A dopaquinone model that mimics the water addition step of cofactor biogenesis in copper amine oxidases.
The consensus mechanism for biogenesis of the 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor in copper amine oxidases involves a key water addition to the dopaquinone intermediate. Although hydration of o-quinones seems straightforward and was implicated previously in aqueous autoxidation of catechols to give ultimately hydroxyquinones, a recent study (Mandal, S.; Lee, Y.; Purdy, M. M.; Sayre, L. M. J. Am. Chem. Soc. 2000, 122, 3574-3584) showed that the observed hydroxyquinones arise not from hydration, but from addition to the o-quinones of H(2)O(2) generated during autoxidation of the catechols. In the enzyme case, hydration of dopaquinone is proposed to be mediated by the active site Cu(II). To establish precedent for this mechanism, we engineered a catechol tethered to a Cu(II)-coordinating unit, such that the corresponding o-quinone could be generated in situ by oxidation with periodate (to avoid generation of H(2)O(2)). Thus, coordination of 4-((2-(bis(2-pyridylmethyl)amino)ethylamino)methyl)-1,2-benzenediol (1) to Cu(II) and subsequent addition of periodate resulted in rapid formation of the TPQ-like corresponding hydroxyquinone. Hydroxyquinone formation was seen also using Zn(II) and Ni(II), but not in the absence of M(II). Under the same conditions, periodate oxidation of the simple catechol 4-tert-butylcatechol does not give hydroxyquinone in the presence or absence of Cu(II). M(II)OH(2) pK(a) data for the Cu(II), Zn(II), and Ni(II) complexes with the pendant tetradentate ligand in the masked (dimethyl ether) catechol form, and kinetic pH-rate profiles of the metal-dependent hydroxyquinone formation from periodate oxidation of catechol 1, suggested a rate-limiting addition step of the ligand-coordinated M(II)OH to the o-quinone intermediate. This study represents the first chemical demonstration of a true o-quinone hydration, which occurs in cofactor biogenesis in copper amine oxidases.
Ling
Ke-Qing
KQ
Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
Sayre
Lawrence M
LM
D000586:Amination; D006631:Amine Oxidase (Copper-Containing) / Q000737:chemistry* / Q000378:metabolism; D016227:Benzoquinones / Q000737:chemistry* / Q000378:metabolism; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D002396:Catechols / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D003067:Coenzymes / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008024:Ligands; D008345:Manganese / Q000737:chemistry; D010084:Oxidation-Reduction; D010504:Periodic Acid / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D014867:Water / Q000737:chemistry / Q000378:metabolism
C086758:2,4,5-trihydroxyphenylalanine quinone; D016227:Benzoquinones; D002396:Catechols; D003067:Coenzymes; D008024:Ligands; D014867:Water; D010504:Periodic Acid; D008345:Manganese; D004295:Dihydroxyphenylalanine; C035157:dopaquinone; C009288:metaperiodate; D006631:Amine Oxidase (Copper-Containing)