Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.3.1 (citrate synthase)
 4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Defects in complex I and alpha-ketoglutarate dehydrogenase (alpha-KGDH) occur in the substantia nigra in Parkinson's disease (PD). Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) are implicated in the cause of PD as endogenous toxins and are inhibitors of complex I. However, their effects on alpha-KGDH and other mitochondrial non-respiratory chain enzymes are unknown. We have examined the effects of six isoquinoline derivatives (isoquinoline, N-methylisoquinolinium, N-n-propylisoquinolinium, 1,2,3,4-tetrahydroisoquinoline, N-methyl-1,2,3,4-tetrahydroisoquinoline and salsolinol) and MPP+ on the activities of alpha-KGDH, citrate synthase (CS) and glutamate dehydrogenase (GDH) in mitochondrial fragments from rat forebrain. None of the compounds examined had any effect on CS or GDH activity. In contrast, all isoquinoline derivatives investigated and MPP+ inhibited alpha-KGDH activity in a concentration-dependent manner with IC50s ranging from 2.0 to 18.9 mM. MPP+ was previously shown to inhibit alpha-KGDH, but this is the first report of inhibition of alpha-KGDH by isoquinoline derivatives. These findings may represent an additional mechanism contributing to mitochondrial dysfunction and cell death in Parkinson's disease.
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PMID:Inhibition of alpha-ketoglutarate dehydrogenase by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 766 87

Berberine (BBR), a natural isoquinoline alkaloid, has been shown to be a promising therapeutic agent for colorectal cancer (CRC), but the molecular mechanism remains unclear. Here, we used mass spectrometry-based label-free proteomics to explore the potential targets of BBR in CRC cells. Comprehensive proteomic profiles demonstrated that of 8051 identified proteins, 503 and 277 differentially expressed proteins (DEPs) were screened out of CACO2 and LOVO cells, respectively. 83 DEPs were overlapped and most of these were down-regulated. A pathway enrichment analysis pinpointed mitochondrial translation, respiratory electron transport and the citric acid (TCA) cycle as biological effectors. The data of proteomics was subsequently confirmed by citrate synthase (CS), Tu translation elongation factor (TUFM), pentatricopeptide repeat domain 3 (PTCD3) and mitochondrial ribosomal protein L48 (MRPL 48) protein measurement. CS protein expression in CRC cells and tissues was higher than it was in normal specimens. Additionally, forcible downregulation of CS led to remarkable cell proliferation inhibition. Taken together, we concluded that the anticancer effects of BBR are attributable to mitochondrial protein synthesis, TCA and respiratory electron transport inhibition and that CS might be a useful therapeutic target in CRC treatment.
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PMID:Comparative pharmacoproteomics reveals potential targets for berberine, a promising therapy for colorectal cancer. 3208 71