Degradation of tyrosinase induced by phenylthiourea occurs following Golgi maturation.
Tyrosinase, the rate-limiting enzyme of melanin synthesis, is a di-copper metalloprotein that catalyzes the conversion of L-tyrosine to L-DOPAquinone. Phenylthiourea (PTU) is a well-known inhibitor of tyrosinase and melanin synthesis and is known to interact with sweet potato catechol oxidase, an enzyme possessing copper binding domain homology to tyrosinase. While PTU is frequently used to induce hypopigmentation in biological systems, little is known about its effects on tyrosinase and other melanogenic proteins. We have found that PTU induces degradation of tyrosinase but not of other melanogenic proteins including the tyrosinase-related metalloproteins tyrosinase-related protein (Tyrp)1 and Tyrp2. Using pulse-chase analysis coupled with glycosidase digestion, we observed that tyrosinase degradation occurs following complete maturation of the protein and that degradation was reversed by cysteine protease inhibitor E64 but not proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal. We conclude that PTU specifically induces tyrosinse degradation following Golgi maturation. Our data suggest that in addition to well-known ER-directed quality control, tyrosinase is also subject to post-Golgi quality control.
Hall
Andrea M
AM
The Ronald O. Perelman Department of Dermatology and the Department of Cell Biology, New York University School of Medicine, New York, NY, USA.
Orlow
Seth J
SJ
D000818:Animals; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006056:Golgi Apparatus / Q000187:drug effects* / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008543:Melanins / Q000378:metabolism; D008544:Melanocytes / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D010670:Phenylthiourea / Q000494:pharmacology*; D061988:Proteasome Inhibitors
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D008543:Melanins; D061988:Proteasome Inhibitors; C063261:acetylleucyl-leucyl-norleucinal; D010670:Phenylthiourea; D010088:Oxidoreductases; C064056:tyrosinase-related protein-1; D014442:Monophenol Monooxygenase; D007930:Leucine; C108192:aloxistatin