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. 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. 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. 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. 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. Likewise, Asp181 in IDH3α is essential for catalysis, while the equivalent Asp192 in IDH3β and Asp190 in IDH3γ enhance NAD- and Mn2+-binding. Since the oxidative decarboxylation catalyzed by IDH3 requires binding of NAD, Mn2+, and the substrate isocitrate, all three subunits participate in the catalytic reaction. 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.
As an isocitrate dehydrogenase, IDH3 catalyzes the reversible oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG) and CO2 as part of the TCA cycle in glucose metabolism. 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. 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. This allosteric regulation allows IDH3 to function as a rate-limiting step in the TCA cycle. Within cells, IDH3 and its subunits have been observed to localize to the mitochondria.
IDH3α expression has been linked to cancer, with high basal expression in multiple cancer cell lines and increased expression indicative of poorer prognosis in cancer patients. IDH3α is proposed to promote tumor growth as a regulator of α-KG, which subsequently regulates HIF-1. HIF-1 is largely known for shifting glucose metabolism from oxidative phosphorylation to aerobic glycolysis in cancer cells (the Warburg effect). Moreover, IDH3α activity leads to angiogenesis and metabolic reprogramming to provide the necessary nutrients for continuous cell growth. Meanwhile, silencing IDH3α is observed to obstruct tumor growth. Thus, IDH3α may prove to be a promising therapeutic target in treating cancer.
^Dimitrov L, Hong CS, Yang C, Zhuang Z, Heiss JD (2015). "New developments in the pathogenesis and therapeutic targeting of the IDH1 mutation in glioma". International Journal of Medical Sciences. 12 (3): 201–13. doi:10.7150/ijms.11047. PMID25678837.
^ abcdZeng, 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 (3 September 2015). "Aberrant IDH3α expression promotes malignant tumor growth by inducing HIF-1-mediated metabolic reprogramming and angiogenesis.". Oncogene. 34 (36): 4758–66. doi:10.1038/onc.2014.411. PMID25531325.
^ 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.
^ abcdefgSoundar, S; O'hagan, M; Fomulu, KS; Colman, RF (28 July 2006). "Identification of Mn2+-binding aspartates from alpha, beta, and gamma subunits of human NAD-dependent isocitrate dehydrogenase.". The Journal of Biological Chemistry. 281 (30): 21073–81. doi:10.1074/jbc.m602956200. PMID16737955.
^ abcdeSoundar, S; Park, JH; Huh, TL; Colman, RF (26 December 2003). "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): 52146–53. doi:10.1074/jbc.m306178200. PMID14555658.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Kim YO, Koh HJ, Kim SH, et al. (2000). "Identification and functional characterization of a novel, tissue-specific NAD(+)-dependent isocitrate dehydrogenase beta subunit isoform". J. Biol. Chem. 274 (52): 36866–75. doi:10.1074/jbc.274.52.36866. PMID10601238.
Weiss C, Zeng Y, Huang J, et al. (2000). "Bovine NAD+-dependent isocitrate dehydrogenase: alternative splicing and tissue-dependent expression of subunit 1". Biochemistry. 39 (7): 1807–16. doi:10.1021/bi991691i. PMID10677231.
Adkins JN, Varnum SM, Auberry KJ, et al. (2003). "Toward a human blood serum proteome: analysis by multidimensional separation coupled with mass spectrometry". Mol. Cell Proteomics. 1 (12): 947–55. doi:10.1074/mcp.M200066-MCP200. PMID12543931.
Soundar S, Park JH, Huh TL, Colman RF (2004). "Evaluation by mutagenesis of the importance of 3 arginines in alpha, beta, and gamma subunits of human NAD-dependent isocitrate dehydrogenase". J. Biol. Chem. 278 (52): 52146–53. doi:10.1074/jbc.M306178200. PMID14555658.
Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID14702039.
Guo D, Han J, Adam BL, et al. (2005). "Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress". Biochem. Biophys. Res. Commun. 337 (4): 1308–18. doi:10.1016/j.bbrc.2005.09.191. PMID16236267.
Soundar S, O'hagan M, Fomulu KS, Colman RF (2006). "Identification of Mn2+-binding aspartates from alpha, beta, and gamma subunits of human NAD-dependent isocitrate dehydrogenase". J. Biol. Chem. 281 (30): 21073–81. doi:10.1074/jbc.M602956200. PMID16737955.
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.