A series of fumarate analogues has been used to explore the molecular mechanism of the activation of dopamine β-mono-oxygenase by fumarate. Mesaconic acid (MA) and trans-glutaconic acid (TGA) both activate the enzyme at low concentrations, similar to fumarate. However, unlike fumarate, TGA and MA interact effectively with the oxidized enzyme to inhibit it at concentrations of 1—5mM. Monoethylfumarate (EFum) does not activate the enzyme, but inhibits it. In contrast with TGA and MA, however, EFum inhibits the enzyme by interacting with the reduced form. The saturated dicarboxylic acid analogues, the geometric isomer and the diamide of fumaric acid do not either activate or inhibit the enzyme. The phenylethylamine—fumarate conjugate, N-(2-phenylethyl)fumaramide (PEA-Fum), is an 600-fold more potent inhibitor than EFum and behaves as a bi-substrate inhibitor for the reduced enzyme. The amide of PEA-Fum behaves similarly, but with an inhibition potency 20-fold less than that of PEA-Fum. The phenylethylamine conjugates of saturated or geometric isomers of fumarate do not inhibit the enzyme. Based on these findings and on steady-state kinetic analysis, an electrostatic model involving an interaction between the amine group of the enzyme-bound substrate and a carboxylate group of fumarate is proposed to account for enzyme activation by fumarate. Furthermore, in light of the recently proposed model for the similar copper enzyme, peptidylglycine α-hydroxylating mono-oxygenase, the above electrostatic model suggests that fumarate may also play a role in efficient electron transfer between the active-site copper centres of dopamine β-mono-oxygenase.
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October 2002
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October 01 2002
Plausible molecular mechanism for activation by fumarate and electron transfer of the dopamine β-mono-oxygenase reaction Available to Purchase
D. Shyamali WIMALASENA;
D. Shyamali WIMALASENA
Department of Chemistry, Wichita State University, Wichita, KS 67260-0051, U.S.A.
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Samantha P. JAYATILLAKE;
Samantha P. JAYATILLAKE
Department of Chemistry, Wichita State University, Wichita, KS 67260-0051, U.S.A.
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Donovan C. HAINES;
Donovan C. HAINES
1
Department of Chemistry, Wichita State University, Wichita, KS 67260-0051, U.S.A.
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Kandatege WIMALASENA
Kandatege WIMALASENA
2
Department of Chemistry, Wichita State University, Wichita, KS 67260-0051, U.S.A.
2To whom correspondence should be addressed (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
February 04 2002
Revision Received:
May 29 2002
Accepted:
May 31 2002
Accepted Manuscript online:
May 31 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 367 (1): 77–85.
Article history
Received:
February 04 2002
Revision Received:
May 29 2002
Accepted:
May 31 2002
Accepted Manuscript online:
May 31 2002
Citation
D. Shyamali WIMALASENA, Samantha P. JAYATILLAKE, Donovan C. HAINES, Kandatege WIMALASENA; Plausible molecular mechanism for activation by fumarate and electron transfer of the dopamine β-mono-oxygenase reaction. Biochem J 1 October 2002; 367 (1): 77–85. doi: https://doi.org/10.1042/bj20020216
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