IDH3B

IDH3B
Identifiers
Aliases	IDH3B , H-IDHB, RP46, isocitrate dehydrogenase 3 (NAD(+)) beta, isocitrate dehydrogenase (NAD(+)) 3 beta, isocitrate dehydrogenase (NAD(+)) 3 non-catalytic subunit beta
External IDs	OMIM: 604526 MGI: 2158650 HomoloGene: 5035 GeneCards: IDH3B
Gene location (Human) Chr. Chromosome 20 (human) [1] Band 20p13 Start 2,658,395 bp [1] End 2,664,219 bp [1]
Gene location (Mouse) Chr. Chromosome 2 (mouse) [2] Band 2|2 F1 Start 130,121,229 bp [2] End 130,126,467 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in left ventricle right lobe of thyroid gland vastus lateralis muscle right ventricle gastrocnemius muscle body of stomach left lobe of thyroid gland triceps brachii muscle skin of abdomen right uterine tube Top expressed in interventricular septum masseter muscle soleus muscle myocardium of ventricle brown adipose tissue sternocleidomastoid muscle intercostal muscle quadriceps femoris muscle skeletal muscle tissue substantia nigra More reference expression data BioGPS More reference expression data
Gene ontology Molecular function NAD binding magnesium ion binding oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor electron transfer activity isocitrate dehydrogenase (NAD+) activity Cellular component nucleus mitochondrial matrix mitochondrion Biological process tricarboxylic acid cycle isocitrate metabolic process electron transport chain 2-oxoglutarate metabolic process NADH metabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3420 170718 Ensembl ENSG00000101365 ENSMUSG00000027406 UniProt O43837 n/a RefSeq (mRNA) NM_001258384 NM_006899 NM_174855 NM_174856 NM_001330763 NM_130884 NM_001362752 RefSeq (protein) NP_001245313 NP_001317692 NP_008830 NP_777280 n/a Location (UCSC) Chr 20: 2.66 – 2.66 Mb Chr 2: 130.12 – 130.13 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial is an enzyme that in humans is encoded by the IDH3B gene. ^{[5] [6]}

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 beta subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. Three alternatively spliced transcript variants encoding different isoforms have been described for this gene. [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]}

Isoforms

The IDH3B gene contains 12 exons and encodes two alternatively spliced isoforms: IDH3β1 (349 residues) and IDH3β2 (354 residues). ^{[13] [14]} These isoforms are tissue-specific and possess optimal pHs matching those of their target tissues. IDH3β1, with an optimal pH of 8.0, is expressed in brain and kidney, whereas IDH3β2, with an optimal pH of 7.6, is expressed in heart and skeletal muscle. ^[14]

Function

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. ^{[8] [9] [10] [11] [15]} 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. ^{[15] [16]} Within cells, IDH3 and its subunits have been observed to localize to the mitochondria. ^{[9] [10] [15]}

Clinical Significance

Homozygous loss-of-function mutations of the IDH3B gene has been linked to retinitis pigmentosa, the neurodegeneration of rods and cones in the retina resulting in blindness. ^{[12] [13] [17]}

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

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|alt=TCACycle_WP78 edit]]

TCACycle_WP78 edit

1. The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78".

See also

• IDH1
• IDH2
• IDH3A
• IDH3G

References

1. GRCh38: Ensembl release 89: ENSG00000101365 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000027406 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Kim YO, Park SH, Kang YJ, Koh HJ, Kim SH, Park SY, Sohn U, Huh TL (Jan 2000). "Assignment of mitochondrial NAD(+)-specific isocitrate dehydrogenase beta subunit gene (IDH3B) to human chromosome band 20p13 by in situ hybridization and radiation hybrid mapping". Cytogenet Cell Genet. 86 (3–4): 240–1. doi:10.1159/000015348. PMID   10575215. S2CID   85139434.
6. "Entrez Gene: IDH3B isocitrate dehydrogenase 3 (NAD+) beta".
7. 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. PMC   4323358 . PMID   25678837.
8. 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 (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 . PMID   25531325.
9. Bzymek, 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. PMID   17432878.
10. Soundar, 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 . PMID   16737955.
11. Soundar, 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 . PMID   14555658.
12. 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 Chemistry. 285 (27): 20520–5. doi: 10.1074/jbc.m110.115386 . PMC   2898308 . PMID   20435888.
13. Hartong, DT; Dange, M; McGee, TL; Berson, EL; Dryja, TP; Colman, RF (October 2008). "Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle". Nature Genetics. 40 (10): 1230–4. doi:10.1038/ng.223. PMC   2596605 . PMID   18806796.
14. Kim, YO; Koh, HJ; Kim, SH; Jo, SH; Huh, JW; Jeong, KS; Lee, IJ; Song, BJ; Huh, TL (24 December 1999). "Identification and functional characterization of a novel, tissue-specific NAD(+)-dependent isocitrate dehydrogenase beta subunit isoform". The Journal of Biological Chemistry. 274 (52): 36866–75. doi: 10.1074/jbc.274.52.36866 . PMID   10601238.
15. Huh, TL; Kim, YO; Oh, IU; Song, BJ; Inazawa, J (1 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): 295–6. doi:10.1006/geno.1996.0120. PMID   8833160.
16. 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. 21 (11): 1504–1510. doi:10.1038/mp.2015.217. PMC   5078854 . PMID   26782057.
17. Fahim, AT; Daiger, SP; Weleber, RG; Pagon, RA; Adam, MP; Ardinger, HH; Wallace, SE; Amemiya, A; Bean, LJH; Bird, TD; Fong, CT; Mefford, HC; Smith, RJH; Stephens, K (1993). "Retinitis Pigmentosa Overview". PMID   20301590.{{cite journal}}: Cite journal requires |journal= (help)

Further reading

• 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 . PMID   10601238.
• 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. PMID   10677231.
• Deloukas P, Matthews LH, Ashurst J, et al. (2002). "The DNA sequence and comparative analysis of human chromosome 20". Nature. 414 (6866): 865–71. Bibcode:2001Natur.414..865D. doi: 10.1038/414865a . PMID   11780052.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi: 10.1073/pnas.242603899 . PMC   139241 . PMID   12477932.
• 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 . PMID   14702039.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC   528928 . PMID   15489334.
• Kil IS, Park JW (2005). "Regulation of mitochondrial NADP+-dependent isocitrate dehydrogenase activity by glutathionylation". J. Biol. Chem. 280 (11): 10846–54. doi: 10.1074/jbc.M411306200 . PMID   15653693.
• Rual JF, Venkatesan K, Hao T, et al. (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID   16189514. S2CID   4427026.
• Lim J, Hao T, Shaw C, et al. (2006). "A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration". Cell. 125 (4): 801–14. doi: 10.1016/j.cell.2006.03.032 . PMID   16713569. S2CID   13709685.
• 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 . PMID   16737955.
• 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. PMID   17432878.

External links

• GeneReviews/NCBI/NIH/UW entry on Retinitis Pigmentosa Overview