IDH3G explained

Isocitrate dehydrogenase [NAD] subunit gamma, mitochondrial is an enzyme that in humans is encoded by the IDH3G gene.^{[1] [2]}

Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation 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 regulated rate-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 periventricular heterotopia. 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]

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.^[3] 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.^{[4] [5] [6]} 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.^{[5] [6] [7] [8]} 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.^[7] 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.^{[5] [7]} Likewise, Asp181 in IDH3α is essential for catalysis, while the equivalent Asp192 in IDH3β and Asp190 in IDH3γ enhance NAD- and Mn²⁺-binding.^[5] Since the oxidative decarboxylation catalyzed by IDH3 requires binding of NAD, Mn²⁺, and the substrate isocitrate, all three subunits participate in the catalytic reaction.^{[6] [7]} 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.^{[5] [6]}

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.^{[4] [5] [6] [7] [9]} 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.^{[4] [5]} 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.^{[5] [6]} This allosteric regulation allows IDH3 to function as a rate-limiting step in the TCA cycle.^{[9] [10]} Within cells, IDH3 and its subunits have been observed to localize to the mitochondria.^{[5] [6] [9]}

Clinical Significance

The IDH3G gene may be involved in drug resistance in gastric cancer.^[11]

See also

• IDH1
• IDH2
• IDH3A
• IDH3B

Further reading

• Sandoval N, Bauer D, Brenner V, Coy JF, Drescher B, Kioschis P, Korn B, Nyakatura G, Poustka A, Reichwald K, Rosenthal A, Platzer M . The genomic organization of a human creatine transporter (CRTR) gene located in Xq28 . Genomics . 35 . 2 . 383–385 . July 1996 . 8661155 . 10.1006/geno.1996.0373 .
• Kim YO, Koh HJ, Kim SH, Jo SH, Huh JW, Jeong KS, Lee IJ, Song BJ, Huh TL . Identification and functional characterization of a novel, tissue-specific NAD(+)-dependent isocitrate dehydrogenase beta subunit isoform . The Journal of Biological Chemistry . 274 . 52 . 36866–36875 . December 1999 . 10601238 . 10.1074/jbc.274.52.36866 . free .
• Weiss C, Zeng Y, Huang J, Sobocka MB, Rushbrook JI . Bovine NAD+-dependent isocitrate dehydrogenase: alternative splicing and tissue-dependent expression of subunit 1 . Biochemistry . 39 . 7 . 1807–1816 . February 2000 . 10677231 . 10.1021/bi991691i .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–1795 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S . Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing . EMBO Reports . 1 . 3 . 287–292 . September 2000 . 11256614 . 1083732 . 10.1093/embo-reports/kvd058 .
• Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proceedings of the National Academy of Sciences of the United States of America . 99 . 26 . 16899–16903 . December 2002 . 12477932 . 139241 . 10.1073/pnas.242603899 . free . 2002PNAS...9916899M .
• Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC) . Genome Research . 14 . 10B . 2121–2127 . October 2004 . 15489334 . 528928 . 10.1101/gr.2596504 .
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A . From ORFeome to biology: a functional genomics pipeline . Genome Research . 14 . 10B . 2136–2144 . October 2004 . 15489336 . 528930 . 10.1101/gr.2576704 .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–1178 . October 2005 . 16189514 . 10.1038/nature04209 . 4427026 . 2005Natur.437.1173R .
• Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S . The LIFEdb database in 2006 . Nucleic Acids Research . 34 . Database issue . D415–D418 . January 2006 . 16381901 . 1347501 . 10.1093/nar/gkj139 .
• Soundar S, O'Hagan M, Fomulu KS, Colman RF . Identification of Mn2+-binding aspartates from alpha, beta, and gamma subunits of human NAD-dependent isocitrate dehydrogenase . The Journal of Biological Chemistry . 281 . 30 . 21073–21081 . July 2006 . 16737955 . 10.1074/jbc.M602956200 . free .
• Bzymek KP, Colman RF . Role of alpha-Asp181, beta-Asp192, and gamma-Asp190 in the distinctive subunits of human NAD-specific isocitrate dehydrogenase . Biochemistry . 46 . 18 . 5391–5397 . May 2007 . 17432878 . 10.1021/bi700061t .

Notes and References

1. Brenner V, Nyakatura G, Rosenthal A, Platzer M . 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 . August 1997 . 9286695 . 10.1006/geno.1997.4822 .
2. Web site: Entrez Gene: IDH3G isocitrate dehydrogenase 3 (NAD+) gamma.
3. Dimitrov L, Hong CS, Yang C, Zhuang Z, Heiss JD . New developments in the pathogenesis and therapeutic targeting of the IDH1 mutation in glioma . International Journal of Medical Sciences . 12 . 3 . 201–213 . 2015 . 25678837 . 4323358 . 10.7150/ijms.11047 .
4. Zeng L, Morinibu A, Kobayashi M, Zhu Y, Wang X, Goto Y, Yeom CJ, Zhao T, Hirota K, Shinomiya K, Itasaka S, Yoshimura M, Guo G, Hammond EM, Hiraoka M, Harada H . Aberrant IDH3α expression promotes malignant tumor growth by inducing HIF-1-mediated metabolic reprogramming and angiogenesis . Oncogene . 34 . 36 . 4758–4766 . September 2015 . 25531325 . 10.1038/onc.2014.411 . free .
5. Bzymek KP, Colman RF . Role of alpha-Asp181, beta-Asp192, and gamma-Asp190 in the distinctive subunits of human NAD-specific isocitrate dehydrogenase . Biochemistry . 46 . 18 . 5391–5397 . May 2007 . 17432878 . 10.1021/bi700061t .
6. Soundar S, O'Hagan M, Fomulu KS, Colman RF . Identification of Mn2+-binding aspartates from alpha, beta, and gamma subunits of human NAD-dependent isocitrate dehydrogenase . The Journal of Biological Chemistry . 281 . 30 . 21073–21081 . July 2006 . 16737955 . 10.1074/jbc.m602956200 . free .
7. Soundar S, Park JH, Huh TL, Colman RF . Evaluation by mutagenesis of the importance of 3 arginines in alpha, beta, and gamma subunits of human NAD-dependent isocitrate dehydrogenase . The Journal of Biological Chemistry . 278 . 52 . 52146–52153 . December 2003 . 14555658 . 10.1074/jbc.m306178200 . free .
8. Dange M, Colman RF . Each conserved active site tyr in the three subunits of human isocitrate dehydrogenase has a different function . The Journal of Biological Chemistry . 285 . 27 . 20520–20525 . July 2010 . 20435888 . 2898308 . 10.1074/jbc.m110.115386 . free .
9. Huh TL, Kim YO, Oh IU, Song BJ, Inazawa J . 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 . March 1996 . 8833160 . 10.1006/geno.1996.0120 .
10. Yoshimi N, Futamura T, Bergen SE, Iwayama Y, Ishima T, Sellgren C, Ekman CJ, Jakobsson J, Pålsson E, Kakumoto K, Ohgi Y, Yoshikawa T, Landén M, Hashimoto K . Cerebrospinal fluid metabolomics identifies a key role of isocitrate dehydrogenase in bipolar disorder: evidence in support of mitochondrial dysfunction hypothesis . Molecular Psychiatry . 21 . 11 . 1504–1510 . November 2016 . 26782057 . 5078854 . 10.1038/mp.2015.217 .
11. Zhou J, Yong WP, Yap CS, Vijayaraghavan A, Sinha RA, Singh BK, Xiu S, Manesh S, Ngo A, Lim A, Ang C, Xie C, Wong FY, Lin SJ, Wan WK, Tan IB, Flotow H, Tan P, Lim KH, Yen PM, Goh LK . An integrative approach identified genes associated with drug response in gastric cancer . Carcinogenesis . 36 . 4 . 441–451 . April 2015 . 25742747 . 10.1093/carcin/bgv014 . free .