o
Isocitrate dehydrogenases (IDHs), comprise a family of enzymes that catalyze oxidative decarboxylation
of isocitrate to alpha-ketoglutarate (2-oxoglutarate).
o Eukaryotic cells express two distinct classes of IDHs that utilize either NAD or NADP as the
electron acceptor and serve diverse biological functions:
o NAD- dependent IDH, IDH3, is located at the mitochondrial matrix and is well known for its
central role for energy production in the Krebs cycle.
o The two NADP- dependent forms, are primarily located either in mitochondria (IDH2) or
cytoplasm (IDH1). In addition to their potential catabolic role in the Krebs cycle, both
mitochondrial and cytosolic IDHs are shown to play an important role in cellular defense against
oxidative damage as a source of NADPH.
o The three IDH isoenzymes are important players in the exchange of metabolites between the
mitochondria and the cytosol.
o IDH3 is part of the TCA cycle were it generates NADH as a fuel for energy production
o IDH1 and 2 are important for shuttling electrons between the mitochondria and the cytosol.
o Moreover, all eukaryotic cytosolic IDHs contain a type 1 peroxisomal targeting sequence at their
C terminus that is sufficient to direct proteins into peroxisomes. Indeed cytosolic IDHs have
been found in peroxisomes of yeast, human and rat liver cells and are shown to be required for
the beta-oxidation of unsaturated fatty acids as a provider of NADPH inside peroxisomes.
Metabolites entering the mitochondria can be processed for energy generation usually through
the production of NADH in the TCA cycle whereas metabolites exported back to the cytosol
take part in anabolic processes. The transport of metabolites is also coupled to electron
exchange between mitochondrial and cytosolic NADH and NADPH both of which cannot move
across the mitochondrial inner membrane.
o
IDH1 gene is located in cr. 2q33.3 and consists of eight exons .
IDH2 gene is located in cr. 15q26.1 and consists of eleven exons.
IDH3A gene encodes the alpha subunit of IDH3. It is located in cr. 15q25.1-q25.2 and consists of eleven
exons .
IDH3B gene, located in cr.20p13, encodes the beta subunit of IDH3. Three alternatively spliced
transcript variants encoding different isoforms have been described for this gene.
IDH3G gene, located in cr.Xq28, encodes the gamma subunit of IDH3. This gene is a candidate gene
for periventricular heterotopia. Several alternatively spliced transcript variants of this gene have been
described, but only some of their full length natures have been determined.
o
Each NADP (+)-dependent isozyme forms an asymemetric homodimer. Structural studies of human
IDH1 in complex with NADP, isocitrate and Ca2+ reveal three biologically relevant conformational states
of the enzyme that differ substantially in the structure of the active site and in the overall structure . A
structural segment at the active site that forms a conserved alpha-helix in all known NADP-IDH
structures assumes a loop conformation in the open, inactive form of human IDH1; a partially unraveled
alpha-helix in the semi-open, intermediate form; and an alpha-helix in the closed, active form. The side
chain of Asp279 of this segment occupies the isocitrate-binding site and forms hydrogen bonds with
Ser94 (the equivalent of the phosphorylation site in bacterial IDHs) in the inactive form and chelates the
metal ion in the active form. The structural data suggest a novel self-regulatory mechanism for IDH1 that
mimics the phosphorylation mechanism used by the bacterial homologs, consistent with biochemical
and biological data. This mechanism might be applicable to other eukaryotic NADP-IDHs .