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Hettema, EH Ewald H, Watts, DJ Donald J, Nuttall, JM James M, (2012) ' Farnesyl diphosphate synthase, the target for nitrogen-containing bisphosphonate drugs, is a peroxisomal enzyme in the model system Dictyostelium discoideum. ' Biochem. J.

 

Abstract:Nitrogen-containing bisphosphonate (NBP) drugs protect against excessive osteoclast-mediated bone resorption. After binding to bone mineral, they are taken up selectively by the osteoclasts and inhibit the essential enzyme farnesyl diphosphate synthase (FDPS). NBPs inhibit also growth of amoebae of Dictyostelium discoideum in which their target is again FDPS. A fusion protein between FDPS and green fluorescent protein (GFP) was found, in D. discoideum, to localise to peroxisomes and to confer resistance to the NBP alendronate. GFP was also directed to peroxisomes by a fragment of FDPS comprising amino acids 1-22. This contains a sequence of nine amino acids that closely resembles the nonapeptide, type 2 peroxisomal targeting signal (PTS2) - there is only a single amino acid mismatch between the two sequences. Mutation analysis confirmed that the atypical PTS2 directs FDPS into peroxisomes. Furthermore, expression of the D. discoideum FDPS-GFP fusion protein in strains of Saccharomyces cerevisiae defective in peroxisomal protein import demonstrated that import of FDPS into peroxisomes was blocked in a strain lacking the PTS2-dependent import pathway. The peroxisomal location of FDPS in D. discoideum indicates that NBPs have to cross the peroxisomal membrane before they can bind to their target.
Status:	aheadofprint	Type:	Journal article	Source:	PUBMED	PubMed ID:	22849378

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	Genes addressed in this paper
	fps
Topics in this paper
Disease Related	X
Non-mammalian Gene Related	X
Strains/Constructs	X
Cellular Location	X
Mutants/Phenotypes	X