Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: BCAT1
Cytogenetic location: 12p12.1 Genomic coordinates (GRCh38): 12:24,810,024-24,949,340 (from NCBI)
Benvenisty et al. (1992) isolated the mouse Bcat1 gene by a subtraction/coexpression strategy with Myc-induced tumors of transgenic mice, and proved that Bcat1 is a direct genetic target for Myc regulation in the mouse. The Bcat1 gene is highly expressed early in embryogenesis, and during organogenesis its expression is localized to the neural tube, the somites, and the mesonephric tubules. The gene is also expressed in several MYC-based tumors. Schuldiner et al. (1996) isolated and compared the structural sequences of the Bcat1 homolog in mice, human, nematode, and yeast and showed that in human, as in mouse, the BCAT1 gene is a target for MYC activity in the oncogenesis process. Eden et al. (1996) characterized a gene similar to BCAT1 in both human and yeast and demonstrated that BCAT1 and BCAT2 in yeast code for mitochondrial and cytosolic branched-chain amino acid aminotransferases.
Using thyroid hormone receptor-beta-1 (THRB1; 190160) as bait in a yeast 2-hybrid screen of a colon carcinoma cell line cDNA library, Lin et al. (2001) cloned a splice variant of BCAT1, which they designated P3. Full-length BCAT1 encodes a deduced 393-amino acid precursor protein with a 27-amino acid N-terminal mitochondrial targeting sequence; the mature protein contains 366 amino acids. The P3 splice variant encodes a deduced 381-amino acid precursor that lacks 12 amino acids near the C terminus of full-length BCAT1. Northern blot analysis detected a 1.7-kb transcript representing both variants in all normal tissues and cell lines examined. Expression was higher in heart, placenta, skeletal muscle, and pancreas and lower in brain, lung, liver, and kidney. Western blot analysis detected BCAT1 at an apparent molecular mass of 42 kD in several human cell lines. Epitope-tagged P3 localized to the mitochondria and to the nucleus of transfected simian kidney cells.
By screening a placenta expression library with antibodies raised against a 41-kD placenta protein, Than et al. (2001) cloned BCAT1 variants, which they designated PP18a and PP18b. The deduced PP18a precursor protein contains 392 amino acids and has a 27-amino acid mitochondrial targeting sequence. The mature 365-amino acid protein has a calculated molecular mass of 41.3 kD. The PP18b variant encodes a deduced 300-amino acid protein with a calculated molecular mass of 33.8 kD. This variant lacks a mitochondrial targeting sequence. Both isoforms contain aminotransferase class IV motifs, including a lysine where a pyridoxal-phosphate group is covalently bound, as well as several putative phosphorylation sites, an N-glycosylation site, and 3 N-myristoylation sites. Western blot analysis detected PP18a in all tissues examined, with highest levels in adrenal gland, heart, pancreas, and kidney. Lower amounts of PP18b were found in nearly all tissues. Western blot analysis of fractionated placenta lysates detected PP18a in the mitochondrial fraction at an apparent molecular mass of 41 kD and PP18b in the cytosolic fraction at about 33 kD.
Jones and Moore (1976) isolated an auxotrophic mutant in Chinese-hamster ovary cells that lacks the ability to grow if alpha-ketoisovaleric acid, alpha-ketoisocaproic acid, and alpha-keto-beta-methylvaleric acid are substituted for valine, leucine, and isoleucine in the culture medium. This auxotroph, called TRANS-minus, is caused by lack of the enzyme BCT. There may be 2 different clinical disorders due to defect of branched-chain amino acid transamination, hypervalinemia (277100) and hyperleucine-isoleucinemia (238340). Since there are 2 distinct BCATs (see BCAT2; 113530), it is possible that one is mutant in each of these 2 conditions.
Using bacterially expressed THRB1 and the P3 isoform of BCAT1, Lin et al. (2001) showed that the 2 proteins interact in vitro and that the interaction was thyroid hormone (T3) independent. P3 interacted with hormone-binding domain E of THRB1. Endogenous simian P3 also associated with transfected THRB1 in a simian kidney cell line. P3 enhanced the repressor activity of unliganded THR and repressed the ligand-dependent activation of THR. The repression also appeared to be mediated by histone deacetylase activity. Lin et al. (2001) concluded that the P3 variant of BCAT1 is a ligand-independent corepressor for THR.
Than et al. (2001) confirmed that BCAT purified from placenta had branched-chain aminotransferase activity.
Hattori et al. (2017) demonstrated that BCAT1, a cytosolic aminotransferase for branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukemia (CML) in humans and in mouse models of CML. BCAT1 is upregulated during progression of CML and promotes BCAA production in leukemia cells by aminating the branched-chain keto acids. Blocking BCAT1 gene expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML both in vitro and in vivo. Stable-isotope tracer experiments combined with nuclear magnetic resonance (NMR)-based metabolic analysis demonstrated the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function through BCAA production in blast crisis CML cells. Importantly, BCAT1 expression not only is activated in human blast crisis CML and de novo acute myeloid leukemia (AML; see 601626), but also predicts disease outcome in patients. Hattori et al. (2017) identified Musashi2 (MSI2; 607897), an oncogenic RNA-binding protein that is required for blast crisis CML, as an upstream regulator of BCAT1 expression. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukemia. Hattori et al. (2017) concluded that their work revealed that altered BCAA metabolism activated through the MSI2-BCAT1 axis drives cancer progression in myeloid leukemia.
By performing high-resolution proteomic analysis of human AML stem cell and non-stem cell populations, Raffel et al. (2017) found the BCAA pathway enriched and BCAT1 protein and transcripts overexpressed in leukemia stem cells. Raffel et al. (2017) showed that BCAT1, which transfers alpha-amino groups from BCAAs to alpha-ketoglutarate, is a critical regulator of intracellular alpha-ketoglutarate homeostasis. Further to its role in the tricarboxylic acid cycle, alpha-ketoglutarate is an essential cofactor for alpha-ketoglutarate-dependent dioxygenases such as EGLN1 (606425) and the ten-eleven translocation (TET) family of DNA demethylases. Knockdown of BCAT1 in leukemia cells caused accumulation of alpha-ketoglutarate, leading to EGLN1-mediated HIF1-alpha (603348) protein degradation. This resulted in a growth and survival defect and abrogated leukemia-initiating potential. By contrast, overexpression of BCAT1 in leukemia cells decreased intracellular alpha-ketoglutarate levels and caused DNA hypermethylation through altered TET activity. AML with high levels of BCAT1 (BCAT1-high) displayed a DNA hypermethylation phenotype similar to cases carrying a mutant isocitrate dehydrogenase (147700) (IDH-mut), in which TET2 (612839) is inhibited by the oncometabolite 2-hydroxyglutarate. High levels of BCAT1 strongly correlated with shorter overall survival in IDH-wildtype-TET2-wildtype, but not IDH-mut or TET2-mut, AML. BCAT1-high AML showed robust enrichment for leukemia stem cell signatures, and paired sample analysis showed a significant increase in BCAT1 levels upon disease relapse. In summary, by limiting intracellular alpha-ketoglutarate, BCAT1 links BCAA catabolism to HIF1-alpha stability and regulation of the epigenomic landscape, mimicking the effects of IDH mutations.
Jones and Moore (1979) provisionally assigned the BCT1 gene to 12pter-q12. Naylor and Shows (1979, 1980) also assigned BCT1 to chromosome 12 and BCT2 to chromosome 19.
To determine the chromosomal localization of Bcat1 in the mouse, Ben-Yosef et al. (1998) used the Jackson Laboratory BSS backcross panel. They found that Bcat1 maps to the distal end of mouse chromosome 6. On the basis of conserved synteny, they suggested that the human BCAT1 gene maps to 12p12. By the same approaches, Ben-Yosef et al. (1998) mapped the mouse Bcat2 gene to mouse chromosome 7 and human 19q13.
Ben-Yosef, T., Eden, A., Benvenisty, N. Characterization of murine BCAT genes: Bcat1, a c-Myc target, and its homolog, Bcat2. Mammalian Genome 9: 595-597, 1998. [PubMed: 9657861] [Full Text: https://doi.org/10.1007/s003359900825]
Benvenisty, N., Leder, A., Kuo, A., Leder, P. An embryonically expressed gene is a target for c-Myc regulation via the c-Myc-binding sequence. Genes Dev. 6: 2513-2523, 1992. [PubMed: 1340466] [Full Text: https://doi.org/10.1101/gad.6.12b.2513]
Eden, A., Simchen, G., Benvenisty, N. Two yeast homologs of ECA39, a target for c-Myc regulation, code for cytosolic and mitochondrial branched-chain amino acid aminotransferases. J. Biol. Chem. 271: 20242-20245, 1996. [PubMed: 8702755] [Full Text: https://doi.org/10.1074/jbc.271.34.20242]
Hattori, A., Tsunoda, M., Konuma, T., Kobayashi, M., Nagy, T., Glushka, J., Tayyari, F., McSkimming, D., Kannan, N., Tojo, A., Edison, A. S., Ito, T. Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia. Nature 545: 500-504, 2017. [PubMed: 28514443] [Full Text: https://doi.org/10.1038/nature22314]
Jones, C., Moore, E. E. Isolation of mutants lacking branched-chain amino acid transaminase. Somat. Cell Genet. 2: 235-243, 1976. [PubMed: 1028171] [Full Text: https://doi.org/10.1007/BF01538962]
Jones, C., Moore, E. E. Assignment of the human gene complementing the auxotrophic marker TRANS-minus (BCT1) to chromosome 12. (Abstract) Cytogenet. Cell Genet. 25: 168 only, 1979.
Jones, C., Moore, E. E. Localization of a gene which complements branched-chain amino acid transaminase deficiency to the short arm of human chromosome 12. Hum. Genet. 66: 206-211, 1984. [PubMed: 6585344] [Full Text: https://doi.org/10.1007/BF00286602]
Lin, H.-M., Kaneshige, M., Zhao, L., Zhang, X., Hanover, J. A., Cheng, S. An isoform of branched-chain aminotransferase is a novel co-repressor for thyroid hormone nuclear receptors. J. Biol. Chem. 276: 48196-48205, 2001. [PubMed: 11574535] [Full Text: https://doi.org/10.1074/jbc.M104320200]
Naylor, S. L., Shows, T. B. Branched-chain aminotransferase genes (BCT-1 and BCT-2) assigned to human chromosomes 12 and 19 using alpha-keto acid selection media. (Abstract) Cytogenet. Cell Genet. 25: 191-192, 1979.
Naylor, S. L., Shows, T. B. Branched-chain aminotransferase deficiency in Chinese hamster cells complemented by two independent genes on human chromosomes 12 and 19. Somat. Cell Genet. 6: 641-652, 1980. [PubMed: 6933702] [Full Text: https://doi.org/10.1007/BF01538643]
Raffel, S., Falcone, M., Kneisel, N., Hansson, J., Wang, W., Lutz, C., Bullinger, L., Poschet, G., Nonnenmacher, Y., Barnert, A., Bahr, C., Zeisberger, P., and 22 others. BCAT1 restricts alpha-KG levels in AML stem cells leading to IDH(mut)-like DNA hypermethylation. Nature 551: 384-388, 2017. Note: Erratum: Nature 560: E28, 2018. [PubMed: 29144447] [Full Text: https://doi.org/10.1038/nature24294]
Schuldiner, O., Eden, A., Ben-Yosef, T., Yanuka, O., Simchen, G., Benvenisty, N. ECA39, a conserved gene regulated by c-Myc in mice, is involved in G1/S cell cycle regulation in yeast. Proc. Nat. Acad. Sci. 93: 7143-7148, 1996. [PubMed: 8692959] [Full Text: https://doi.org/10.1073/pnas.93.14.7143]
Tanaka, K., Rosenberg, L. E. Disorders of branched chain amino acid and organic acid metabolism. In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S.; Goldstein, J. L.; Brown, M. S. (eds.): The Metabolic Basis of Inherited Disease. (5th ed.) New York: McGraw-Hill (pub.) 1983. Pp. 450-451.
Than, N. G., Sumegi, B., Than, G. N., Bellyei, S., Bohn, H. Molecular cloning and characterization of placental tissue protein 18 (PP18a)/human mitochondrial branched-chain aminotransferase (BCATm) and its novel alternatively spliced PP18b variant. Placenta 22: 235-243, 2001. [PubMed: 11170829] [Full Text: https://doi.org/10.1053/plac.2000.0603]