Summary: Monomeric isocitrate dehydrogenase
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Isocitrate dehydrogenase Edit Wikipedia article
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
|isocitrate dehydrogenase (NAD+)|
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
|Monomeric isocitrate dehydrogenase|
crystal structure of the monomeric isocitrate dehydrogenase in complex with isocitrate and mn
Isocitrate dehydrogenase (IDH) (EC 22.214.171.124) and (EC 126.96.36.199) is an enzyme that catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate) and CO2. This is a two-step process, which involves oxidation of isocitrate (a secondary alcohol) to oxalosuccinate (a ketone), followed by the decarboxylation of the carboxyl group beta to the ketone, forming alpha-ketoglutarate. In humans, IDH exists in three isoforms: IDH3 catalyzes the third step of the citric acid cycle while converting NAD+ to NADH in the mitochondria. The isoforms IDH1 and IDH2 catalyze the same reaction outside the context of the citric acid cycle and use NADP+ as a cofactor instead of NAD+. They localize to the cytosol as well as the mitochondrion and peroxisome.
The following is a list of human isocitrate dehydrogenase isozymes:
Each NADP+-dependent isozyme functions as a homodimer:
The isocitrate dehydrogenase 3 isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit:
The NAD-IDH is composed of 3 subunits, is allosterically regulated, and requires an integrated Mg2+ or Mn2+ ion. The closest homologue that has a known structure is the E. coli NADP-dependent IDH, which has only 2 subunits and a 13% identity and 29% similarity based on the amino acid sequences, making it dissimilar to human IDH and not suitable for close comparison. All the known NADP-IDHs are homodimers.
Most isocitrate dehydrogenases are dimers, to be specific, homodimers (two identical monomer subunits forming one dimeric unit). In comparing C. glutamicum and E. coli, monomer and dimer, respectively, both enzymes were found to "efficiently catalyze identical reactions." However, C. glutamicum was recorded as having ten times as much activity than E. coli and seven times more affinitive/specific for NADP. C. glutamicum favored NADP+ over NAD+. In terms of stability with response to temperature, both enzymes had a similar Tm or melting temperature at about 55 °C to 60 °C. However, the monomer C. glutamicum showed a more consistent stability at higher temperatures, which was expected. The dimer E. coli showed stability at a higher temperature than normal due to the interactions between the two monomeric subunits.
The structure of Mycobacterium tuberculosis (Mtb) ICDH-1 bound with NADPH and Mn(2+) bound has been solved by X-ray crystallography. It is a homodimer in which each subunit has a Rossmann fold, and a common top domain of interlocking β sheets. Mtb ICDH-1 is most structurally similar to the R132H mutant human ICDH found in glioblastomas. Similar to human R132H ICDH, Mtb ICDH-1 also catalyzes the formation of α-hydroxyglutarate.
The IDH step of the citric acid cycle, due to its large negative free energy change, is one of the irreversible reactions in the citric acid cycle, and, therefore, must be carefully regulated to avoid unnecessary depletion of isocitrate (and therefore an accumulation of alpha-ketoglutarate). The reaction is stimulated by the simple mechanisms of substrate availability (isocitrate, NAD+ or NADP+, Mg2+ / Mn2+ ), product inhibition (by NADH (or NADPH outside the citric acid cycle) and alpha-ketoglutarate), and competitive feedback inhibition (by ATP).
Isocitrate dehydrogenase catalysis|catalyze the chemical reactions
- Isocitrate + NAD+ 2-oxoglutarate + CO2 + NADH + H+
- Isocitrate + NADP+ 2-oxoglutarate + CO2 + NADPH + H+
- Isocitrate + NADP+ Mg2+(metal ion) alpha-ketoglutarate + NADPH + H+ + CO2
The overall free energy for this reaction is -8.4 kJ/mol.
Within the citric acid cycle, isocitrate, produced from the isomerization of citrate, undergoes both oxidation and decarboxylation. Using the enzyme Isocitrate Dehydrogenase (IDH), isocitrate is held within its active site by surrounding arginine, tyrosine, asparagine, serine, threonine, and aspartic acid amino acids. The first box shows the overall isocitrate dehydrogenase reaction. The reactants necessary for this enzyme mechanism to work are isocitrate, NAD+/NADP+, and Mn2+ or Mg2+. The products of the reaction are alpha-ketoglutarate, carbon dioxide, and NADH + H+/NADPH + H+. Water molecules are used to help deprotonate the oxygens (O3) of isocitrate.
The second box is Step 1, which is the oxidation of the alpha-C (C#2). Oxidation is the first step that isocitrate goes through. In this process, the alcohol group off the alpha-carbon (C#2) is deprotonated and the electrons flow to the alpha-C forming a ketone group and removing a hydride off C#2 using NAD+/NADP+ as an electron accepting cofactor. The oxidation of the alpha-C allows for a position where electrons (in the next step) will be coming down from the carboxyl group and pushing the electrons (making the double bonded oxygen) back up on the oxygen or grabbing a nearby proton off a nearby Lysine amino acid.
The third box is Step 2, which is the decarboxylation of oxalosuccinate. In this step, the carboxyl group oxygen is deprotonated by a nearby Tyrosine amino acid and those electrons flow down to carbon 2. Carbon dioxide leaves the beta carbon of isocitrate as a leaving group with the electrons flowing to the ketone oxygen off the alpha-C placing a negative charge on the oxygen of the alpha-C and forming an alpha-beta unsaturated double bond between carbons 2 and 3. The lone pair on the alpha-C oxygen picks up a proton from a nearby Lysine amino acid.
The fourth box is Step 3, which is the saturation of the alpha-beta unsaturated double bond between carbons 2 and 3. In this step of the reaction, Lysine deprotonates the oxygen off the alpha carbon and the lone pair of electrons on the oxygen of the alpha carbon comes down reforming the ketone double bond and pushing the lone pair (forming the double bond between the alpha and beta carbon) off, picking up a proton from the nearby Tyrosine amino acid. This reaction results in the formation of alpha-ketoglutarate, NADH + H+/NADPH + H+, and CO2.
Two aspartate amino acid residues (below left) are interacting with two adjacent water molecules (w6 and w8) in the Mn2+ isocitrate porcine IDH complex to deprotonate the alcohol off the alpha-carbon atom. The oxidation of the alpha-C also takes place in this picture where NAD+ accepts a hydride resulting in oxalosuccinate. Along with the sp3 to sp2 stereochemical change around the alpha-C, there is a ketone group that is formed form the alcohol group. The formation of this ketone double bond allows for resonance to take place as electrons coming down from the leaving carboxylate group move towards the ketone.
The decarboxylation of oxalosuccinate (below center) is a key step in the formation of alpha-ketoglutarate. In this reaction, the lone pair on the adjacent Tyrosine hydroxyl abstracts the proton off the carboxyl group. This carboxyl group is also referred to as the beta subunit in the isocitrate molecule. The deprotonation of the carboxyl group causes the lone pair of electrons to move down making carbon dioxide and separating from oxalosuccinate. The electrons continue to move towards the alpha carbon pushing the double bond electrons (making the ketone) up to abstract a proton off an adjacent Lysine residue. An alpha-beta unsaturated double bond results between carbon 2 and three. As you can see in the picture, the green ion represents either Mg2+ or Mn2+, which is a cofactor necessary for this reaction to occur. The metal-ion forms a little complex through ionic interactions with the oxygen atoms on the fourth and fifth carbons (also known as the gamma subunit of isocitrate).
After the carbon dioxide is split from the oxalosuccinate in the decarboxylation step (below right), the enol will tautomerize to the keto from. The formation of the ketone double bond is started by the deprotonation of that oxygen off the alpha carbon (C#2) by the same Lysine that protonated the oxygen in the first place. The lone pair of electrons moves down kicking off the lone pairs that were making the double bond. This lone pair of electrons abstracts a proton off the Tyrosine that deprotonated the carboxyl group in the decarboxylation step. The reason that we can say that the Lys and Tyr residues will be the same from the previous step is because they are helping in holding the isocitrate molecule in the active site of the enzyme. These two residues will be able to form hydrogen bonds back and forth as long as they are close enough to the substrate.
The isocitrate dehydrogenase enzyme as stated above produces alpha-ketoglutarate, carbon dioxide, and NADH + H+/NADPH + H+. There are three changes that occurred throughout the reaction. The oxidation of Carbon 2, the decarboxylation (loss of carbon dioxide) off Carbon 3, and the formation of a ketone group with a stereochemical change from sp3 to sp2.
The Isocitrate Dehydrogenase (IDH) enzyme structure in Escherichia coli was the first structure to be elucidated and understood. Since then, the Escherichia coli IDH structure has been used by most researchers to make comparisons to other isocitrate dehydrogenase enzymes. There is much detailed knowledge about this bacterial enzyme, and it has been found that most isocitrate dehydrogenases are similar in structure and therefore also in function. This similarity of structure and function gives a reason to believe that the structures are conserved as well as the amino acids. Therefore, the active sites amongst most prokaryotic isocitrate dehydrogenase enzymes should be conserved as well, which is observed throughout many studies done on prokaryotic enzymes. Eukaryotic isocitrate dehydrogenase enzymes on the other hand, have not been fully discovered yet. Each dimer of IDH has two active sites. Each active site binds a NAD+/NADP+ molecule and a divalent metal ion (Mg2+,Mn2+). In general, each active site has a conserved sequence of amino acids for each specific binding site. In Desulfotalea psychrophila (DpIDH) and porcine (PcIDH) there are three substrates bound to the active site.
- Isocitrate binds within the active site to a conserved sequence of about eight amino acids through hydrogen bonds. These acids include (may vary in residue but with similar properties) tyrosine, serine, asparagine, arginine, arginine, arginine, tyrosine, and lysine. Their positions on the backbone vary but they are all within a close range (i.e. Arg131 DpIDH and Arg133 PcIDH, Tyr138 DpIDH and Tyr140 PcIDH).
- The metal ion (Mg2+, Mn2+) binds to three conserved amino acids through hydrogen bonds. These amino acids include three Aspartate residues.
- NAD+ and NADP+ bind within the active site within four regions with similar properties amongst IDH enzymes. These regions vary but are around [250–260], [280–290], [300–330], and [365–380]. Again regions vary but the proximity of regions are conserved.
Specific mutations in the isocitrate dehydrogenase gene IDH1 have been found in several brain tumors including astrocytoma, oligodendroglioma and glioblastoma multiforme, with mutations found in nearly all cases of secondary glioblastomas, which develop from lower-grade gliomas, but rarely in primary high-grade glioblastoma multiforme. Patients whose tumor had an IDH1 mutation had longer survival. It is not known how the IDH1 mutation contributes to development of glioblastoma multiforme. Furthermore mutations of IDH2 and IDH1 were found in up to 20% of cytogenetically normal acute myeloid leukemia (AML). These mutations are known to produce (D)-2-hydroxyglutarate from alpha-ketoglutarate. Somatic mosaic mutations of this gene have also been found associated to Ollier disease and Maffucci syndrome.
- PDB 1CW7; Cherbavaz DB, Lee ME, Stroud RM, Koshland DE (January 2000). "Active site water molecules revealed in the 2.1 A resolution structure of a site-directed mutant of isocitrate dehydrogenase". J. Mol. Biol. 295 (3): 377–85. doi:10.1006/jmbi.1999.3195. PMID 10623532.
- Corpas FJ, Barroso JB, Sandalio LM, Palma JM, Lupiáñez JA, del Río LA (1999). "Peroxisomal NADP-Dependent Isocitrate Dehydrogenase. Characterization and Activity Regulation during Natural Senescence". Plant Physiol. 121 (3): 921–928. doi:10.1104/pp.121.3.921. PMC 59455. PMID 10557241.
- PDB 1LWD; Ceccarelli C, Neil B (2002). "The Crystal Structure of Porcine Mitochondrial NADP+-dependent Isocitrate Dehydrogenase Complexed with Mn2+ and Isocitrate". Journal of Biological Chemistry 277 (45): 43454–43462. doi:10.1074/jbc.M207306200. PMID 12207025.
- Chen R, Yang H (November 2000). "A highly specific monomeric isocitrate dehydrogenase from Corynebacterium glutamicum". Arch. Biochem. Biophys. 383 (2): 238–45. doi:10.1006/abbi.2000.2082. PMID 11185559.
- Quartararo CE, Hazra S, Hadi T, Blanchard JS (2013). "Structural, kinetic and chemical mechanism of isocitrate dehydrogenase-1 from Mycobacterium tuberculosis". Biochemistry 52 (10): 1765–75. doi:10.1021/bi400037w. PMID 23409873.
- Tadhg P. Begley; McMurry, John (2005). The Organic Chemistry of Biological Pathways. Roberts and Co. Publishers. pp. 189–190. ISBN 0-9747077-1-6.
- Cox, Michael; Nelson, David R.; Lehninger, Albert L (2005). Lehninger Principles of Biochemistry. San Francisco: W.H. Freeman. pp. 609–611. ISBN 0-7167-4339-6.
- Yasutake Y, Watanabe S, Yao M, Takada Y, Fukunaga N, Tanaka I (2003). "Crystal Structure of the Monomeric Isocitrate Dehydrogenase in the Presence of NADP+". Journal of Biological Chemistry 278 (38): 36897–36904. doi:10.1074/jbc.M304091200. PMID 12855708.
- Garrett, Reginald; Grisham, Charles M. (2012). Biochemistry. Cengage Learning. p. 621. ISBN 978-1133106296.
- Aoshima M, Igarashi Y (March 2008). "Nondecarboxylating and decarboxylating isocitrate dehydrogenases: oxalosuccinate reductase as an ancestral form of isocitrate dehydrogenase". Journal of bacteriology 190 (6): 2050–5. doi:10.1128/JB.01799-07. PMC 2258884. PMID 18203822.
- Fedøy AE, Yang N, Martinez A, Leiros HK, Steen IH (September 2007). "Structural and functional properties of isocitrate dehydrogenase from the psychrophilic bacterium Desulfotalea psychrophila reveal a cold-active enzyme with an unusual high thermal stability". J. Mol. Biol. 372 (1): 130–49. doi:10.1016/j.jmb.2007.06.040. PMID 17632124.
- Capper D, Zentgraf H, Balss J, Hartmann C, von Deimling A (November 2009). "Monoclonal antibody specific for IDH1 R132H mutation". Acta Neuropathol. 118 (5): 599–601. doi:10.1007/s00401-009-0595-z. PMID 19798509.
- Hartmann C, Hentschel B, Wick W, et al. (December 2010). "Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas". Acta Neuropathol. 120 (6): 707–18. doi:10.1007/s00401-010-0781-z. PMID 21088844.
- Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (September 2008). "An integrated genomic analysis of human glioblastoma multiforme". Science 321 (5897): 1807–12. doi:10.1126/science.1164382. PMC 2820389. PMID 18772396.
- Ward PS, Patel J, Wise DR, et al. (March 2010). "The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate". Cancer Cell 17 (3): 225–34. doi:10.1016/j.ccr.2010.01.020. PMC 2849316. PMID 20171147.
- Amary MF, Damato S, Halai D, Eskandarpour M, Berisha F, Bonar F, McCarthy S, Fantin VR, Straley KS, Lobo S, Aston W, Green CL, Gale RE, Tirabosco R, Futreal A, Campbell P, Presneau N, Flanagan AM (2011). "Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2". Nat. Genet. 43 (12): 1262–5. doi:10.1038/ng.994. PMID 22057236.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Monomeric isocitrate dehydrogenase Provide feedback
NADP(+)-dependent isocitrate dehydrogenase (ICD) is an important enzyme of the intermediary metabolism, as it controls the carbon flux within the citric acid cycle and supplies the cell with 2-oxoglutarate EC:188.8.131.52 and NADPH for biosynthetic purposes .
Ishii A, Suzuki M, Sahara T, Takada Y, Sasaki S, Fukunaga N; , J Bacteriol 1993;175:6873-6880.: Genes encoding two isocitrate dehydrogenase isozymes of a psychrophilic bacterium, Vibrio sp. strain ABE-1. PUBMED:8226630 EPMC:8226630
Eikmanns BJ, Rittmann D, Sahm H; , J Bacteriol 1995;177:774-782.: Cloning, sequence analysis, expression, and inactivation of the Corynebacterium glutamicum icd gene encoding isocitrate dehydrogenase and biochemical characterization of the enzyme. PUBMED:7836312 EPMC:7836312
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR004436
This family of enzymes catalyses the NADP(+)-dependent oxidative decarboxylation of isocitrate to form 2-oxoglutarate, CO2, and NADPH within the Krebs cycle (EC). Thus this enzyme supplies the cell with a key intermediate in energy metabolism, and precursors for biosynthetic pathways. The activity of this enzyme, which is controlled by phosphorylation, helps regulate carbon flux between the Krebs cycle and the glyoxylate bypass, which is an alternate route that accumulates carbon for biosynthesis when acetate is the sole carbon source for growth [PUBMED:7836312]. The phosphorylation state of this enzyme is controlled by isocitrate dehydrogenase kinase/phosphatase. This family has been found in a number of bacterial species including Azotobacter vinelandii, Corynebacterium glutamicum, Rhodomicrobium vannielii, and Neisseria meningitidis.
The structure of isocitrate dehydrogenase from Azotobacter vinelandii (SWISSPROT) has been determined [PUBMED:12467571]. This molecule consists of two distinct domains, a small domain and a large domain, with a folding topology similar to that of dimeric isocitrate dehydrogenase from Escherichia coli (SWISSPROT). The structure of the large domain repeats a motif observed in the dimeric enzyme. Such a fusional structure by domain duplication enables a single polypeptide chain to form a structure at the catalytic site that is homologous to the dimeric enzyme, the catalytic site of which is located at the interface of two identical subunits.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||isocitrate dehydrogenase (NADP+) activity (GO:0004450)|
|Biological process||tricarboxylic acid cycle (GO:0006099)|
|oxidation-reduction process (GO:0055114)|
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|Number in seed:||5|
|Number in full:||1265|
|Average length of the domain:||682.90 aa|
|Average identity of full alignment:||61 %|
|Average coverage of the sequence by the domain:||98.77 %|
|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:||9|
|Download:||download the raw HMM for this family|
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We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
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 is 1 interaction 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 IDH domain has been found. There are 11 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.
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