Isocitrate dehydrogenase [NAD] subunit gamma, mitochondrial is an
enzyme that in humans is encoded by the IDH3Ggene.[5][6]
Isocitrate dehydrogenases (IDHs)
catalyze the oxidative de
carboxylation of
isocitrate to
2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes
NAD(+) as the
electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two
NADP(+)-dependent isocitrate dehydrogenases, one of which is
mitochondrial and the other predominantly
cytosolic. NAD(+)-dependent isocitrate dehydrogenases catalyze the
allosterically regulatedrate-limiting step of the
tricarboxylic acid cycle. Each isozyme is a
heterotetramer that is composed of two alpha
subunits, one beta subunit, and one gamma subunit. The protein encoded by this gene is the gamma subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. This gene is a candidate gene for
periventricularheterotopia. Several alternatively spliced transcript variants of this gene have been described, but only some of their full length natures have been determined. [provided by RefSeq, Jul 2008][6]
Structure
IDH3 is one of three isocitrate dehydrogenase isozymes, the other two being
IDH1 and
IDH2, and encoded by one of five isocitrate dehydrogenase genes, which are IDH1, IDH2, IDH3A, IDH3B, and IDH3G.[7] The genes IDH3A, IDH3B, and IDH3G encode subunits of IDH3, which is a
heterotetramer composed of two 37-kDa α subunits (IDH3α), one 39-kDa β subunit (IDH3β), and one 39-kDa γ subunit (IDH3γ), each with distinct
isoelectric points.[8][9][10] Alignment of their
amino acid sequences reveals ~40% identity between IDH3α and IDH3β, ~42% identity between IDH3α and IDH3γ, and an even closer identity of 53% between IDH3β and IDH3γ, for an overall 34% identity and 23% similarity across all three subunit types.[9][10][11][12] Notably,
Arg88 in IDH3α is essential for IDH3 catalytic activity, whereas the equivalent Arg99 in IDH3β and Arg97 in IDH3γ are largely involved in the enzyme's allosteric regulation by ADP and NAD.[11] Thus, it is possible that these subunits arose from
gene duplication of a common ancestral gene, and the original catalytic Arg
residue were adapted to allosteric functions in the β- and γ-subunits.[9][11] Likewise,
Asp181 in IDH3α is essential for catalysis, while the equivalent Asp192 in IDH3β and Asp190 in IDH3γ enhance NAD- and Mn2+-binding.[9] Since the oxidative decarboxylation catalyzed by IDH3 requires binding of NAD, Mn2+, and the
substrate isocitrate, all three subunits participate in the catalytic reaction.[10][11] Moreover, studies of the enzyme in pig heart reveal that the αβ and αγ dimers constitute two binding sites for each of its
ligands, including isocitrate, Mn2+, and NAD, in one IDH3 tetramer.[9][10]
Function
As an isocitrate dehydrogenase, IDH3 catalyzes the irreversible oxidative decarboxylation of isocitrate to yield
α-ketoglutarate (α-KG) and CO2 as part of the
TCA cycle in glucose metabolism.[8][9][10][11][13] This step also allows for the concomitant
reduction of NAD+ to NADH, which is then used to generate
ATP through the
electron transport chain. Notably, IDH3 relies on NAD+ as its
electron acceptor, as opposed to NADP+ like IDH1 and IDH2.[8][9] IDH3 activity is regulated by the energy needs of the cell: when the cell requires energy, IDH3 is activated by ADP; and when energy is no longer required, IDH3 is inhibited by ATP and NADH.[9][10] This allosteric regulation allows IDH3 to function as a rate-limiting step in the TCA cycle.[13][14] Within cells, IDH3 and its subunits have been observed to
localize to the
mitochondria.[9][10][13]
Clinical Significance
The IDH3G gene may be involved in drug resistance in
gastric cancer.[15]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
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|alt=TCACycle_WP78
]]
TCACycle_WP78
^The interactive pathway map can be edited at WikiPathways:
"TCACycle_WP78".
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Brenner V, Nyakatura G, Rosenthal A, Platzer M (November 1997). "Genomic organization of two novel genes on human Xq28: compact head to head arrangement of IDH gamma and TRAP delta is conserved in rat and mouse". Genomics. 44 (1): 8–14.
doi:
10.1006/geno.1997.4822.
PMID9286695.
^
abcdefghiBzymek, KP; Colman, RF (8 May 2007). "Role of alpha-Asp181, beta-Asp192, and gamma-Asp190 in the distinctive subunits of human NAD-specific isocitrate dehydrogenase". Biochemistry. 46 (18): 5391–7.
doi:
10.1021/bi700061t.
PMID17432878.
Sandoval N, Bauer D, Brenner V, et al. (1996). "The genomic organization of a human creatine transporter (CRTR) gene located in Xq28". Genomics. 35 (2): 383–5.
doi:
10.1006/geno.1996.0373.
PMID8661155.
Bzymek KP, Colman RF (2007). "Role of alpha-Asp181, beta-Asp192, and gamma-Asp190 in the distinctive subunits of human NAD-specific isocitrate dehydrogenase". Biochemistry. 46 (18): 5391–7.
doi:
10.1021/bi700061t.
PMID17432878.