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Establishing an Artificial Pathway for the Biosynthesis of Octopamine and Synephrine.

ACS Synth Biol

June 2024

State Key Laboratory of Materials-Oriented Chemical Engineering, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, People's Republic of China.

Article Synopsis
  • The study developed an artificial pathway using two enzymes, tyramine β-hydroxylase (TBH) and phenylethanolamine-N-methyltransferase (PNMT), to produce the compounds octopamine and synephrine.
  • The research successfully expressed a functional TBH enzyme and optimized its activity, allowing for the initial conversion of tyramine into octopamine, followed by the production of synephrine from octopamine through effective PNMT expression and reaction conditions.
  • Ultimately, the researchers constructed a one-pot cascade reaction combining both enzymes, achieving notable yields of octopamine and synephrine, marking a significant advancement in their biosynthesis.
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Substrate specificity is critically important for enzyme catalysis. In the adrenaline-synthesizing enzyme PNMT (phenylethanolamine N-methyltransferase), minor changes in substituents can convert substrates into inhibitors. Here we report the crystal structures of six human PNMT complexes, including the first structure of the enzyme in complex with its physiological ligand R-noradrenaline.

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Mode of binding of methyl acceptor substrates to the adrenaline-synthesizing enzyme phenylethanolamine N-methyltransferase: implications for catalysis.

Biochemistry

December 2005

Institute for Molecular Bioscience and ARC Special Research Centre for Functional and Applied Genomics, University of Queensland, Brisbane, Queensland, 4072 Australia.

Here we report three crystal structure complexes of human phenylethanolamine N-methyltransferase (PNMT), one bound with a substrate that incorporates a flexible ethanolamine side chain (p-octopamine), a second bound with a semirigid analogue substrate [cis-(1R,2S)-2-amino-1-tetralol, cis-(1R,2S)-AT], and a third with trans-(1S,2S)-2-amino-1-tetralol [trans-(1S,2S)-AT] that acts as an inhibitor of PNMT rather than a substrate. A water-mediated interaction between the critical beta-hydroxyl of the flexible ethanolamine group of p-octopamine and an acidic residue, Asp267, is likely to play a key role in positioning the side chain correctly for methylation to occur at the amine. A second interaction with Glu219 may play a lesser role.

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Selective activation of beta3-adrenoceptors by octopamine: comparative studies in mammalian fat cells.

Naunyn Schmiedebergs Arch Pharmacol

April 1999

Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 317, Institut Fédératif de Recherches 31, CHU Rangueil, Toulouse, France.

Numerous synthetic agonists selectively stimulate beta3-adrenoceptors (ARs). The endogenous catecholamines, noradrenaline and adrenaline, however, stimulate all the beta-AR subtypes, and no selective physiological agonist for beta3-ARs has been described so far. The aim of this study was to investigate whether any naturally occurring amine can stimulate selectively beta3-ARs.

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Objective: An increased basal growth hormone (GH) secretion and a parodoxical GH response to the oral glucose tolerance test (OGTT) have been reported in patients with liver cirrhosis. It has been suggested that the ratio between branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) (BCAA/ AAA ratio) may determine in part the brain concentration of the AAAs, since the BCAAs compete with the AAAs for entry across the blood-brain barrier, leading to the accumulation of false neurotransmitters such as octopamine and phenylethanolamine, which are able to stimulate GH secretion (via alpha 2-adrenergic stimulation). In this study we investigated the role of amino acids, particularly the BCAA/AAA ratio, in the paradoxical response of GH to the OGTT in patients with liver cirrhosis.

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