The Biomedical Importance of the Missing Pathway for Farnesol and Geranylgeraniol Salvage

Abstract

Isoprenoids are the output of the polymerization of five-carbon, branched isoprenic chains derived from isopentenyl pyrophosphate (IPP) and its isomer, dimethylallyl pyrophosphate (DMAPP). Isoprene units are consecutively condensed to form longer structures such as farnesyl and geranylgeranyl pyrophosphate (FPP and GGPP, respectively), necessary for the biosynthesis of several metabolites. Polyprenyl transferases and synthases use polyprenyl pyrophosphates as their natural substrates; however, it is known that free polyprenols, such as farnesol (FOH), and geranylgeraniol (GGOH) can be incorporated into prenylated proteins, ubiquinone, cholesterol, and dolichols. Furthermore, FOH and GGOH have been shown to block the effects of isoprenoid biosynthesis inhibitors such as fosmidomycin, bisphosphonates, or statins in several organisms. This phenomenon is the consequence of a short pathway, which was observed for the first time more than 25 years ago: the polyprenol salvage pathway, which works via the phosphorylation of FOH and GGOH. Biochemical studies in bacteria, animals, and plants suggest that this pathway can be carried out by two enzymes: a polyprenol kinase and a polyprenyl-phosphate kinase. However, to date, only a few genes have been unequivocally identified to encode these enzymes in photosynthetic organisms. Nevertheless, pieces of evidence for the importance of this pathway abound in studies related to infectious diseases, cancer, dyslipidemias, and nutrition, and to the mitigation of the secondary effects of several drugs. Furthermore, nowadays it is known that both FOH and GGOH can be incorporated via dietary sources that produce various biological effects. This review presents, in a simplified but comprehensive manner, the most important data on the FOH and GGOH salvage pathway, stressing its biomedical importance The main objective of this review is to bring to light the need to discover and characterize the kinases associated with the isoprenoid salvage pathway in animals and pathogens.

Beyond the MEP Pathway: A novel kinase required for prenol utilization by malaria parasites

“…In line with our findings, bioinformatic deep learning signal prediction indicates that this enzyme is localized in the endoplasmic reticulum of malaria parasites [ 47 ]. In fact, other studies indicate that the majority of prenol kinase activities in animals and bacteria are located in the approximately 10,000 x g supernatant of tissue homogenates, rough and smooth microsomes, and associated with the inner, luminal surface of the vesicles [ 32 ].…”

“…There is no evidence that prenyl synthases/transferases would preferably bind prenols, or any other polyprenyl derivative, rather than polyprenyl-PP. Prenols may orient parallel to the membrane, while polyprenyl pyrophosphates favour a perpendicular orientation, making their pyrophosphate moieties physically available for interaction with polyprenyl transferases and synthases [30][31][32]. Therefore, a FOH/GGOH salvage pathway was proposed to exist, acting via phosphorylation to incorporate these molecules into the major isoprenoid metabolism [32].…”

“…Prenol phosphorylation has been biochemically demonstrated to occur in membrane extracts of animal and plant tissues, as well as in archaea [ 32 ]. In 1998, Bentinger et al .…”

Farnesol as an antifungal agent: comparisons among MTLa and MTLα haploid and diploid Candida albicans and Saccharomyces cerevisiae

“…Another possibility is that the ploidy state and/or mating type may determine more or less active farnesol metabolism in the cell, hence more or less resistance to growth inhibition or killing by farnesol. In this regard, neither C. albicans nor S. cerevisiae appears to have the two-step farnesol salvage pathway ( Crick et al, 1997 ) whereby farnesol is converted to FPP ( Verdaguer et al, 2022 ). This pathway is present in plants, animals, and bacteria but the relevant genes ( VTE5 and VTE6 from Arabidopsis thaliana ) have no homologs in either the Candida or Saccharomyces Genome Databases.…”

Engineering Saccharomyces cerevisiae YPH499 for Overproduction of Geranylgeraniol

“…Geranylgeraniol (GGOH, C 20 H 34 O, diterpenoid), a plant-derived acyclic diterpene alcohol, shows good antiplasmodial and antiproliferative activity. , However, the low yield of GGOH produced through plant extraction and the long growth cycle of plants limit the commercial process. , GGOH biosynthesis has emerged as a promising strategy to avoid these drawbacks. Saccharomyces cerevisiae, as a result of its robustness in fermentation, “generally recognized as safe” (GRAS) status, convenience of genetic techniques, and mevalonate (MVA) pathway (effective isoprenoid precursor supplier), has been used to produce various terpenoids. , Jiang et al proved that S.…”