IDH

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Isocitrate dehydrogenase (IDH) is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to produce α-ketoglutarate (α-ketoglutarate) and CO₂. This is a two-step process, which involves the oxidation of isocitrate (secondary alcohol) to oxalosuccinate (ketone), and then decarboxylation of the carboxyl group into a ketone to form α-ketoglutarate. In humans, IDH exists in three isoforms: IDH3 catalyzes the third step of the citric acid cycle and at the same time converts NAD⁺ into NADH in the mitochondria. The isomers IDH1 and IDH2 catalyze the same reaction outside the range of the citric acid cycle and use NADP⁺ as a cofactor instead of NAD⁺. They are localized in the cytoplasm as well as mitochondria and peroxisomes.

Figure 1. Protein structure of isocitrate dehydrogenase dimer.

Clinical significance

Elevated: Acute hepatitis, chronic hepatitis, liver cirrhosis, liver cancer, liver metastatic cancer, cholelithiasis, cholecystitis, bile duct obstruction, pancreatitis, right heart insufficiency, pulmonary infarction, neonatal jaundice, hemolytic disease, etc.

Decrease: Large area of liver cell necrosis.

Factors leading to increased ICD activity: hemolysis, Mn²⁺, Co²⁺, Mg²⁺, aminosalicylic acid, amphotericin B, androgens, anesthetics, carbon tetrachloride, chenodeoxycholic acid, chlorpromazine (chloropromazine) Oxazine), ethanol, isoniazid, methotrexate, butazone.

Factors that cause the decrease of ICD activity: ethylenediaminetetraacetic acid (EDTA), oxalate, sodium chloride, heavy metal ions, fluoride, β-chloromercury benzoic acid, iodoacetate, Ba²⁺, Zn²⁺, CN -Wait.

Structure

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 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⁺.

Active 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.

Regulation

The IDH step of the citric acid cycle is usually (but not always) an irreversible reaction in the citric acid cycle because it has a large negative free energy change. Therefore, careful adjustments must be made to avoid depletion of isocitrate (and thus avoid the accumulation of α-ketoglutarate). Substrate availability (isocitrate, NAD + or NADP⁺, Mg²⁺ / Mn²⁺), product inhibition (by NADH or NADPH outside the citric acid cycle) and α-ketoglutarate) and competitive feedback inhibition (by the simple mechanism of ATP inhibition stimulates the response).