Some studies on the biosynthesis of ubiguinone, isoprenoid alcohols, squalene and sterols by marine invertebrates.
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ABSTRACT:
SUBMITTER: Walton MJ
PROVIDER: S-EPMC1178687 | biostudies-other | 1972 Apr
REPOSITORIES: biostudies-other
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Project description:Production of natural rubber by Parthenium argentaum (guayule) requires increased yield for economic sustainability. An RNAi gene silencing strategy was used to engineer isoprenoid biosynthesis by downregulation of squalene synthase (SQS), such that the pool of farnesyl diphosphate (FPP) substrate might instead be available to initiate natural rubber synthesis. Downregulation of SQS resulted in significantly reduced squalene and slightly increased rubber, but not in the same tissues nor to the same extent, partially due to an apparent negative feedback regulatory mechanism that downregulated mevalonate pathway isoprenoid production, presumably associated with excess geranyl pyrophosphate levels. A detailed metabolomics analysis of isoprenoid production in guayule revealed significant differences in metabolism in different tissues, including in active mevalonate and methylerythritol phosphate pathways in stem tissue, where rubber and squalene accumulate. New insights and strategies for engineering isoprenoid production in guayule were identified.
| S-EPMC9030042 | biostudies-literature
Project description:Plasmodium falciparum is the etiological agent of human malaria, one of the most widespread diseases in tropical and subtropical regions. Drug resistance is one of the biggest problems in controlling the disease, which leads to the need to discover new antimalarial compounds. One of the most promissory drugs purposed is fosmidomycin, an inhibitor of the biosynthesis of isoprene units by the methylerythritol 4-phosphate (MEP) pathway, which in some cases failed in clinical studies. Once formed, isoprene units are condensed to form longer structures such as farnesyl and geranylgeranyl pyrophosphate, which are necessary for Heme O and A formation, ubiquinone, and dolichyl phosphate biosynthesis as well as for protein isoprenylation. Even though the natural substrates of polyprenyl transferases and synthases are polyprenyl pyrophosphates, it was already demonstrated that isoprenoid alcohols (polyprenols) such as farnesol (FOH) and geranylgeraniol (GGOH) can rescue parasites from fosmidomycin. This study better investigated how this rescue phenomenon occurs by performing drug-rescue assays. Similarly, to FOH and GGOH, it was observed that phytol (POH), a 20-carbon plant isoprenoid, as well as unsaponifiable lipid extracts from foods rescue parasites from the antimalarial effect of fosmidomycin. Contrarily, neither dolichols nor nonaprenol rescue parasites from fosmidomycin. Considering this, here we characterized the transport of FOH, GGOH, and POH. Once incorporated, it was observed that these substances are phosphorylated, condensed into longer isoprenoid alcohols, and incorporated into proteins and dolichyl phosphates. Through proteomic and radiolabelling approaches, it was found that prenylated proteins are naturally attached to several isoprenoids, derived from GGOH, dolichol, and POH if exogenously added. Furthermore, the results suggest the presence of at least two promiscuous protein prenyltransferases in the parasite: one enzyme which can use FPP among other unidentified substrates and another enzyme that can use GGPP, phytyl pyrophosphate (PPP), and dolichols, among other substrates not identified here. Thus, further evidence was obtained for dolichols and other isoprenoid products attached to proteins. This study helps to better understand the apicoplast-targeting antimalarial mechanism of action and a novel post-translational modification of proteins in P. falciparum.
| S-EPMC9751614 | biostudies-literature
Project description:Plasmodium falciparum is the etiological agent of human malaria, one of the most widespread diseases in tropical and subtropical world regions. One of the biggest problems in controlling the disease is the emergence of drug resistance, which leads to the need to discover new antimalarial compounds. One of the most promissory drugs purposed is fosmidomycin, an inhibitor of the biosynthesis of isoprene units by the methylerythritol 4-phosphate (MEP) pathway which in some cases failed in clinic studies. Once formed, isoprene units are condensed to form longer structures such as farnesyl and geranylgeranyl pyrophosphate (GGPP), which are necessary for heme O and A formation, ubiquinone, and dolichyl phosphate biosynthesis as well as for protein isoprenylation. Even though the natural substrates of polyprenyl transferases and syntheses are polyprenyl pyrophosphates, it was already demonstrated that isoprenoid alcohols (polyprenols) such as farnesol (FOH) and geranylgeraniol (GGOH) can rescue parasites from fosmidomycin. This study better investigated how this rescue phenomenon occurs by performing drug-rescue assays. By this, it was observed that phytol (POH), a 20-carbon plant isoprenoid, rescues parasites from the fosmidomycin effect, similarly to FOH or GGOH. Contrarily, neither dolichols nor nonaprenol rescue parasites from fosmidomycin. Considering this, here we characterized the transport of FOH, GGOH, and POH. Once incorporated, it was observed that these substances are phosphorylated, condensed into longer isoprenoid alcohols, and incorporated into proteins and dolichyl phosphates. Through proteomic and radiolabelling approaches, it was found that prenylated proteins are naturally attached to several isoprenoids including GGOH, dolichol, and POH if exogenously added. Furthermore, results suggest the presence of at least two promiscuous protein prenyltransferases in the parasite: one enzyme which can use FPP among other unidentified substrates and another enzyme that can use GGOH, POH, and dolichols among other substrates not identified here. Thus, was obtained further evidence for dolichols and other isoprenoid products attached to proteins. This study helps better understand apicoplast-targeting antimalarials mechanism of action as well as novel posttranslational modifications of proteins.
2022-11-28 | PXD036092 | Pride
Project description:1. The subcutaneous and omental adipose tissue of man, the epididymal fat pads of the rat and the fat tail of the Syrian sheep incorporate mevalonic acid into non-saponifiable lipids. 2. Time studies showed that the rates of decarboxylation of mevalonic acid and synthesis of non-saponifiable lipids slightly decline after 20min. but subsequently remain linear for 6hr. 3. About one-half of the incorporated radioactivity in the non-saponifiable lipids was in squalene, 20% in lanosterol and cholesterol, and the remainder in unidentified substances.
| S-EPMC1264833 | biostudies-other
Project description:Virtually all polyunsaturated fatty acids (PUFA) originate from primary producers but can be modified by bioconversions as they pass up the food chain in a process termed trophic upgrading. Therefore, although the main primary producers of PUFA in the marine environment are microalgae, higher trophic levels have metabolic pathways that can produce novel and unique PUFA. However, little is known about the pathways of PUFA biosynthesis and metabolism in the levels between primary producers and fish that are largely filled by invertebrates. It has become increasingly apparent that, in addition to trophic upgrading, de novo synthesis of PUFA is possible in some lower animals. The unequivocal identification of PUFA biosynthetic pathways in many invertebrates is complicated by the presence of other organisms within them. These organisms include bacteria and algae with PUFA biosynthesis pathways, and range from intestinal flora to symbiotic relationships that can involve PUFA translocation to host organisms. This emphasizes the importance of studying biosynthetic pathways at a molecular level, and the continual expansion of genomic resources and advances in molecular analysis is facilitating this. The present paper highlights recent research into the molecular and biochemical mechanisms of PUFA biosynthesis in marine invertebrates, particularly focusing on cephalopod molluscs.
| S-EPMC3826146 | biostudies-literature
Project description:The development of novel cholesterol biosynthesis inhibitors is a task of major concern due to the diverse roles of cholesterol and its precursors in physiological processes. Therefore, appropriate screening assays are required, which can be used to identify and quantify specific inhibitors targeting the desired enzyme. Here, we developed a whole-cell screening assay based on a HL60 cell line, which can be used to characterize inhibitors interacting with enzymes of the isoprenoid part of cholesterol biosynthesis. Due to the change of the isoprenoid pattern under enzyme inhibition, an identification of the targeted enzyme is possible. With the described assay, we can distinguish between free and pyrophosphorylated isoprenoids after enzymatic cleavage in cellular and extracellular matrices. The approach was validated in line with the European Medicines Agency guideline on bioanalytical method validation. As proof of concept, literature-described inhibitors of the isoprenoid pathway were tested. We characterized the effect of 11 isoprenoid biosynthesis inhibitors, and we identified 6-fluoromevalonate as an isopentenyl pyrophosphate isomerase inhibitor, a biological activity that was previously unknown. Furthermore, isoprenoid patterns revealed that, independent of the analyzed matrix, the predominant form of the detected isoprenoids were dephosphorylated isoprenoids and only small amounts were present as pyrophosphates.
| S-EPMC11823600 | biostudies-literature
Project description:The more than 50,000 isoprenoids found in nature are all derived from the 5-carbon diphosphates isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). Natively, IPP and DMAPP are generated by the mevalonate (MVA) and 2-C-methyl-d-erythritol-4-phosphate (MEP) pathways, which have been engineered to produce compounds with numerous applications. However, as these pathways are inherently constrained by carbon, energy inefficiencies, and their roles in native metabolism, engineering for isoprenoid biosynthesis at high flux, titer, and yield remains a challenge. To overcome these limitations, here we develop an alternative synthetic pathway termed the isoprenoid alcohol (IPA) pathway that centers around the synthesis and subsequent phosphorylation of IPAs. We first established a lower IPA pathway for the conversion of IPAs to isoprenoid pyrophosphate intermediates that enabled the production of greater than 2 g/L geraniol from prenol as well as limonene, farnesol, diaponeurosporene, and lycopene. We then designed upper IPA pathways for the generation of (iso)prenol from central carbon metabolites with the development of a route to prenol enabling its synthesis at more than 2 g/L. Using prenol as the linking intermediate further facilitated an integrated IPA pathway that resulted in the production of nearly 0.6 g/L total monoterpenoids from glycerol as the sole carbon source. The IPA pathway provides an alternative route to isoprenoids that is more energy efficient than native pathways and can serve as a platform for targeting a repertoire of isoprenoid compounds with application as high-value pharmaceuticals, commodity chemicals, and fuels.
| S-EPMC6600936 | biostudies-literature
Project description:Malaria kills nearly 1 million people each year, and the protozoan parasite Plasmodium falciparum has become increasingly resistant to current therapies. Isoprenoid synthesis via the methylerythritol phosphate (MEP) pathway represents an attractive target for the development of new antimalarials. The phosphonic acid antibiotic fosmidomycin is a specific inhibitor of isoprenoid synthesis and has been a helpful tool to outline the essential functions of isoprenoid biosynthesis in P. falciparum. Isoprenoids are a large, diverse class of hydrocarbons that function in a variety of essential cellular processes in eukaryotes. In P. falciparum, isoprenoids are used for tRNA isopentenylation and protein prenylation, as well as the synthesis of vitamin E, carotenoids, ubiquinone, and dolichols. Recently, isoprenoid synthesis in P. falciparum has been shown to be regulated by a sugar phosphatase. We outline what is known about isoprenoid function and the regulation of isoprenoid synthesis in P. falciparum, in order to identify valuable directions for future research.
| S-EPMC4248697 | biostudies-literature
Project description: Not available
| S-EPMC3191736 | biostudies-literature
Project description:Isoprenoids and their derivatives represent the largest group of organic compounds in nature and are distributed universally in the three domains of life. Isoprenoids are biosynthesized from isoprenyl diphosphate units, generated by two distinctive biosynthetic pathways: mevalonate pathway and methylerthritol 4-phosphate pathway. Archaea and eukaryotes exclusively have the former pathway, while most bacteria have the latter. Some bacteria, however, are known to possess the mevalonate pathway genes. Understanding the evolutionary history of these two isoprenoid biosynthesis pathways in each domain of life is critical since isoprenoids are so interweaved in the architecture of life that they would have had indispensable roles in the early evolution of life. Our study provides a detailed phylogenetic analysis of enzymes involved in the mevalonate pathway and sheds new light on its evolutionary history. The results suggest that a potential mevalonate pathway is present in the recently discovered superphylum Candidate Phyla Radiation (CPR), and further suggest a strong evolutionary relationship exists between archaea and CPR. Interestingly, CPR harbors the characteristics of both the bacterial-type and archaeal-type mevalonate pathways and may retain signatures regarding the ancestral isoprenoid biosynthesis pathway in the last universal common ancestor. Our study supports the ancient origin of the mevalonate pathway in the three domains of life as previously inferred, but concludes that the evolution of the mevalonate pathway was more complex.
| S-EPMC6107057 | biostudies-literature