Isocitrate dehydrogenase
Isocitrate dehydrogenase (IDH) is the name for enzymes and enzyme complexes that catalyze the oxidative cleavage of carbon dioxide from isocitrate , resulting in α-ketoglutarate . This reaction is part of the citric acid cycle and is therefore central to the metabolism of all living things. The reverse reaction, which occurs only in some bacteria , uses the enzyme isocitrate lyase .
The catalyzed reaction:
CO 2 is split off from isocitrate and ketoglutarate is formed.
Structurally, IDHs consist of alternating α-layers and β-sheets in a sandwich arrangement. There are two different enzyme groups, depending on whether NAD + ( EC 1.1.1.41 ) or NADP + ( EC 1.1.1.42 ) is a cofactor . Both have Mg 2+ or Mn 2+ as a metal ion. Homologues of the first group consist of three subunits (heterotetramer ααβγ) and are located in the mitochondrion , while the second group are homodimers, with one isoform each in the mitochondrion and in the cytosol . IDH occur in all living things. In humans, the three IDH isoforms are encoded in five genes , the defects of which can lead to hereditary metabolic disorders:
gene | protein | amino acids | UniProt | OMIM | comment |
---|---|---|---|---|---|
IDH1 | IDH (NADP), cytoplasmic | 414 | O75874 | 147700 | Gliomas |
IDH2 | IDH (NADP), mitochondrial | 413 | P48735 | 147650 | Gliomas , 2-hydroxyglutaric aciduria |
IDH3A | IDH (NAD), mitochondrial, subunit alpha | 339 | P50213 | 601149 | |
IDH3B | IDH (NAD), mitochondrial, subunit beta | 351 | O43837 | 604526 | Retinitis pigmentosa |
IDH3G | IDH (NAD), mitochondrial, subunit gamma | 354 | P51553 | 147700 |
Reaction mechanism
The performance in the first step oxidation of isocitrate 1 provides beside NADH the 2-oxocarboxylic acid oxalosuccinate 2 , which as a bidentate ligand on the keto group and its alpha- constant carboxy group , the metal ion (Mn 2+ or Mg 2+ complexed). As a result, the carbonyl function is polarized, which immensely increases the tendency of the beta carboxy group to decarboxylate, so that the enol form of 2-oxoglutarate 3 stabilized by complex formation is formed in the decarboxylation step that now follows . After protonation, 2-oxoglutarate (α-ketoglutarate) 4 is released. Mitochondrial NAD + -dependent isocitrate dehydrogenase, unlike the NADP + -dependent no oxalosuccinate as substrate binding, to form 2-oxoglutarate.
Like any dehydrogenase, isocitrate dehydrogenase can be regulated by ATP or ADP . The ATP causes an indirect inhibition, the ADP an indirect activation of the dehydrogenase, as they act on the kinase subunit. ATP stimulates the kinase subunit, which phosphorylates subunit I of isocitrate dehydrogenase, which inactivates it. Correspondingly, ADP acts as an antagonist and leads to an indirect activation of isocitrate dehydrogenase. This regulation process through phosphorylation and dephosphorylation is called interconversion.
literature
- PT Tan, AH Wei: The epigenomics revolution in myelodysplasia: a clinico-pathological perspective. In: Pathology . Volume 43, Number 6, October 2011, pp. 536-546, doi: 10.1097 / PAT.0b013e32834a4061 . PMID 21881538 . (Review).
- L. Dang, S. Jin, SM Su: IDH mutations in glioma and acute myeloid leukemia. In: Trends in Molecular Medicine . Volume 16, Number 9, September 2010, pp. 387-397, doi: 10.1016 / j.molmed.2010.07.002 . PMID 20692206 . (Review).
- M. Rossetto, P. Ciccarino, et al. a .: Metabolism of glioma and IDH1 / IDH2 mutations. In: Revue neurologique. Volume 167, number 10, October 2011, pp. 699-703, doi: 10.1016 / j.neurol.2011.08.002 . PMID 21885076 . (Review).
- A. Nekrutenko, DM Hillis, et al. a .: Cytosolic isocitrate dehydrogenase in humans, mice, and voles and phylogenetic analysis of the enzyme family. In: Molecular biology and evolution. Volume 15, Number 12, December 1998, pp. 1674-1684, PMID 9866202 .
Individual evidence
- ↑ InterPro : IPR004434 Isocitrate dehydrogenase NAD-dependent (English)
- ^ Orphanet: 2-Hydroxyglutaric aciduria
- ↑ DT Hartong, M. Dange et al. a .: Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle. In: Nature genetics. Volume 40, number 10, October 2008, pp. 1230-1234, doi: 10.1038 / ng.223 . PMID 18806796 . PMC 2596605 (free full text).