Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P80404 (GABA transaminase)
 786 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carefully balanced deoxynucleoside triphosphate (dNTP) pools are essential for both nuclear and mitochondrial genome replication and repair. Two synthetic pathways operate in cells to produce dNTPs, e.g., the de novo and the salvage pathways. The key regulatory enzymes for de novo synthesis are ribonucleotide reductase (RNR) and thymidylate synthase (TS), and this process is considered to be cytosolic. The salvage pathway operates both in the cytosol (TK1 and dCK) and the mitochondria (TK2 and dGK). Mitochondrial dNTP pools are separated from the cytosolic ones owing to the double membrane structure of the mitochondria, and are formed by the salvage enzymes TK2 and dGK together with NMPKs and NDPK in postmitotic tissues, while in proliferating cells the mitochondrial dNTPs are mainly imported from the cytosol produced by the cytosolic pathways. Imbalanced mitochondrial dNTP pools lead to mtDNA depletion and/or deletions resulting in serious mitochondrial diseases. The mtDNA depletion syndrome is caused by deficiencies not only in enzymes in dNTP synthesis (TK2, dGK, p53R2, and TP) and mtDNA replication (mtDNA polymerase and twinkle helicase), but also in enzymes in other metabolic pathways such as SUCLA2 and SUCLG1, ABAT and MPV17. Basic questions are why defects in these enzymes affect dNTP synthesis and how important is mitochondrial nucleotide synthesis in the whole cell/organism perspective? This review will focus on recent studies on purine and pyrimidine metabolism, which have revealed several important links that connect mitochondrial nucleotide metabolism with amino acids, glucose, and fatty acid metabolism.
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PMID:Mitochondrial purine and pyrimidine metabolism and beyond. 2790 31

The maintenance of mitochondrial DNA (mtDNA) depends on a number of nuclear gene-encoded proteins including a battery of enzymes forming the replisome needed to synthesize mtDNA. These enzymes need to be in balanced quantities to function properly that is in part achieved by exchanging intramitochondrial contents through mitochondrial fusion. In addition, mtDNA synthesis requires a balanced supply of nucleotides that is achieved by nucleotide recycling inside the mitochondria and import from the cytosol. Mitochondrial DNA maintenance defects (MDMDs) are a group of diseases caused by pathogenic variants in the nuclear genes involved in mtDNA maintenance resulting in impaired mtDNA synthesis leading to quantitative (mtDNA depletion) and qualitative (multiple mtDNA deletions) defects in mtDNA. Defective mtDNA leads to organ dysfunction due to insufficient mtDNA-encoded protein synthesis, resulting in an inadequate energy production to meet the needs of affected organs. MDMDs are inherited as autosomal recessive or dominant traits, and are associated with a broad phenotypic spectrum ranging from mild adult-onset ophthalmoplegia to severe infantile fatal hepatic failure. To date, pathogenic variants in 20 nuclear genes known to be crucial for mtDNA maintenance have been linked to MDMDs, including genes encoding enzymes of mtDNA replication machinery (POLG, POLG2, TWNK, TFAM, RNASEH1, MGME1, and DNA2), genes encoding proteins that function in maintaining a balanced mitochondrial nucleotide pool (TK2, DGUOK, SUCLG1, SUCLA2, ABAT, RRM2B, TYMP, SLC25A4, AGK, and MPV17), and genes encoding proteins involved in mitochondrial fusion (OPA1, MFN2, and FBXL4).
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PMID:Mitochondrial DNA maintenance defects. 2821 79

Renal cell carcinoma (RCC) is a common form of cancer of the urinary tract. The present study aimed to identify driver genes in RCC using a bioinformatics approach. GSE53757 and GSE40435 microarray data were analyzed, and differentially expressed genes were filtered prior to gene ontology (GO) and pathway analysis. A protein-protein interaction (PPI) network was established. Overall survival and recurrence were investigated and based on data presented in cBioPortal. The COPS7B gene within the PPI network was selected for further study in vitro. The present study identified 174 and 149 genes possessing a significant signal to noise ratio in GSE53757 and GSE40435, respectively. In total, 53 of these genes were selected based upon inclusion in both datasets. GO analysis indicated that PRKCDBP, EHD2, KCNJ10, ATP1A1, KCNJ1 and EHD2 may be involved in various biological processes. Furthermore, ALDH6A1, LDHA, SUCLG1 and ABAT may be involved in the propanoate metabolism pathway. A network consisting of 106 genes, and one typical cluster were constructed. In addition, COPS7B was selected, as it was associated with decreased overall survival and increased recurrence rates, in order to elucidate its function in RCC. Furthermore, upregulation of COPS7B was demonstrated to be predictive of advanced stage disease and metastasis of RCC. Finally, COPS7B-knockdown inhibited RCC cell proliferation and invasion ability. Collectively, these results provided novel insights into COPS7B function, indicating that COPS7B may serve as a prognostic marker and therapeutic target in RCC.
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PMID:Novel insights into biomarkers associated with renal cell carcinoma. 2992 89