Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04040 (Catalase)
 3,577 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aerial oxidation of dopamine at concentrations as low as 50 microM in the presence of ferrous ions in phosphate buffer (pH 7.4) led in the early stages (6-8 h) to the formation of the quinone of the neurotoxin 6-hydroxydopamine, 2, followed (24 h) by a complex product pattern comprising main components norepinephrine (5), 3, 4-dihydroxybenzaldehyde (4), and the neurotoxic alkaloid 6, 7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (3). Product formation required the assistance of metal ions such as Mn(II), Zn(II), and iron, in either the ferrous or ferric form. Product yields were shown to vary linearly with iron and dopamine concentration in the early phases of the reaction (2 h). Biologically relevant antioxidants, like glutathione and ascorbate, and metal chelators, e. g., 2,2'-bipyridyl, inhibited dopamine conversion to products 2-5, but not substrate consumption, while hydroxyl radical scavengers such as DMSO and mannitol did not alter the course of the reaction. On the contrary, mannitol increased product yields, an effect seen for other monosaccharides. Catalase exhibited a significant inhibitory effect particularly on the formation of 3 and 4. By using (18)O(2), evidence was obtained for incorporation of the label into the carbonyl oxygen of 4, but not into the hydroxyl group of 5. On the basis of these and other results, a complete mechanistic picture of the oxidation is drawn involving conversion of dopamine to the corresponding o-quinone and its quinonemethide tautomer with concomitant reduction of O(2) to H(2)O(2). Nucleophilic attack by H(2)O to the quinonemethide gives rise to 5, while H(2)O(2) addition leads to benzaldehyde 4 via a beta-aminohydroperoxide intermediate. This latter reaction path also gives formaldehyde which yields the isoquinoline 3 by Pictet-Spengler condensation with dopamine. The quinone 2 results from H(2)O(2) attack at the 6-position of dopamine o-quinone in agreement with previous studies. These results provide an insight into new routes of nonenzymatic conversion of dopamine to its metabolite norepinephrine and neurotoxic species which may become operative under conditions relevant to neurodegeneration.
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PMID:New reaction pathways of dopamine under oxidative stress conditions: nonenzymatic iron-assisted conversion to norepinephrine and the neurotoxins 6-hydroxydopamine and 6, 7-dihydroxytetrahydroisoquinoline. 1056 35

Tetrahydroisoquinoline (TIQ) derivatives are putative neurotoxins that may contribute to the degeneration of dopaminergic neurons in Parkinson's disease. One TIQ, norsalsolinol (NorSAL), is present in dopamine-rich areas of human brain, including the substantia nigra. Here, we demonstrate that NorSAL reduces cell viability and induces apoptosis via cytochrome c release and caspase 3 activation in SH-SY5Y human neuroblastoma cells. Cytochrome c release, caspase 3 activation, and apoptosis induction were all inhibited by the antioxidant N-acetylcysteine. Thus, reactive oxygen species (ROS) contribute to apoptosis induced by NorSAL. Treatment with NorSAL also increased levels of oxidative damage to DNA, a stimulus for apoptosis, in SH-SY5Y. To clarify the mechanism of intracellular DNA damage, we examined the DNA damage caused by NorSAL using (32)P-5'-end-labeled isolated DNA fragments. NorSAL induced DNA damage in the presence of Cu(II). Catalase and bathocuproine, a Cu(I) chelator, inhibited this DNA damage, suggesting that ROS such as the Cu(I)-hydroperoxo complex derived from the reaction of H(2)O(2) with Cu(I), promote DNA damage by NorSAL. In summary, NorSAL-generated ROS induced oxidative DNA damage, which led to caspase-dependent apoptosis in neuronal cells.
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PMID:The mechanisms of oxidative DNA damage and apoptosis induced by norsalsolinol, an endogenous tetrahydroisoquinoline derivative associated with Parkinson's disease. 1901 44