Abstract
Introduction: Farnesyl pyrophosphate synthase (FPPS) catalyzes the condensation of isopentenyl diphosphate with dimethylallyl diphosphate to give rise to one molecule of geranyl diphosphate, which on a further reaction with another molecule of isopentenyl diphosphate forms the 15-carbon isoprenoid farnesyl diphosphate. This molecule is the obliged precursor for the biosynthesis of sterols, ubiquinones, dolichols, heme A, and prenylated proteins. The blockade of FPPS prevents the synthesis of farnesyl diphosphate and the downstream essential products. Due to its crucial role in isoprenoid biosynthesis, this enzyme has been winnowed as a molecular target for the treatment of different bone disorders and to control parasitic diseases, particularly, those produced by trypanosomatids and Apicomplexan parasites.
Areas covered: This article discusses some relevant structural features of farnesyl pyrophosphate synthase. It also discusses the precise mode of action of relevant modulators, including both bisphosphonate and non-bisphosphonate inhibitors and the recent advances made in the development of effective inhibitors of the enzymatic activity of this target enzyme.
Expert opinion: Notwithstanding their lack of drug-like character, bisphosphonates are still the most advantageous class of inhibitors of the enzymatic activity of farnesyl pyrophosphate synthase. The poor drug-like character is largely compensated by the high affinity of the bisphosphonate moiety by bone mineral hydroxyapatite in humans. Several bisphosphonates are currently in use for the treatment of a variety of bone disorders. Currently, the great prospects that bisphosphonates behave as antiparasitic agents is due to their accumulation in acidocalcisomes, organelles with equivalent composition to bone mineral, hence facilitating their antiparasitic action.
FPPS is present in all organisms and constitutes a key enzyme within the mevalonate pathway and the isoprenoid synthesis.
FPPS catalyses the condensation between dimethyl allyl pyrophosphate and isopentenyl pyrophosphate to give rise to geranyl pyrophosphate and the subsequent reaction with a further molecule of isopentenyl pyrophosphate to yield farnesyl pyrophosphate.
FPPS possesses three inhibition binding sites: the allylic site (dimethyl allyl pyrophosphate and geranyl pyrophosphate), the homoallylic site (isopentenyl pyrophosphate), and the allosteric site.
Bisphosphonate-based inhibitors have been developed as extremely effective inhibitors binding to the allylic site.
Recently, allosteric inhibitors of drug-like character have been designed and biologically tested.
Financial & Competing Interests Disclosure
This work was supported by grants from the National Research Council of Argentina (CONICET) (PIP 112-201101-00797), the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) (PICT 2012 #0457), and the Universidad de Buenos Aires (20020130100223BA). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.