Identification of compounds that bind mitochondrial F1F0 ATPase by screening a triazine library for correction of albinism.
A triazine-based combinatorial library of small molecules was screened in albino murine melanocytes to identify compounds that induce pigmentation. Six compounds (of 1536 screened) produced at least 3-fold increases in pigmentation. Immunohistochemical studies demonstrated that the compounds conferred correct routing of the mistrafficked enzyme tyrosinase, which is critical to normal melanogenesis. Affinity matrices of the immobilized compounds allowed the cellular target to be identified as the mitochondrial F1F0-ATP synthase. Oligomycin and aurovertin B, small molecules known to inhibit the mitochondrial ATP synthase, were shown to compete with the triazine-based compounds for their cellular target in albino melanocytes and confer similar effects on pigmentation and tyrosinase rerouting. This is the first demonstration of the mitochondrial ATP synthase as a potential therapeutic target for restoring pigmentation in albino melanocytes.
Williams
Darren
D
The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY 10016, USA.
Jung
Da-Woon
DW
Khersonsky
Sonya M
SM
Heidary
Noushin
N
Chang
Young-Tae
YT
Orlow
Seth J
SJ
D016115:Albinism, Oculocutaneous / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001313:Aurovertins / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D008543:Melanins / Q000378:metabolism*; D008544:Melanocytes; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009840:Oligomycins / Q000494:pharmacology; D010858:Pigmentation / Q000187:drug effects; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology*
D001313:Aurovertins; D004791:Enzyme Inhibitors; D008543:Melanins; D009840:Oligomycins; D014227:Triazines; C034402:aurovertin B; D014442:Monophenol Monooxygenase; D025261:Mitochondrial Proton-Translocating ATPases; D006180:Proton-Translocating ATPases