Hydrazine and amphetamine binding to amine oxidases: old drugs with new prospects.
Tranylcypromine (TCP), an amphetamine, is a reversible inhibitor of copper-containing amine oxidases. We have solved the structure of the complex of TCP with the amine oxidase from E. coli (ECAO) and shown that only the (+)-enantiomer of TCP binds. Kinetic studies on 2-phenylethylamine and TCP binding to wild-type ECAO and mutational variants fully support the model in which binding of the protonated amine is the first step in the catalytic cycle. Hydrazines are irreversible inhibitors of copper-containing amine oxidases. Binding of hydrazines leads to an adduct ("Adduct 1") with a chromophore at 430 nm which converts at higher pH to another adduct ("Adduct 2") with a chromophore at 520 nm. We have determined the structures of Adduct 1 and 2 for 2-hydrazinopyridine reacted with ECAO. It has been found that Adduct 1 corresponds to the hydrazone and azo tautomers whilst Adduct 2 corresponds to the azo tautomer coordinated to the active site copper. The implications of these results in developing more specific drugs are discussed.
Knowles
P
P
Astbury Centre for Structural Biology, University of Leeds, Leeds, UK. knowles.shadwell@ntlworld.com
Kurtis
C
C
Murray
J
J
Saysell
C
C
Tambyrajah
W
W
Wilmot
C
C
McPherson
M
M
Phillips
S
S
Dooley
D
D
Brown
D
D
Rogers
M
M
Mure
M
M
D006631:Amine Oxidase (Copper-Containing) / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D000662:Amphetamines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D020134:Catalytic Domain / Q000187:drug effects* / Q000502:physiology; D003300:Copper / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006834:Hydrazines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D007536:Isomerism; D008968:Molecular Conformation; D015394:Molecular Structure; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011728:Pyridones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014191:Tranylcypromine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
D000662:Amphetamines; D004791:Enzyme Inhibitors; D006834:Hydrazines; D008996:Monoamine Oxidase Inhibitors; D011728:Pyridones; D014191:Tranylcypromine; C062607:2-hydrazinopyridine; D003300:Copper; D006631:Amine Oxidase (Copper-Containing)