The First Crystal Structure of Tyrosinase: All Questions Answered?

Decker, Heinz; Schweikardt, Thorsten; Tuczek, Felix

doi:10.1002/anie.200601255

Cited by 309 publications

(234 citation statements)

References 26 publications

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“…As expected 12,13 , the tyrosine hydroxyl group is directed towards ZnA (at the equivalent position of CuA) at a distance of 1.9 Å and its benzyl ring is oriented through hydrophobic p-p interactions with H208 (Fig. 1a).…”

Section: Resultssupporting

confidence: 60%

“…However, the flexibility of F261 is restricted owing to the thioether bond fixing one of the histidines 4 (which is flexible in bacterial tyrosinases 6,15 ), and therefore it cannot allow for any substrate rotation during the reaction. During the monophenolase reaction, a rotation of the tyrosine is suggested to occur, allowing the electrophilic attack that leads to hydroxylation 12,16 (Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

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Determination of tyrosinase substrate-binding modes reveals mechanistic differences between type-3 copper proteins

et al. 2014

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Tyrosinase is responsible for the two initial enzymatic steps in the conversion of tyrosine to melanin. Many tyrosinase mutations are the leading cause of albinism in humans, and it is a prominent biotechnology and pharmaceutical industry target. Here we present crystal structures that show that both monophenol hydroxylation and diphenol oxidation occur at the same site. It is suggested that concurrent presence of a phenylalanine above the active site and a restricting thioether bond on the histidine coordinating CuA prevent hydroxylation of monophenols by catechol oxidases. Furthermore, a conserved water molecule activated by E195 and N205 is proposed to mediate deprotonation of the monophenol at the active site. Overall, the structures reveal precise steps in the enzymatic catalytic cycle as well as differences between tyrosinases and other type-3 copper enzymes.

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Section: Resultssupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Determination of tyrosinase substrate-binding modes reveals mechanistic differences between type-3 copper proteins

et al. 2014

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“…The recent crystallographic determination of the structure of the dinuclear copper active centre of Streptomyces tyrosinase (Matoba et al 2006) permits the assignment of the likely orientation of substrate binding. The normal cresolase presentation of phenols assumes that the orientation of the phenyl ring in the enzymesubstrate complex is approximately orthogonal to the plane defined by the copper and oxygen atoms (Decker et al 2006), as proposed by Canters and co-workers (Van Gastel et al 2000;Bubacco et al 2003). This differs in orientation significantly from the assumed catecholase configuration in Scheme 1.…”

Section: Resultsmentioning

confidence: 94%

The Mechanism of Suicide-Inactivation of Tyrosinase: A Substrate Structure Investigation

Land

Ramsden

Riley

2007

Tohoku J. Exp. Med.

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. The Mechanism of Suicide-Inactivation of Tyrosinase: A Substrate Structure Investigation. Tohoku J. Exp. Med., 2007, 212 (4), [341][342][343][344][345][346][347][348] Tyrosinase is a copper-containing mono-oxygenase, widely distributed in nature, able to catalyze the oxidation of both phenols and catechols to the corresponding ortho-quinones. Tyrosinase is characterised by a hitherto unexplained irreversible inactivation which occurs during the oxidation of catechols. Although the corresponding catechols are formed during tyrosinase oxidation of monophenols, inactivation in the presence of monophenolic substrates is minimal. Previous studies have established the kinetic features of the inactivation reaction which is first-order in respect of the enzyme concentration. The inactivation reaction exhibits the same pH-profile and saturation properties as the oxidation reaction, classing the process as a mechanism-based suicide inactivation. The recent elucidation of the crystallographic structure of tyrosinase has stimulated a new approach to this long-standing enigma. Here we report the results of an investigation of the tyrosinase-catalysed oxidation of a range of hydroxybenzenes which establish the structural requirements associated with inactivation. We present evidence for an inactivation mechanism based on catechol hydroxylation, with loss of one of the copper atoms at the active site. The inactivation mechanism involves two linked processes occurring in situ: (a) catechol presentation resulting in α -oxidation, and (b) deprotonation of an adjacent group. On the basis of our experimental data we believe that a similar mechanism may account for the inhibitory action of resorcinols.tyrosinase; suicideinactivation; catecholase; cresolase; α -oxidation; deprotonation © 2007 Tohoku University Medical Press When catechols are oxidised by tyrosinase there is a consistent anomaly in the oxygen stoichiometry. This phenomenon is amplified as the enzyme concentration is reduced. At low enzyme concentration the reaction ceases before either the substrate or the oxygen are depleted and further substrate supplementation or re-oxygenation have no effect. However, further enzyme addition re-initiates the reaction and the extent of further oxidation is a linear function of the amount of enzyme added. The effect is not due to a nonspecific influence of protein addition and re-initiation of oxidation is not observed when heat-inactivated tyrosinase is added to the reaction mixture. It is clear, therefore, that, during the oxidation of the substrate, a process occurs that

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“…[1] The related catechol oxidases only catalyzet he second reaction, using o-diphenols as substrates. [2] Starting from tyrosine, the final product of the tyrosinasecatalyzed reaction is dopaquinone, which is ap recursor of melanin. [3,4] Melanins are pigments that are widespreadi no rganisms ranging from bacteria, fungi, plants,t om ammals.…”

Section: Introductionmentioning

confidence: 99%

“…[9] Studies of tyrosinases from lower organismsh ave been extensively reviewed elsewhere. [1,2,10,11] We have also generated models of TYR and TYRP2 in view of their high homology with TYRP1, based on whichw ed iscusst heir catalytic function/mechanism and analyze the molecular basis of OCA1-related mutations. Finally,w ed iscuss perspectivesf or antimelanogenic compound design.…”

Section: Introductionmentioning

confidence: 99%

Structure and Function of Human Tyrosinase and Tyrosinase‐Related Proteins

Lai

Wichers

Soler-López

et al. 2017

Chemistry A European J

182

198

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Melanin is the main pigment responsible for the color of human skin, hair and eye. Its biosynthesis requires three melanogenic enzymes,t yrosinase (TYR), andt he tyrosinase-relatedp roteins TYRP1 and TYRP2. Thed ifficulty of isolating pure and homogeneous proteins from endogenous sources has hampered their study,and resulted in many contradictory findings regarding their physiological functions. In this review,w es ummarize recent advances on the structure and function of TYR and TYRPs by virtue of the crystal structure of human TYRP1, which is the first available structureo f am ammalian melanogenic enzyme. This structure, combined with tyrosinase structures from other lower eukaryotes and mutagenesis studies of key actives ite residues,s heds light on the mechanism of TYR and TYRPs. Furthermore, a TYRP1-based homology model of TYR provides ah igh-quality platform to map and analyze albinism-related mutations, as wella st he design of specific antimelanogenic compounds. Finally,w ep rovide perspectives for future structure/ functionstudies of TYR and TYRPs.

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The First Crystal Structure of Tyrosinase: All Questions Answered?

Cited by 309 publications

References 26 publications

Determination of tyrosinase substrate-binding modes reveals mechanistic differences between type-3 copper proteins

Determination of tyrosinase substrate-binding modes reveals mechanistic differences between type-3 copper proteins

The Mechanism of Suicide-Inactivation of Tyrosinase: A Substrate Structure Investigation

Structure and Function of Human Tyrosinase and Tyrosinase‐Related Proteins

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