Isocitrate dehydrogenase

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Ribbon model of the IDH (NADP +) monomer from E. coli with isocitrate: magnesium and NADP as spherical caps , according to PDB  1AI3 .

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:

Isocitrate+ NAD (P) +
alpha-ketoglutarate+ CO 2 + NAD (P) H + H +

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

Section from subunit 1: catalytic center with Mg 2+ ion; the amino acid residue ASP-283 comes from subunit 2

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

Individual evidence

  1. ↑ InterPro : IPR004434 Isocitrate dehydrogenase NAD-dependent (English)
  2. ^ Orphanet: 2-Hydroxyglutaric aciduria
  3. ↑ 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).

Web links

Wikibooks: Biochemistry and Pathobiochemistry: Citric Acid Cycle  - Learning and Teaching Materials