Distribution of the branched chain aminotransferase proteins in the human brain and their role in glutamate regulation

Hull, Jonathon; Hindy, Maya El; Kehoe, Patrick Gavin; Chalmers, Katy A; Love, Seth; Conway, Myra E.

doi:10.1111/jnc.12044

Cited by 61 publications

(84 citation statements)

References 61 publications

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“…All IDH-WT tumours examined have increased expression of the BCAA metabolic proteins relative to normal brain tissue (Hull et al, 2012). Western blot analysis has demonstrated that in IDH-WT tumours there was a significant increase in the expression of hBCATm (p=0.036) and hBCATc (p=0.007) relative to IDH mutation glioblastomas ( Figure 1A and B).…”

Section: Resultsmentioning

confidence: 95%

“…Under normal physiological conditions, the hBCAT isoforms show both tissue and cell specific expression (Hull et al, 2012), which makes their co-expression in gliomas most unusual, highlighting new regulatory mechanisms for the BCAT genes under pathogenic conditions. Here, we report that the mitochondrial isoform, hBCATm, was also significantly (p=0.036) increased in IDH-WT tumours and more importantly is a negative predictor of patient survival in IDH-WT glioblastomas (p=0.003) and also in grade IV tumours alone (p=0.043).…”

Section: P a G Ementioning

confidence: 99%

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Decreased expression of the mitochondrial BCAT protein correlates with improved patient survival in IDH‐WT gliomas

Conway¹,

Hull²,

Hindy³

et al. 2016

Brain Pathology

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We recommend you cite the published version. The publisher's URL is: http://dx.doi.org/10.1111/bpa.12385 Refereed: YesThis is the peer reviewed version of the following article: Conway, M. E., Hull, J., El Hindy, M., Taylor, S., El Amraoui, F., Paton?Thomas, C., White, P., Williams, H., Haynes, H., Bertoni, A., Radlwimmer, B., Hutson, S. and Kurian, K. (2016) Decreased expression of the mitochondrial bcat protein correlates with improved patient survival in idh?wt gliomas. Brain Pathology, which has been published in final form at http://dx.doi.org/10.1111/bpa.12385. This article may be used for non?commercial purposes in accordance with Wiley Terms and Conditions for Self?Archiving. Disclaimer UWE has obtained warranties from all depositors as to their title in the material deposited and as to their right to deposit such material. UWE makes no representation or warranties of commercial utility, title, or fitness for a particular purpose or any other warranty, express or implied in respect of any material deposited.UWE makes no representation that the use of the materials will not infringe any patent, copyright, trademark or other property or proprietary rights. UWE accepts no liability for any infringement of intellectual property rights in any material deposited but will remove such material from public view pending investigation in the event of an allegation of any such infringement. Methods:Glioblastomas, of grades II-IV, from 53 patients were graded by a neuropathologist, where the IDH and MGMT status were assessed. Tumours positive for hBCATm, hBCATc and BCKDC were characterised using immunohistochemistry andWestern blot analysis using antibodies specific to these proteins. Results:Here, we report that in IDH-WT tumours, the expression of hBCATm is significantly increased (p=0.034) relative to IDH mutation gliomas, and significantly correlates with patient survival, on Kaplan-Meier analysis, where low hBCATm expression is a positive prognostic factor (p=0.003). Moreover, increased hBCATm expression in these glioblastomas correlated with tumour grade indicating their role as a predictive biomarker of glioma progression. Multiple banding was observed for the branched-chain α-keto acid dehydrogenase complex, which catalyses the committed step in BCAA metabolism, but a significant change in expression was absent (p=0.690). Conclusion:Until now, IDH-WT glioblastomas have a uniformly poor prognosis, however we demonstrate for the first time that relatively low hBCATm may select for a better performing subset within this group and may represent a therapeutic target in these hard to treat patients.

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Section: Resultsmentioning

confidence: 95%

Section: P a G Ementioning

confidence: 99%

Decreased expression of the mitochondrial BCAT protein correlates with improved patient survival in IDH‐WT gliomas

Conway¹,

Hull²,

Hindy³

et al. 2016

Brain Pathology

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“…Like the rat/mouse, BCATc is primarily found in neurons that are GABAergic or glutamatergic with more immunopositive GABAergic neurons [22]. As in rodents, neurons that were neither glutamatergic nor GABAergic were also labeled (serotonergic, dopaminergic) with some neuroendocrine cells also showing BCATc immunolabeling.…”

Section: Shuttling Of Bcaa Metabolites and Their Role In Brain Metabomentioning

confidence: 97%

The Cytosolic and Mitochondrial Branched Chain Aminotransferase

Conway

Hutson

2015

Branched Chain Amino Acids in Clinical Nutrition

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Key Points• The branched chain aminotransferases (BCAT) are PLP-dependent proteins which catalyze the transfer of an amino group from the donor amino acid to α-ketoglutarate, forming glutamate and the respective keto acids.• Structurally the BCAT proteins are homodimers, where the active site between each isoform is largely conserved.• The cytosolic and mitochondrial isoforms show cell and tissue specific expression where the aminotransferase proteins play an integrated role in shuttling metabolites between cells and tissues.• These anaplerotic shuttles interface with core metabolic pathways and protein complexes such as the branched chain α-keto acid dehydrogenase complex and glutamate dehydrogenase, respectively, indicating a role in the regeneration of key metabolites such as the primary neurotransmitter glutamate.• Leucine is a nutrient signal and involved in mTOR signalling, which controls the synthesis of cellular protein levels. • Moreover, the BCAT proteins have a unique redox-active CXXC motif regulated through changes in the redox environment, likely to play a key role in this signalling mechanism. • Site-directed mutagenesis studies have identified that the N-terminal cysteine acts as the 'redox sensor' and the C-terminal cysteine as its resolving partner, which permits reversible regulation.• Oxidation, S-nitrosation and S-glutathionylation are important redox regulators of BCAT activity and are reversibly controlled through the glutaredoxin/glutathione system. • Biochemical and X-ray crystallography studies of the redox-active mutant proteins describe the importance of the N-terminal cysteine in the orientation of the substrate and its interaction with key residues of the interdomain loop.

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“…These proteins have a mitochondrial (m) and cytosolic (c) isoform with tissue-specific locations, with hBCATm, the most ubiquitous isoform, thought to be responsible for the majority of transamination outside the central nervous system with the highest levels of hBCATm recorded in the pancreas, kidney, stomach, and brain (70). hBCATc, is largely associated with neuronal cells and is predominantly found in the soma and proximal dendrites of glutamatergic and GABAergic neuronal cells, supporting its role in contributing to both the storage and metabolic pools of the neurotransmitter glutamate and as the precursor for GABA production in GABAergic neurons (71)(72)(73). Although hBCATm is ubiquitously expressed throughout the body, there is extensive immuno-positive staining for hBCATm specific to brain vasculature, indicating a new role for hBCATm in brain glutamate regulation (71,74).…”

Section: Metabolic Redox Chaperones: the Hbcat Proteins Transaminatiomentioning

confidence: 99%

“…hBCATc, is largely associated with neuronal cells and is predominantly found in the soma and proximal dendrites of glutamatergic and GABAergic neuronal cells, supporting its role in contributing to both the storage and metabolic pools of the neurotransmitter glutamate and as the precursor for GABA production in GABAergic neurons (71)(72)(73). Although hBCATm is ubiquitously expressed throughout the body, there is extensive immuno-positive staining for hBCATm specific to brain vasculature, indicating a new role for hBCATm in brain glutamate regulation (71,74). BCAT catalyse the transfer of the α-amino group from the hydrophobic branched-chain amino acids (BCAAs) leucine, isoleucine, and valine, to α-ketoglutarate releasing their respective keto acids, ketoisocaproate, keto methyl valerate, and ketoisovaline and glutamate, regenerating the enzyme (75,76).…”

Section: Metabolic Redox Chaperones: the Hbcat Proteins Transaminatiomentioning

confidence: 99%

The redox switch that regulates molecular chaperones

Conway

Lee

2015

Biomolecular Concepts

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Modification of reactive cysteine residues plays an integral role in redox-regulated reactions. Oxidation of thiolate anions to sulphenic acid can result in disulphide bond formation, or overoxidation to sulphonic acid, representing reversible and irreversible endpoints of cysteine oxidation, respectively. The antioxidant systems of the cell, including the thioredoxin and glutaredoxin systems, aim to prevent these higher and irreversible oxidation states. This is important as these redox transitions have numerous roles in regulating the structure/function relationship of proteins. Proteins with redox-active switches as described for peroxiredoxin (Prx) and protein disulphide isomerase (PDI) can undergo dynamic structural rearrangement resulting in a gain of function. For Prx, transition from cysteine sulphenic acid to sulphinic acid is described as an adaptive response during increased cellular stress causing Prx to form higher molecular weight aggregates, switching its role from antioxidant to molecular chaperone. Evidence in support of PDI as a redox-regulated chaperone is also gaining impetus, where oxidation of the redox-active CXXC regions causes a structural change, exposing its hydrophobic region, facilitating polypeptide folding. In this review, we will focus on these two chaperones that are directly regulated through thiol-disulphide exchange and detail how these redox-induced switches allow for dual activity. Moreover, we will introduce a new role for a metabolic protein, the branched-chain aminotransferase, and discuss how it shares common mechanistic features with these well-documented chaperones. Together, the physiological importance of the redox regulation of these proteins under pathological conditions such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis will be discussed to illustrate the impact and importance of correct folding and chaperone-mediated activity.

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Distribution of the branched chain aminotransferase proteins in the human brain and their role in glutamate regulation

Cited by 61 publications

References 61 publications

Decreased expression of the mitochondrial BCAT protein correlates with improved patient survival in IDH‐WT gliomas

Decreased expression of the mitochondrial BCAT protein correlates with improved patient survival in IDH‐WT gliomas

The Cytosolic and Mitochondrial Branched Chain Aminotransferase

The redox switch that regulates molecular chaperones

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