Identification of the F1F0 mitochondrial ATPase as a target for modulating skin pigmentation by screening a tagged triazine library in zebrafish

A triazine-based combinatorial library of small molecules was screened in zebrafish to identify compounds that produced interesting phenotypes. One compound (of 1536 screened) induced a dramatic increase in the pigmentation of early stage zebrafish embryos. This compound, PPA, was also found to incr...

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Bibliographic Details
Published in:Molecular bioSystems 2005-05, Vol.1 (1), p.85-92
Main Authors: Jung, Da-Woon, Williams, Darren, Khersonsky, Sonya M, Kang, Tae-Wook, Heidary, Noushin, Chang, Young-Tae, Orlow, Seth J
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Cells, Cultured
Embryo, Nonmammalian
Melanins - metabolism
Melanocytes - physiology
Membrane Potentials
Mice
Mice, Inbred C57BL
Mitochondrial Membranes - physiology
Mitochondrial Proteins - antagonists & inhibitors
Mitochondrial Proteins - physiology
Mitochondrial Proton-Translocating ATPases - antagonists & inhibitors
Mitochondrial Proton-Translocating ATPases - physiology
Molecular Sequence Data
Oligomycins - pharmacology
Skin Pigmentation - physiology
Triazines - pharmacology
Zebrafish
Zebrafish Proteins - antagonists & inhibitors
Zebrafish Proteins - physiology
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Summary:A triazine-based combinatorial library of small molecules was screened in zebrafish to identify compounds that produced interesting phenotypes. One compound (of 1536 screened) induced a dramatic increase in the pigmentation of early stage zebrafish embryos. This compound, PPA, was also found to increase pigmentation in cultured mammalian melanocytes. The cellular target was identified as the mitochondrial F1F0-ATP synthase (ATPase) by affinity chromatography. Oligomycin, a small molecule known to inhibit the mitochondrial ATPase, competed with PPA for its cellular target in melanocytes. In addition, PPA was shown to alter the membrane potential of mitochondria, consistent with inhibition of the mitochondrial ATPase. Thus, PPA has been successfully used as a chemical probe in a forward chemical genetic approach to establish a link between the phenotype and the protein. The results attest to the power of screening small molecule libraries in zebrafish as a means of identifying mammalian targets and suggest the mitochondrial ATPase as a target for modulating pigmentation in both melanocytes and melanoma cells.
ISSN:1742-206X
1742-2051
DOI:10.1039/b417765g