Brain proteomics supports the role of glutamate metabolism and suggests other metabolic alterations in protein l-isoaspartyl methyltransferase (PIMT)-knockout mice. 2013

Hongqian Yang, and Jonathan D Lowenson, and Steven Clarke, and Roman A Zubarev
Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Scheeles väg 2, SE-17 177 Stockholm, Sweden.

Protein l-isoaspartyl methyltransferase (PIMT) repairs the isoaspartyl residues (isoAsp) that originate from asparagine deamidation and aspartic acid (Asp) isomerization to Asp residues. Deletion of the gene encoding PIMT in mice (Pcmt1) leads to isoAsp accumulation in all tissues measured, especially in the brain. These PIMT-knockout (PIMT-KO) mice have perturbed glutamate metabolism and die prematurely of epileptic seizures. To elucidate the role of PIMT further, brain proteomes of PIMT-KO mice and controls were analyzed. The isoAsp levels from two of the detected 67 isoAsp sites (residue 98 from calmodulin and 68 from glyceraldehyde-3-phosphate dehydrogenase) were quantified and found to be significantly increased in PIMT-KO mice (p < 0.01). Additionally, the abundance of at least 151 out of the 1017 quantified proteins was found to be altered in PIMT-KO mouse brains. Gene ontology analysis revealed that many down-regulated proteins are involved in cellular amino acid biosynthesis. For example, the serine synthesis pathway was suppressed, possibly leading to reduced serine production in PIMT-KO mice. Additionally, the abundances of enzymes in the glutamate-glutamine cycle were altered toward the accumulation of glutamate. These findings support the involvement of PIMT in glutamate metabolism and suggest that the absence of PIMT also affects other processes involving amino acid synthesis and metabolism.

UI MeSH Term Description Entries
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D001921 Brain The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM. Encephalon
D005260 Female Females
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D057507 Mice, 129 Strain Strains of mice arising from a parental inbred stock that was subsequently used to produce substrains of knockout and other mutant mice with targeted mutations. 129 Mice,129 Mouse,129 Strain Mice,129 Strain Mouse,Bar Harbor 129 Mice,Bar Harbor 129 Mouse,Mice, 129,Mice, Strain 129,Mouse, 129,Mouse, 129 Strain,Strain 129 Mice,Strain Mice, 129
D018345 Mice, Knockout Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes. Knockout Mice,Mice, Knock-out,Mouse, Knockout,Knock-out Mice,Knockout Mouse,Mice, Knock out
D018698 Glutamic Acid A non-essential amino acid naturally occurring in the L-form. Glutamic acid is the most common excitatory neurotransmitter in the CENTRAL NERVOUS SYSTEM. Aluminum L-Glutamate,Glutamate,Potassium Glutamate,D-Glutamate,Glutamic Acid, (D)-Isomer,L-Glutamate,L-Glutamic Acid,Aluminum L Glutamate,D Glutamate,Glutamate, Potassium,L Glutamate,L Glutamic Acid,L-Glutamate, Aluminum

Related Publications

Hongqian Yang, and Jonathan D Lowenson, and Steven Clarke, and Roman A Zubarev
January 2023, Vitamins and hormones,
Hongqian Yang, and Jonathan D Lowenson, and Steven Clarke, and Roman A Zubarev
February 1999, Seikagaku. The Journal of Japanese Biochemical Society,
Hongqian Yang, and Jonathan D Lowenson, and Steven Clarke, and Roman A Zubarev
August 2002, Journal of neuroscience research,
Hongqian Yang, and Jonathan D Lowenson, and Steven Clarke, and Roman A Zubarev
November 2020, The Biochemical journal,
Hongqian Yang, and Jonathan D Lowenson, and Steven Clarke, and Roman A Zubarev
August 2002, Journal of neuroscience research,
Hongqian Yang, and Jonathan D Lowenson, and Steven Clarke, and Roman A Zubarev
June 2010, Chemistry & biodiversity,
Hongqian Yang, and Jonathan D Lowenson, and Steven Clarke, and Roman A Zubarev
July 2021, Scientific reports,
Hongqian Yang, and Jonathan D Lowenson, and Steven Clarke, and Roman A Zubarev
June 2025, Biochemistry,
Hongqian Yang, and Jonathan D Lowenson, and Steven Clarke, and Roman A Zubarev
June 1995, Protein expression and purification,
Hongqian Yang, and Jonathan D Lowenson, and Steven Clarke, and Roman A Zubarev
January 2017, Frontiers in microbiology,
Copied contents to your clipboard!