Medical implications from the crystal structure of a copper‐containing amine oxidase complexed with the antidepressant drug tranylcypromine

Abstract

The X-ray crystal structure of the copper-containing quinoprotein amine oxidase from E. coli has been determined in complex with the antidepressant drug tranylcypromine to 2.4 A resolution. The drug is a racemic mix of two enantiomers, but only one is seen bound to the enzyme. The other enantiomer is not acting as a substrate for the enzyme as no catalytic activity was detected when the enzyme was initially exposed to the drug. The inhibition of human copper amine oxidases could be a source of side-effects in its use as an antidepressant to inhibit the flavin-containing monoamine oxidases in the brain.

Complexes of the copper-containing amine oxidase fromArthrobacter globiformiswith the inhibitors benzylhydrazine and tranylcypromine

“…In the structure of the 2-hydrazinopyridine (2-HP) complex of ECAO, the TPQ cofactor is linked covalently to 2-HP via the 5-position of the quinone ring (Wilmot et al, 1997). A similar link is observed in the complex of TCP and ECAO (Wilmot et al, 2004). In this case, the TCP acts as a reversible inhibitor or nonhydrolysable substrate analogue.…”

The copper-containing amine oxidase fromArthrobacter globiformis: refinement at 1.55 and 2.20 Å resolution in two crystal forms

“…In the reductive half-reaction, the TPQ reacts with the amine substrate, releasing water and producing an intermediate substrate Schiff base. Several crystal structures of the molecule trapped in this state have been reported (O'Connell et al, 2004;Wilmot et al, 1997Wilmot et al, , 2004. A proton is abstracted, converting the substrate Schiff base to a product Schiff base.…”

Fluorinated phenylcyclopropylamines

“…A Schiff base might be produced reversibly with the cyclopropylamine that cannot undergo proton abstraction from the trans isomers. The formation of a Schiff base complex of tranylcypromine and E. coli amine oxidase has already been observed by X-ray analysis [24]. Indeed, tranylcypromine ( 1 ), like 3a , is also a competitive inhibitor.…”

“…A crystal structure of the adduct formed between 1 and CAO from E. coli (ECAO) shows that, although racemic 1 was used, only the (1 S ,2 R )-enantiomer was found in the active site (see Figure 6). Steric constraints thus permit only this enantiomer to fit into the active site and form a Schiff’s base with C(5) of TPQ [24]. In this arrangement the proton at the C α atom points away from the aspartate residue and therefore cannot be abstracted.…”