Branched chain amino acid transaminase 1 explained

Branched chain amino acid transaminase 1 is a protein that in humans is encoded by the BCAT1 gene.[1] It is the first enzyme in the branched-chain amino acid (BCAA) degradation pathway and facilitates the reversible transamination of BCAAs and glutamate. BCAT1 resides in the cytoplasm, while its isoform, BCAT2, is found in the mitochondria.

Function

This gene encodes the cytosolic form of the enzyme branched-chain amino acid transaminase. This enzyme catalyzes the reversible transamination of branched-chain alpha-keto acids (BCKAs) to the branched-chain amino acids (BCAAs) valine, leucine and isoleucine, which are essential for cell growth. In humans, its primary role is the deamination of BCAAs, as humans lack the enzymes for de novo synthesis of BCKAs. The respective cosubstrates are alpha-ketoglutarate and glutamate. The respective reactions are:[2]

L-leucine + 2-oxoglutarate = 4-methyl-2-oxopentanoate + L-glutamate

L-isoleucine + 2-oxoglutarate = (S)-3-methyl-2-oxopentanoate + L-glutamate

L-valine + 2-oxoglutarate = 3-methyl-2-oxobutanoate + L-glutamate

Cells can further degrade BCKAs by the branched-chain keto acid dehydrogenase complex from which the carbon backbones of each BCAA may enter distinct degradation pathways.[3]

The oncogenic transcription factor Myc is frequently reported to drive BCAT1 expression.[4] [5] [6]

Clinical significance

Two different clinical disorders have been attributed to a defect of branched-chain amino acid transamination: hypervalinemia and hyperleucine-isoleucinemia.[7] As there is also a gene encoding a mitochondrial form of this enzyme (BCAT2), mutations in either gene may contribute to these disorders.

Overexpression of BCAT1 has been associated with a variety of cancers, among them glioblastoma,[8] breast cancer,[9] acute myeloid leukemia,[10] gastric cancer[11] and chronic myeloid leukemia.[12]

Further reading

Notes and References

  1. Web site: Entrez Gene: Branched chain amino acid transaminase 1. 2016-04-21 .
  2. Web site: BCAT1 - Branched-chain-amino-acid aminotransferase, cytosolic - Homo sapiens (Human) - BCAT1 gene & protein. www.uniprot.org. en. 2018-08-06.
  3. Web site: BCKDH in the BCAA degradation pathway. August 6, 2018. Genome.jp. August 6, 2018.
  4. Zhou W, Feng X, Ren C, Jiang X, Liu W, Huang W, Liu Z, Li Z, Zeng L, Wang L, Zhu B, Shi J, Liu J, Zhang C, Liu Y, Yao K . Over-expression of BCAT1, a c-Myc target gene, induces cell proliferation, migration and invasion in nasopharyngeal carcinoma . Molecular Cancer . 12 . 53 . June 2013 . 23758864 . 3698204 . 10.1186/1476-4598-12-53 . free .
  5. 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 . Proceedings of the National Academy of Sciences of the United States of America . 93 . 14 . 7143–8 . July 1996 . 8692959 . 38950 . 10.1073/pnas.93.14.7143. 1996PNAS...93.7143S . free .
  6. Ben-Yosef T, Eden A, Benvenisty N . Characterization of murine BCAT genes: Bcat1, a c-Myc target, and its homolog, Bcat2 . Mammalian Genome . 9 . 7 . 595–7 . July 1998 . 9657861 . 10.1007/s003359900825. 21062787 .
  7. Wang XL, Li CJ, Xing Y, Yang YH, Jia JP . Hypervalinemia and hyperleucine-isoleucinemia caused by mutations in the branched-chain-amino-acid aminotransferase gene . Journal of Inherited Metabolic Disease . 38 . 5 . 855–61 . September 2015 . 25653144 . 10.1007/s10545-015-9814-z . 24253640 .
  8. Tönjes M, Barbus S, Park YJ, Wang W, Schlotter M, Lindroth AM, Pleier SV, Bai AH, Karra D, Piro RM, Felsberg J, Addington A, Lemke D, Weibrecht I, Hovestadt V, Rolli CG, Campos B, Turcan S, Sturm D, Witt H, Chan TA, Herold-Mende C, Kemkemer R, König R, Schmidt K, Hull WE, Pfister SM, Jugold M, Hutson SM, Plass C, Okun JG, Reifenberger G, Lichter P, Radlwimmer B . 6 . BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1 . Nature Medicine . 19 . 7 . 901–908 . July 2013 . 23793099 . 4916649 . 10.1038/nm.3217 .
  9. Thewes V, Simon R, Hlevnjak M, Schlotter M, Schroeter P, Schmidt K, Wu Y, Anzeneder T, Wang W, Windisch P, Kirchgäßner M, Melling N, Kneisel N, Büttner R, Deuschle U, Sinn HP, Schneeweiss A, Heck S, Kaulfuss S, Hess-Stumpp H, Okun JG, Sauter G, Lykkesfeldt AE, Zapatka M, Radlwimmer B, Lichter P, Tönjes M . 6 . The branched-chain amino acid transaminase 1 sustains growth of antiestrogen-resistant and ERα-negative breast cancer . Oncogene . 36 . 29 . 4124–4134 . July 2017 . 28319069 . 10.1038/onc.2017.32 . 25098058 .
  10. Raffel S, Falcone M, Kneisel N, Hansson J, Wang W, Lutz C, Bullinger L, Poschet G, Nonnenmacher Y, Barnert A, Bahr C, Zeisberger P, Przybylla A, Sohn M, Tönjes M, Erez A, Adler L, Jensen P, Scholl C, Fröhling S, Cocciardi S, Wuchter P, Thiede C, Flörcken A, Westermann J, Ehninger G, Lichter P, Hiller K, Hell R, Herrmann C, Ho AD, Krijgsveld J, Radlwimmer B, Trumpp A . 6 . BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation . Nature . 551 . 7680 . 384–388 . November 2017 . 29144447 . 10.1038/nature24294 . 2017Natur.551..384R . 205261267 .
  11. Xu Y, Yu W, Yang T, Zhang M, Liang C, Cai X, Shao Q . Overexpression of BCAT1 is a prognostic marker in gastric cancer . Human Pathology . 75 . 41–46 . May 2018 . 29447920 . 10.1016/j.humpath.2018.02.003 .
  12. Hattori A, Tsunoda M, Konuma T, Kobayashi M, Nagy T, Glushka J, Tayyari F, McSkimming D, Kannan N, Tojo A, Edison AS, Ito T . Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia . Nature . 545 . 7655 . 500–504 . May 2017 . 28514443 . 5554449 . 10.1038/nature22314 . 2017Natur.545..500H .

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