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2511002191
  • Open Access
  • Review

Tyrosinase, a Timeless Enzyme: Transition-State Analogues as Probes of Structure-Function Relationships and Inhibition

  • Hélène Jamet 1,   
  • Catherine Belle 1,   
  • Montserrat Soler-López 2,   
  • Ariane Jalila Simaan 3,   
  • Marius Réglier 3,*

Received: 22 Sep 2025 | Revised: 27 Oct 2025 | Accepted: 06 Nov 2025 | Published: 18 Nov 2025

Abstract

Tyrosinase (TYR) is a type-3 copper enzyme that catalyzes the key steps of melanogenesis, namely the two-step oxidation of monophenols to catechols and their subsequent conversion into ortho-quinones. This catalytic activity underlies the biosynthesis of melanin pigments and links TYR to a broad spectrum of biological processes and human health conditions, from pigmentation disorders to melanoma. The binuclear copper center of TYR is highly conserved across species, with both coppers coordinated by three histidine residues. Nevertheless, variations in the access channel and in the second coordination sphere introduce important differences in substrate selectivity and activity control. Structural and mechanistic studies have greatly benefited from the use of so-called transition-state analogs (TSAs)—more accurately, stable mimics of catalytic intermediates in the two-step reaction. Classical examples such as kojic acid, tropolone, L-mimosine, and 2-hydroxypyridine N-oxide (HOPNO) have provided fundamental insights into TYR active site geometry, electron transfer, and ligand interactions. Derivatives embedding the HOPNO motif, either into aurone scaffolds or amino acid frameworks, have further highlighted the structural plasticity of the enzyme as well as the striking differences in inhibitor recognition across fungal, bacterial, and human TYRs. These findings underscore the importance of working with the appropriate enzymatic models when seeking biomedical applications. From a translational perspective, the design of selective TYR inhibitors remains a major challenge, particularly given the strong metal-chelating properties of many TSA-like compounds and their potential off-target effects on other metalloenzymes. Embedding the HOPNO motif into amino acids or peptides represents a promising strategy to achieve selectivity while retaining high affinity. Finally, beyond the active site, recent evidence showing that mutations within the cysteine-rich domain can disrupt enzyme folding and abolish TYR activity suggests unexplored avenues for inhibition, broadening the horizon for both biomedical and cosmetic applications.

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Jamet, H.; Belle, C.; Soler-López, M.; Simaan, A. J.; Réglier, M. Tyrosinase, a Timeless Enzyme: Transition-State Analogues as Probes of Structure-Function Relationships and Inhibition. Bioelectrochemistry and Biosensors 2026, 1 (1), 3.
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