Proteomics

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Redirected nuclear glutamate dehydrogenase supplies Tet3 with a-ketoglutarate in neurons


ABSTRACT: Tet3 is an Fe2+-dependent enzyme that oxidizes genomic 5-methylcytosine to 5-hydroxymethylcytosine with the help of alpha-ketoglutarate and oxygen. It is the most abundant Tet enzyme in differentiated tissues including brain. Adult brain contains the highest 5-hydroxymethylcytosine levels. How alpha-ketoglutarate is made available for the oxidation of mC in brain cells and how the Tet activity is linked to neural activity are unsolved questions. Our experiments with full mouse brains show that Tet3 interacts in the nucleus directly with selected enzymes of the mitochondrial citric acid cycle. This leads to the formation of isocitrate. Tet3 also interacts with aspartate aminotransferase, which produces oxaloacetate. Although oxaloacetate and isocitrate are biosynthetic alpha-ketoglutarate precursors, they function as inhibitors of Tet3 and are needed to protect the reactive Fe2+ center from degrading DNA. The supply of Tet3 with alpha-ketoglutarate is established by a direct interaction of Tet3 with glutamate dehydrogenase (Glud1), which converts the neurotransmitter glutamate directly into alpha-ketoglutarate. This links Tet3 function to neural activity.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Andrea Künzel  

LAB HEAD: Thomas Carell

PROVIDER: PXD004518 | Pride | 2021-05-10

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
20141202_AFK_Tet3FL_Gehirn1.RAW Raw
20141202_AFK_Tet3FL_Gehirn2.RAW Raw
20141202_AFK_Tet3FL_Gehirn3.RAW Raw
20141202_AFK_Tet3FL_Gehirn4.RAW Raw
20141202_AFK_Tet3ohneCXXC_Gehirn1.RAW Raw
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Publications


Tet3 is the main α-ketoglutarate (αKG)-dependent dioxygenase in neurons that converts 5-methyl-dC into 5-hydroxymethyl-dC and further on to 5-formyl- and 5-carboxy-dC. Neurons possess high levels of 5-hydroxymethyl-dC that further increase during neural activity to establish transcriptional plasticity required for learning and memory functions. How αKG, which is mainly generated in mitochondria as an intermediate of the tricarboxylic acid cycle, is made available in the nucleus has remained an u  ...[more]

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