Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P17174 (
aspartate aminotransferase
)
14,872
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
A significant problem faced by pharmaceutical companies today is the failure of lead compounds in the later stages of development due to unexpected toxicities. We have used two-dimensional differential in-gel electrophoresis and mass spectrometry to identify a proteomic signature associated with hepatocellular steatosis in rats after dosing with a compound in preclinical development. Liver toxicity was monitored over a 5 day dosing regime using blood biochemical parameter measurements and histopathological analysis. As early as 6 h postdosing, livers showed hepatocellular vacuolation, which increased in extent and severity over the course of the study. Alterations in plasma glucose, alanine aminotransferase, and
aspartate aminotransferase
were not detected until the third day of dosing and changed in magnitude up to the final day. The proteomic changes were observed at the earliest time point, and many of these could be associated with known toxicological mechanisms involved in liver steatosis. This included up-regulation of pyruvate dehydrogenase, phenylalanine hydroxylase, and 2-oxoisovalerate dehydrogenase, which are involved in acetyl-CoA production, and down-regulation of
sulfite oxidase
, which could play a role in triglyceride accumulation. In addition, down-regulation of the chaperone-like protein, glucose-regulated protein 78, was consistent with the decreased expression of the secretory proteins serum paraoxonase, serum albumin, and peroxiredoxin IV. The correlation of these protein changes with the clinical and histological data and their occurrence before the onset of the biochemical changes suggest that they could serve as predictive biomarkers of compounds with a propensity to induce liver steatosis.
...
PMID:A proteomic investigation of drug-induced steatosis in rat liver. 1514 17
Molybdenum cofactor deficiency and isolated
sulfite oxidase
deficiency are two rare genetic disorders that are caused by impairment of the mitochondrial enzyme
sulfite oxidase
. Sulfite oxidase is catalyzing the terminal reaction of cellular cysteine catabolism, the oxidation of sulfite to sulfate. Absence of
sulfite oxidase
leads to the accumulation of sulfite, which has been identified as a cellular toxin. However, the molecular pathways leading to the production of sulfite are still not completely understood. In order to identify novel treatment options for both disorders, the understanding of cellular cysteine catabolism - and its alterations upon loss of
sulfite oxidase
- is of utmost importance. Here we applied a new detection method of sulfite in cellular extracts to dissect the contribution of cytosolic and mitochondrial
glutamate oxaloacetate transaminase
(GOT) in the transformation of cysteine sulfinic acid to sulfite and pyruvate. We found that the cytosolic isoform GOT1 is primarily responsible for the production of sulfite. Moreover, loss of
sulfite oxidase
activity results in the accumulation of sulfite, H
2
S and persulfidated cysteine and glutathione, which is consistent with an increase of SQR protein levels. Surprisingly, none of the known H
2
S-producing pathways were found to be upregulated under conditions of sulfite toxicity suggesting an alternative route of sulfite-induced shift from oxidative to H
2
S dependent cysteine catabolism.
...
PMID:The role of glutamate oxaloacetate transaminases in sulfite biosynthesis and H
2
S metabolism. 3327 57
