Adrenaline and Noradrenaline: Partners and Actors in the Same Play"

Costa, Vera Marisa; Carvalho, Félix; Bastos, Maria Lourdes; Carvalho, Rui A.; Carvalho, Márcia; Remião, Fernando

doi:10.5772/36070

Cited by 2 publications

(3 citation statements)

References 226 publications

(318 reference statements)

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“…The main role of norepinephrine is to orchestrate the response of the body to stress, culminating in increased heart rate and blood pressure, as well as enhanced energy metabolization and neural reflexes . Human PNMT (hPNMT) is predominantly expressed in the adrenal gland where the role of epinephrine is recognized as a hormone . In addition, hPNMT can be found in several other organs including the heart and retina, as well as in the brain where epinephrine produced by hPNMT constitutes 5–10% of the catecolamine content. − The role of epinephrine in the human central nervous system (CNS) has yet to be fully established; however, it has been implicated in processes including cardiovascular homeostasis, adrenergic receptor activation, learning and memory, and regulation of the circadian cycle .…”

Section: Introductionmentioning

confidence: 99%

“…Human PNMT (hPNMT) is predominantly expressed in the adrenal gland where the role of epinephrine is recognized as a hormone . In addition, hPNMT can be found in several other organs including the heart and retina, as well as in the brain where epinephrine produced by hPNMT constitutes 5–10% of the catecolamine content. − The role of epinephrine in the human central nervous system (CNS) has yet to be fully established; however, it has been implicated in processes including cardiovascular homeostasis, adrenergic receptor activation, learning and memory, and regulation of the circadian cycle . Studies suggest that hPNMT may also play a role in human disease states including hypertension, myocardial infarction, Alzheimer’s, and Parkinson’s diseases. , Therefore, inhibitors of PNMT could provide tools to regulate the levels of epinephrine in the CNS and thus offer insight into the functional roles of epinephrine-forming neurons.…”

Section: Introductionmentioning

confidence: 99%

“…3−5 The role of epinephrine in the human central nervous system (CNS) has yet to be fully established; however, it has been implicated in processes including cardiovascular homeostasis, adrenergic receptor activation, learning and memory, and regulation of the circadian cycle. 2 Studies suggest that hPNMT may also play a role in human disease states including hypertension, 6 myocardial infarction, 7 Alzheimer's, 8 and Parkinson's diseases. 9,10 Therefore, inhibitors of PNMT could provide tools to regulate the levels of epinephrine in the CNS and thus offer insight into the functional roles of epinephrine-forming neurons.…”

Section: ■ Introductionmentioning

confidence: 99%

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Transition-State Analogues of Phenylethanolamine N-Methyltransferase

2020

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Phenylethanolamine N-methyltransferase (PNMT) is a critical enzyme in catecholamine synthesis. It transfers the methyl group of S-adenosylmethionine (SAM) to catalyze the synthesis of epinephrine from norepinephrine. Epinephrine has been associated with diverse human processes, including the regulation of blood pressure and respiration, as well as neurodegeneration found in Alzheimer’s disease. Human PNMT (hPNMT) proceeds through an SN2 transition state (TS) in which the transfer of the methyl group is rate limiting. TS analogue enzyme inhibitors are specific for their target and bind orders of magnitude more tightly than their substrates. Molecules resembling the TS of hPNMT were designed, synthesized, and kinetically characterized. This new inhibitory scaffold was designed to mimic the geometry and electronic properties of the hPNMT TS. Synthetic efforts resulted in a tight-binding inhibitor with a K i value of 12.0 nM. This is among the first of the TS analogue inhibitors of methyltransferase enzymes to show an affinity in the nanomolar range. Isothermal titration calorimetry (ITC) measurements indicated negative cooperative binding of inhibitor to the dimeric protein, driven by favorable entropic contributions. Structural analysis revealed that inhibitor 3 binds to hPNMT by filling the catalytic binding pockets for the cofactor (SAM) and the substrate (norepinephrine) binding sites.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Transition-State Analogues of Phenylethanolamine N-Methyltransferase

2020

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The Heart As a Target for Xenobiotic Toxicity: The Cardiac Susceptibility to Oxidative Stress

Costa

Carvalho

Duarte

et al. 2013

Chem. Res. Toxicol.

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The heart is a target organ for oxidative stress-related injuries. Because of its very high energetic metabolic demand, the heart has the highest rate of production of reactive oxygen species, namely, hydrogen peroxide (H2O2), per gram of tissue. Additionally, the heart has lower levels of antioxidants and total activity of antioxidant enzymes when compared to other organs. Furthermore, drugs that have relevant antioxidant activity and that are used in the treatment of oxidative stress related cardiac diseases demonstrate better clinical cardiac outcomes than other drugs with similar receptor affinity but with no antioxidant activity. Several xenobiotics particularly target the heart and promote toxicity. Anticancer drugs, like anthracyclines, cyclophosphamide, mitoxantrone, and more recently tyrosine kinase targeting drugs, are well-known cardiac toxicants whose therapeutic application has been associated to a high prevalence of heart failure. High levels of catecholamines or drugs of abuse, namely, amphetamines, cocaine, and even the consumption of alcohol for long periods of time, are linked to cardiovascular abnormalities. Oxidative stress may be one common link for the cardiac toxicity elicited by these compounds. We aim to revise the mechanisms involved in cardiac lesions caused by the above-mentioned substances specially focusing in oxidative stress related pathways. Oxidative stress biomarkers can be useful in the early recognition of cardiotoxicity in patients treated with these drugs and aid to minimize the setting of cardiac irreversible events.

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Adrenaline and Noradrenaline: Partners and Actors in the Same Play"

Cited by 2 publications

References 226 publications

Transition-State Analogues of Phenylethanolamine N-Methyltransferase

Transition-State Analogues of Phenylethanolamine N-Methyltransferase

The Heart As a Target for Xenobiotic Toxicity: The Cardiac Susceptibility to Oxidative Stress

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