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.
^Brenner V, Nyakatura G, Rosenthal A, Platzer M (Nov 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". Genomics44 (1): 8–14. doi:10.1006/geno.1997.4822. PMID9286695.
^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 Sciences12 (3): 201–13. doi:10.7150/ijms.11047. PMID25678837.
^ abcZeng, 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.". Oncogene34 (36): 4758–66. 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.". Biochemistry46 (18): 5391–7. 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 chemistry281 (30): 21073–81. 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 chemistry278 (52): 52146–53. PMID14555658.
^Dange, M; Colman, RF (2 July 2010). "Each conserved active site tyr in the three subunits of human isocitrate dehydrogenase has a different function.". The Journal of biological chemistry285 (27): 20520–5. PMID20435888.
^ abcHuh TL, Kim YO, Oh IU, Song BJ, Inazawa J (May 1997). "Assignment of the human mitochondrial NAD+ -specific isocitrate dehydrogenase alpha subunit (IDH3A) gene to 15q25.1→q25.2by in situ hybridization". Genomics32 (2): 295–6. doi:10.1006/geno.1996.0120. PMID8833160.
^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 (19 January 2016). "Cerebrospinal fluid metabolomics identifies a key role of isocitrate dehydrogenase in bipolar disorder: evidence in support of mitochondrial dysfunction hypothesis.". Molecular psychiatry. PMID26782057.
Sandoval N, Bauer D, Brenner V, et al. (1996). "The genomic organization of a human creatine transporter (CRTR) gene located in Xq28.". Genomics35 (2): 383–5. doi:10.1006/geno.1996.0373. PMID8661155.
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.". Biochemistry39 (7): 1807–16. doi:10.1021/bi991691i. PMID10677231.
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.". Biochemistry46 (18): 5391–7. doi:10.1021/bi700061t. PMID17432878.