Inhibition of six copper-containing amine oxidases by the antidepressant drug tranylcypromine.
Abstract: Potential inhibitory effects of the clinically utilized monoamine oxidase inhibitor tranylcypromine (TCP) on mammalian, plant, bacterial, and fungal copper-containing amine oxidases have been examined. The following enzymes have been investigated: human kidney diamine oxidase (HKAO), bovine plasma amine oxidase (BPAO), equine plasma amine oxidase (EPAO), pea seedling amine oxidase (PSAO), Arthrobacter globiformis amine oxidase (AGAO), and Pichia pastoris lysyl oxidase (PPLO). Only BPAO, EPAO, and AGAO were found to lose significant levels of activity when incubated with varying amounts of TCP. Inhibition of BPAO was completely reversible, with dialysis restoring full activity. TCP inhibition of AGAO was also found to be ultimately reversible; however, dialysis did not remove all bound compounds. Chemical displacement with either substrate or a substrate analogue successfully removed all bound TCP, indicating that this compound has a high affinity for the active site of AGAO. The notable lack of TCP inhibition on HKAO argues against the inhibition of diamine oxidase as a potential source for some of the deleterious side effects occurring in patients treated with this antidepressant. The marked differences observed in behavior among these enzymes speaks to the importance of intrinsic structural differences between the active sites of copper amine oxidases (CAO) which affect reactivity with a given inhibitor.
Publication Date: 2003-04-11 PubMed ID: 12686142DOI: 10.1016/s1570-9639(03)00062-1Google Scholar: Lookup
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- Journal Article
- Research Support
- U.S. Gov't
- P.H.S.
Summary
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This research paper focuses on analyzing the inhibitory effects of the therapeutic drug tranylcypromine on several copper-containing amine oxidases derived from various organisms.
Experimental Procedure
- The researchers tested the effects of the drug tranylcypromine (TCP) on a group of six different copper-containing amine oxidases. These enzymes originated from different sources including human, cow, horse, peas, bacteria (Arthrobacter globiformis), and fungi (Pichia pastoris).
- The study employed varying amounts of TCP to examine its inhibitory effect on these enzymes’ activities.
Key Findings
- Out of the six enzymes tested, only bovine plasma amine oxidase (BPAO), equine plasma amine oxidase (EPAO), and Arthrobacter globiformis amine oxidase (AGAO) showed any significant loss of activity due to TCP exposure.
- The inhibitory effects of TCP on BPAO were found to be reversible. Dialysis was able to restore the enzyme to full activity.
- TCP’s inhibitory effect on AGAO was also reversible, but not completely removed by dialysis. Instead, using a chemical displacement method with either the substrate or a substrate analogue fully removed the bound TCP, indicating a strong affinity of the compound for the enzyme’s active site.
- Interestingly, TCP showed no inhibitory effect on human kidney diamine oxidase (HKAO), debunking the theory that the inhibition of this particular enzyme contributes to the side effects seen in patients using this drug as an antidepressant.
Implications of the Study
- This study sheds light on the complex interactions between TCP and various types of copper amine oxidases (CAO), and highlights the significant influence of the intrinsic structural differences between different CAO active sites on their reactivity with this inhibitor.
- The finding that TCP does not inhibit HKAO may be important for understanding the exact mechanisms of action and side effects of this antidepressant drug, providing a possible direction for further research.
Cite This Article
APA
Shepard EM, Heggem H, Juda GA, Dooley DM.
(2003).
Inhibition of six copper-containing amine oxidases by the antidepressant drug tranylcypromine.
Biochim Biophys Acta, 1647(1-2), 252-259.
https://doi.org/10.1016/s1570-9639(03)00062-1 Publication
Researcher Affiliations
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA.
MeSH Terms
- Amine Oxidase (Copper-Containing) / antagonists & inhibitors
- Antidepressive Agents / pharmacology
- Benzylamines / pharmacology
- Enzyme Inhibitors / pharmacology
- Oxidation-Reduction
- Phenylhydrazines / pharmacology
- Spectrum Analysis
- Tranylcypromine / pharmacology
Grant Funding
- GM 27659 / NIGMS NIH HHS
Citations
This article has been cited 7 times.- Ramsay RR, Albreht A. Kinetics, mechanism, and inhibition of monoamine oxidase. J Neural Transm (Vienna) 2018 Nov;125(11):1659-1683.
- Ramsay RR, Tipton KF. Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs. Molecules 2017 Jul 15;22(7).
- Hruschka S, Yoshida S, Kirk KL, Haufe G. Fluorinated phenylcyclopropylamines. Part 6: Effects of electron withdrawing or donating aryl substituents on the inhibition of tyramine oxidase from Arthrobacter sp. by diastereomeric 2-aryl-2-fluoro-cyclopropylamines. J Fluor Chem 2008 Sep;129(9):875-880.
- Langley DB, Trambaiolo DM, Duff AP, Dooley DM, Freeman HC, Guss JM. Complexes of the copper-containing amine oxidase from Arthrobacter globiformis with the inhibitors benzylhydrazine and tranylcypromine. Acta Crystallogr Sect F Struct Biol Cryst Commun 2008 Jul 1;64(Pt 7):577-83.
- Shepard EM, Dooley DM. Intramolecular electron transfer rate between active-site copper and TPQ in Arthrobacter globiformis amine oxidase. J Biol Inorg Chem 2006 Nov;11(8):1039-48.
- Contakes SM, Juda GA, Langley DB, Halpern-Manners NW, Duff AP, Dunn AR, Gray HB, Dooley DM, Guss JM, Freeman HC. Reversible inhibition of copper amine oxidase activity by channel-blocking ruthenium(II) and rhenium(I) molecular wires. Proc Natl Acad Sci U S A 2005 Sep 20;102(38):13451-6.
- Song Y, Chang J, Yu B. Unravelling the target landscape of tranylcypromines for new drug discovery. Acta Pharm Sin B 2025 Jun;15(6):2985-3007.
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