Isocitrate dehydrogenase [NAD] subunit gamma, mitochondrial is anenzyme that in humans is encoded by theIDH3Ggene.[5][6]
Isocitrate dehydrogenases (IDHs)catalyze the oxidative decarboxylation ofisocitrate to2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizesNAD(+) as theelectron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and twoNADP(+)-dependent isocitrate dehydrogenases, one of which ismitochondrial and the other predominantlycytosolic. NAD(+)-dependent isocitrate dehydrogenases catalyze theallosterically regulatedrate-limiting step of thetricarboxylic acid cycle. Each isozyme is aheterotetramer that is composed of two alphasubunits, 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 forperiventricularheterotopia. 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]
IDH3 is one of three isocitrate dehydrogenase isozymes, the other two beingIDH1 andIDH2, and encoded by one of five isocitrate dehydrogenase genes, which areIDH1,IDH2,IDH3A,IDH3B, andIDH3G.[7] The genesIDH3A,IDH3B, andIDH3G encode subunits of IDH3, which is aheterotetramer composed of two 37-kDa α subunits (IDH3α), one 39-kDa β subunit (IDH3β), and one 39-kDa γ subunit (IDH3γ), each with distinctisoelectric points.[8][9][10] Alignment of theiramino 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 fromgene duplication of a common ancestral gene, and the original catalytic Argresidue 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 thesubstrate 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 itsligands, including isocitrate, Mn2+, and NAD, in one IDH3 tetramer.[9][10]
As an isocitrate dehydrogenase, IDH3 catalyzes the irreversible oxidative decarboxylation of isocitrate to yieldα-ketoglutarate (α-KG) and CO2 as part of theTCA cycle in glucose metabolism.[8][9][10][11][13] This step also allows for the concomitantreduction of NAD+ to NADH, which is then used to generateATP through theelectron transport chain. Notably, IDH3 relies on NAD+ as itselectron 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 tolocalize to themitochondria.[9][10][13]
^"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 (August 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 (May 2007). "Role of alpha-Asp181, beta-Asp192, and gamma-Asp190 in the distinctive subunits of human NAD-specific isocitrate dehydrogenase".Biochemistry.46 (18):5391–5397.doi:10.1021/bi700061t.PMID17432878.
^abcHuh TL, Kim YO, Oh IU, Song BJ, Inazawa J (March 1996). "Assignment of the human mitochondrial NAD+ -specific isocitrate dehydrogenase alpha subunit (IDH3A) gene to 15q25.1-->q25.2by in situ hybridization".Genomics.32 (2):295–296.doi:10.1006/geno.1996.0120.PMID8833160.
Sandoval N, Bauer D, Brenner V, Coy JF, Drescher B, Kioschis P, et al. (July 1996). "The genomic organization of a human creatine transporter (CRTR) gene located in Xq28".Genomics.35 (2):383–385.doi:10.1006/geno.1996.0373.PMID8661155.
Weiss C, Zeng Y, Huang J, Sobocka MB, Rushbrook JI (February 2000). "Bovine NAD+-dependent isocitrate dehydrogenase: alternative splicing and tissue-dependent expression of subunit 1".Biochemistry.39 (7):1807–1816.doi:10.1021/bi991691i.PMID10677231.
Bzymek KP, Colman RF (May 2007). "Role of alpha-Asp181, beta-Asp192, and gamma-Asp190 in the distinctive subunits of human NAD-specific isocitrate dehydrogenase".Biochemistry.46 (18):5391–5397.doi:10.1021/bi700061t.PMID17432878.
