Olefin oxygenation and N-dealkylation by dopamine .beta.-monooxygenase: catalysis and mechanism-based inhibition

Padgette, Stephen R.; Wimalasena, Kandatege; Herman, Heath H.; Sirimanne, Sarath R.; May, Sheldon W.

doi:10.1021/bi00342a021

Cited by 61 publications

(68 citation statements)

References 43 publications

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“…We previously reported that 3Ј-and 4Ј-OHAPP derivatives are not taken into resealed chromaffin granule ghosts at a detectable rate (Padgette et al, 1985;Perera et al, 2003). However, as 4Ј-halo APP derivatives are significantly more hydrophobic and are freely taken up by SH-SY5Y and other cells; we expected that these derivatives may also be taken up into chromaffin granule ghosts through simple diffusion.…”

Section: Resultsmentioning

confidence: 94%

“…In addition, data in Table 1 show that 4Ј-halogen substitution increases the VMAT inhibition potency from -F to -I, parallel to their overall hydrophobicities. Previous studies have shown that APP derivatives possess potent irreversible inhibition properties toward MAO (McDonald et al, 1985) and D␤M (Padgette et al, 1985). The structural similarities, gradually increasing VMAT inhibition potencies and hydrophobicities within the series of 4Ј-halogen substitutes APP derivatives make them a unique series of probes that can be used to examine the effects of the perturbation of DA metabolism in catecholaminergic neurons.…”

Section: Resultsmentioning

confidence: 99%

“…Among APP derivatives tested, 4Ј-OH, 3Ј-OH, and 4Ј-halo derivatives are the most potent (Perera et al, 2003). Previous studies have shown that APP derivatives are also potent turnover-dependent, irreversible inhibitors for D␤M (May et al, 1983;Padgette et al, 1985) and MAO (McDonald et al, 1985). Thus, the specific toxicity of 4Ј-halo derivatives to SH-SY5Y cells could be associated with a combination of factors that are not present in non-neuronal cells, including efficient and nonspecific passage into cells and storage vesicles, reversible inhibition of VMAT and/or irreversible inhibition of D␤M and MAO leading to perturbation of catecholamine metabolism.…”

Section: Discussionmentioning

confidence: 96%

“…Synthesis and characterization of all APP derivatives have been previously reported (Padgette et al, 1985;Perera et al, 2003). MPP ϩ I was synthesized as described by Das et al (1993).…”

Section: Methodsmentioning

confidence: 99%

“…We have recently characterized a series of 3-amino-2-phenylpropene (APP) derivatives as novel reversible inhibitors for the bovine adrenal chromaffin granule VMAT (Perera et al, 2003), which have been previously characterized as irreversible D␤M (May et al, 1983;Padgette et al, 1985) and MAO (McDonald et al, 1985) inhibitors. We have reported that VMAT inhibition potencies of 4Ј-halogenated APP derivatives were dependent on the 4Ј-substituent and increased in the order 4Ј-F Ͻ 4Ј-Cl Ͻ 4Ј-Br Ͻ 4Ј-I.…”

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confidence: 99%

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Perturbation of Dopamine Metabolism by 3-Amino-2-(4′-halophenyl)propenes Leads to Increased Oxidative Stress and Apoptotic SH-SY5Y Cell Death

Samms¹,

Perera²,

Wimalasena³

et al. 2007

Mol Pharmacol

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We have recently characterized a series of 3-amino-2-phenylpropene (APP) derivatives as reversible inhibitors for the bovine adrenal chromaffin granule vesicular monoamine transporter (VMAT) that have been previously characterized as potent irreversible dopamine-␤-monooxygenase (D␤M) and monoamine oxidase (MAO) inhibitors. Halogen substitution on the 4Ј-position of the aromatic ring gradually increases VMAT inhibition potency from 4Ј-F to 4Ј-I, parallel to the hydrophobicity of the halogen. We show that these derivatives are taken up into both neuronal and non-neuronal cells, and into resealed chromaffin granule ghosts efficiently through passive diffusion. Uptake rates increased according to the hydrophobicity of the 4Ј-substituent. More importantly, these derivatives are highly toxic to human neuroblastoma SH-SY5Y but not toxic to M-1, Hep G2, or human embryonic kidney 293 non-neuronal cells at similar concentrations. They drastically perturb dopamine (DA) uptake and metabolism in SH-SY5Y cells under sublethal conditions and are able to deplete both vesicular and cytosolic catecholamines in a manner similar to that of amphetamines. In addition, 4Ј-IAPP treatment significantly increases intracellular reactive oxygen species (ROS) and decreases glutathione (GSH) levels in SH-SY5Y cells, and cell death is significantly attenuated by the common antioxidants ␣-tocopherol, N-acetyl-L-cysteine and GSH, but not by the nonspecific caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone. DNA fragmentation analysis further supports that cell death is probably due to a caspase-independent ROSmediated apoptotic pathway. Based on these and other findings, we propose that drastic perturbation of DA metabolism in SH-SY5Y cells by 4Ј-halo APP derivatives causes increased oxidative stress, leading to apoptotic cell death.Oxidative stress in the central and peripheral nervous systems plays a significant role in neurodegenerative disorders, aging, and the toxicity of a large number of neurotoxins (Cadet and Brannock, 1998;Halliwell, 2006). Auto-oxidizable catecholamines dopamine (DA), NE, and E and their metabolites are known to generate H 2 O 2 , reactive oxygen species (ROS), and organic radicals under aerobic conditions because of their intrinsic redox properties (Hald and Lotharius, 2005;Ogawa et al., 2005). Therefore, catecholaminergic neurons are inherently subjected to higher oxidative stress and more free radical damage than other types of neurons (Graham, 1978;Adams et al., 2001). Although most reactive radical species are effectively scavenged by enzymatic defense mechanisms and cellular antioxidants in vivo, excessive generation may lead to extensive cellular damage (Fridovich, 1986;Frei et al., 1989).Numerous studies indicate that efficient uptake, biosynthetic conversion, and storage of catecholamines in vesicles are mandatory for proper functioning of catecholaminergic neurons. The vital proteins responsible, including vesicular H ϩ -ATPase (V-H ϩ -ATPase), cytochrome b 561 (b 561 ), dopamine-␤...

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

“…Synthesis and characterization of all APP derivatives have been previously reported (Padgette et al, 1985;Perera et al, 2003). MPP ϩ I was synthesized as described by Das et al (1993).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Perturbation of Dopamine Metabolism by 3-Amino-2-(4′-halophenyl)propenes Leads to Increased Oxidative Stress and Apoptotic SH-SY5Y Cell Death

Samms¹,

Perera²,

Wimalasena³

et al. 2007

Mol Pharmacol

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Oxygenation and Oxygenases

May¹

2002

Encyclopedia of Catalysis

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Biological oxygenation reactions in which molecular oxygen is incorporated directly into organic subsrates are catalyzed by the enzymes known as oxygenases. These enzymes, first discovered in 1955, have since been found to be very widely distributed in nature. In dioxygenase‐catalyzed reactions, both atoms of the oxygen molecule are incorporated into the organic substrate, whereas monooxygenases incorporate only one of these oxygen atoms into the substrate. Currently, over 200 oxygenases enzymes are known, and these enzymes are all classified in EC groups 1.13 and 1.14. Among the reactions catalyzed by oxygenases are hydroxylations of methane and other alkanes, aromatics, flavonoids, menthol, and cholesterol; oxygenation of olefins, sulfur, and other heteroatoms; oxygenative cleavage of aromatic rings; and oxygenative decarboxylations. Oxygenases also catalyze the first step in the biosynthesis of prostaglandins; key steps in the biosynthesis and interconversion of antibiotics; and important bioremediation reactions critical to maintenance of the environment. A number of biotechnological applications for oxygenases have been emerging in recent years, and progress is also being made in the development of nonenzymatic model systems that might mimic the functional or structural properties of oxygenase enzymes.

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