Enzymatic Oxidation of Dopamine: The Role of Prostaglandin H Synthase

Abstract

An enzyme responsible for the oxidation of dopamine and formation of neuromelanin in brain has not been identified. Prostaglandin H synthase is prominent in brain and possesses peroxidase activity that may cooxidize dopamine to reactive dopamine quinones. This study examined the ability of purified prostaglandin H synthase to catalyze the oxidation of dopamine in vitro. Dopamine oxidation was determined by monitoring the formation of aminochrome and by examining catechol‐modified residues on protein present in the reaction mixture. Aminochrome was formed from dopamine in the presence of prostaglandin H synthase, and the reaction rate was dependent on the concentration of substrate and enzyme in the reaction mixture. Both arachidonic acid and hydrogen peroxide could serve as substrates for the prostaglandin H synthase‐catalyzed oxidation of dopamine. Indomethacin blocked the reaction when arachidonic acid was used as a substrate, but not when hydrogen peroxide was used. Enzymatically oxidized dopamine covalently bound to protein, as indicated by the presence of cysteinyl‐dopamine residues. Binding was significantly reduced in the absence of enzyme or in the presence of antioxidants. These results suggest that the peroxidase activity of prostaglandin H synthase is responsible for catalyzing the oxidation of dopamine to reactive dopamine quinones. It is possible that prostaglandin H synthase is responsible for the oxidation of dopamine and formation of neuromelanin in vivo, which may have implications for the development of Parkinson's disease. Furthermore, drugs such as aspirin that modulate the activity of this enzyme may provide a potential therapeutic approach for the prevention of Parkinson's disease.

Protective Role of Kv7 Channels in Oxygen and Glucose Deprivation-Induced Damage in Rat Caudate Brain Slices

“…Aberrant dopamine levels can induce damage through the formation of oxidative metabolites, derived from both spontaneous and enzyme-mediated dopamine oxidation. 24,25 In addition, receptor-mediated mechanisms have been proposed to explain dopamine-induced neurotoxicity and the possible neuroprotective effects of dopamine D1 and D2 receptor antagonists have been investigated in several studies. 26 In our TTC staining experiments, both SCH23390 (D1 receptor antagonist) and metoclopramide (D2 receptor antagonist) failed to reduce OGD-induced damage and did not revert the enhanced toxicity caused by linopirdine, suggesting that, in our model, brain damage occurred in a dopamine receptor-independent manner.…”

Reactive oxygen species generation by the ethylene-bis-dithiocarbamate (EBDC) fungicide mancozeb and its contribution to neuronal toxicity in mesencephalic cells

“…Although PD is not associated with GABAergic neurodegeneration until much latter stages of disease progression, other neurodegenerative conditions like Huntington's disease, an inherited neurodegenerative disorder, are demarcated by the loss of GABAergic neurons in the striatum (Fix, 2005). The DAergic neuronal cell population has been hypothesized to be vulnerable to oxidative stress because of the auto-oxidation of DA itself (Hastings, 1995). Mesencephalic GABAergic neurons are not at risk of such intrinsic oxidative stress, but are equally as vulnerable as DA neurons to an exogenous oxidative stress such as H 2 O 2 exposure .…”

“…That is, DA is metabolized to 3,4-dihydroxyphenyl acetic acid via monamine oxidase, producing H 2 O 2 (Halliwell, 1992). In addition, the oxidation of dopamine produces dopamine quinones, reactive species that can cause damage to lipids, proteins, and DNA (Hastings, 1995). Mn-EBDCs, like MB and MZ, can catalyze the oxidation of catechols (Fitsanakis et al, 2002).…”

“…The substantia nigra (SN) region of the brain is vulnerable to oxidative stress because of its local environment. The auto-oxidation of dopamine (Hastings, 1995), the enzymatic deamination of DA by monoamine oxidases (Halliwell, 1992), and the high iron content which catalyzes Fenton reactions (Dexter et al, 1989) make the SN vulnerable to oxidative stress and cellular injury. Pesticide exposure in experimental rodent and cell culture models has been linked to ROS generation and/or an inflammatory response that potentiates ROS production.…”

Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration

“…Aside from production of extracellular prostanoids, COX-2 can also damage intracellular protein-bound sulfhydryl groups through the oxidation of catechols such as dopamine (19). To investigate whether such a mechanism is in play here, we quantified ventral midbrain content of protein 5-cysteinyl-dopamine, a stable modification engendered by the COX-related oxidation of dopamine (19). In saline-injected mice, baseline levels of protein 5-cysteinyl-dopamine were slightly lower in mice treated than those not treated with rofecoxib (Fig.…”