891389432 pp.209-- | ||
