Topaquinone Biogenesis in Cu Amine Oxidases

Abstract

Copper‐containing amine and lysyl oxidase (LOX) enzymes are responsible for catalyzing the oxidative deamination of biogenic primary amines or lysine residues in connective tissue precursor proteins. These two enzyme classes each undergo remarkable posttranslational, self‐processing reactions that are dependent solely on copper and molecular oxygen. The formation of the mature enzymes involves oxidation of an absolutely conserved tyrosine residue within the polypeptide sequence of the protein and results in formation of a quinone species. The autocatalytic process generates trihydroxyphenylalanine quinone (TPQ) in copper‐containing amine oxidases (CuAO) and lysyl tyrosine quinone (LTQ) in LOXs. The discovery of TPQ was the first of its kind and helped establish a new paradigm in biology for the modification and synthesis of amino acid derivatives that in turn exhibit unique chemical functionality. For copper‐containing amine and LOX enzymes, the quinone cofactors themselves are responsible for the coordination of amine substrates in Schiff base complexes, which then can be hydrolyzed to yield aldehyde product and a reduced aminoquinol that must then be reoxidized to afford the resting state of the enzyme. In terms of the biogenesis mechanisms, the tyrosine residue that undergoes oxidation is bound in close proximity to a type II copper center. Initial steps in TPQ and LTQ biosynthesis are proposed to be identical, and one possibility invokes coordination of tyrosine to copper(II) to introduce some radical or charge‐transfer character into the ring that could increase susceptibility to attack by molecular oxygen to yield a copper(II)‐peroxoquinone species; this moiety is then converted into 3,4‐dihydroxyphenylalanine quinone or dopaquinone. At this stage, TPQ biogenesis proceeds through attack of solvent water or hydroxide to the O2 position of the ring, whereas LTQ biogenesis proceeds through attack of a conserved polypeptide‐derived lysine residue to the O2 position of the ring. This chapter summarizes the discoveries of TPQ and LTQ and the large repertoire of experimental work that has gone into understanding the biogenesis mechanisms for these two extraordinary biological cofactors.

Plant Copper Metalloenzymes As Prospects for New Metabolism Involving Aromatic Compounds

“…In order to regenerate TPQ, Cu(II) bound to reduced TPQ is in equilibrium with Cu(I) bound to the semiquinone version of TPQ. The superoxide attacks the semiquinone of the TPQ ring, and proton-coupled electron transfer results in the iminoquinone form of TPQ with release of hydrogen peroxide ( Dooley et al, 2017 ). Lastly, the release of ammonia in the presence of water re-oxidizes TPQ ( Mills et al, 2012 ).…”