Structure and Function of Human Tyrosinase and Tyrosinase‐Related Proteins

Abstract

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.

Membrane transport proteins in melanosomes: Regulation of ions for pigmentation

“…TYR, TYRP1, and TYRP2 share a signaling peptide-like domain, a cysteine-rich region, a single transmembrane domain at the C-termini, and residues for coordinating the binding of the two metal ions. TYR contains two Cu 2+ binding sites, and TYRPs hold two Zn 2+ binding sites [15,16]. The requirement of Cu 2+ ions for TYR has been clearly demonstrated.…”

“…The cy-steinylDOPA passes several enzymatic reactions involving oxidation and polymerization yielding pheomelanin (Fig. 2) [4,15,16].…”

“…TYR and TYRPs belong to tyrosinase family [16]. Production of melanin (eumelanin) is dependent on the activities of TYR and TYRPs in which TYR is the rate-limiting enzyme [17].…”

“…TYRP1 contains Zn 2+ binding sites but biochemical experiments have failed to prove the direct binding of Zn 2+ [43]. Moreover, mouse and human TYRP1 seem to exhibit different enzymatic properties [16]. Nevertheless, both Cu 2+ and Zn 2+ are bona fide cofactors of enzymatic reactions in melanosomal tyrosinase family.…”

Dopachrome tautomerase variants in patients with oculocutaneous albinism

“…We and others have shown that over 50% of OCA patients with molecular diagnosis have a mutation in TYR (OCA1) encoding tyrosinase while around 2-3% have a defective TYRP1 (OCA3) encoding tyrosinase related 1 protein 1,5–8 . Both enzymes are well known to control pigment synthesis 9 . Of note, a third enzyme, dopachrome tautomerase, DCT acts downstream of TYR but upstream of TYRP1 on the DHICA melanin synthesis pathway 10,11 making the corresponding gene ( DCT/TYRP2 ) an obvious candidate for human albinism.…”