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Chemical Communications (Cambridge,... Mar 2022The biosynthesis of 2-methylisoborneol was reconstituted by elongation of dimethylallyl diphosphate (DMAPP) with ()- and ()-2-methylisopentenyl diphosphate (2-Me-IPP)...
The biosynthesis of 2-methylisoborneol was reconstituted by elongation of dimethylallyl diphosphate (DMAPP) with ()- and ()-2-methylisopentenyl diphosphate (2-Me-IPP) using farnesyl diphosphate synthase (FPPS), followed by terpene cyclisation. The stereochemical course of the FPPS reaction was studied in detail using stereoselectively deuterated 2-Me-IPP isotopomers.
Topics: Camphanes; Diphosphates; Geranyltranstransferase; Terpenes
PubMed: 35262160
DOI: 10.1039/d2cc00636g -
Chembiochem : a European Journal of... May 2022The structural diversity of terpenes is particularly notable and many studies are carried out to increase it further. In the terpene biosynthetic pathway this diversity... (Review)
Review
The structural diversity of terpenes is particularly notable and many studies are carried out to increase it further. In the terpene biosynthetic pathway this diversity is accessible from only two common precursors, i. e. isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Methods recently developed (e. g. the Terpene Mini Path) have allowed DMAPP and IPP to be obtained from a two-step enzymatic conversion of industrially available isopentenol (IOH) and dimethylallyl alcohol (DMAOH) into their corresponding diphosphates. Easily available IOH and DMAOH analogues then offer quick access to modified terpenoids thus avoiding the tedious chemical synthesis of unnatural diphosphates. The aim of this minireview is to cover the literature devoted to the use of these analogues for widening the accessible terpene chemical space.
Topics: Biosynthetic Pathways; Diphosphates; Hemiterpenes; Organophosphorus Compounds; Terpenes
PubMed: 34905641
DOI: 10.1002/cbic.202100642 -
Biochemical Society Transactions Feb 2016Post-translational modifications (PTMs) add regulatory features to proteins that help establish the complex functional networks that make up higher organisms. Advances... (Review)
Review
Post-translational modifications (PTMs) add regulatory features to proteins that help establish the complex functional networks that make up higher organisms. Advances in analytical detection methods have led to the identification of more than 200 types of PTMs. However, some modifications are unstable under the present detection methods, anticipating the existence of further modifications and a much more complex map of PTMs. An example is the recently discovered protein modification polyphosphorylation. Polyphosphorylation is mediated by inorganic polyphosphate (polyP) and represents the covalent attachment of this linear polymer of orthophosphate to lysine residues in target proteins. This modification has eluded MS analysis as both polyP itself and the phosphoramidate bonds created upon its reaction with lysine residues are highly unstable in acidic conditions. Polyphosphorylation detection was only possible through extensive biochemical characterization. Two targets have been identified: nuclear signal recognition 1 (Nsr1) and its interacting partner, topoisomerase 1 (Top1). Polyphosphorylation occurs within a conserved N-terminal polyacidic serine (S) and lysine (K) rich (PASK) cluster. It negatively regulates Nsr1-Top1 interaction and impairs Top1 enzymatic activity, namely relaxing supercoiled DNA. Modulation of cellular levels of polyP regulates Top1 activity by modifying its polyphosphorylation status. Here we discuss the significance of the recently identified new role of inorganic polyP.
Topics: Animals; DNA Topoisomerases, Type I; Diphosphates; Humans; Lysine; Models, Biological; Phosphorylation; Polyphosphates
PubMed: 26862182
DOI: 10.1042/BST20150210 -
Journal of Medicinal Chemistry Sep 2023We report on the synthesis and evaluation of three different nucleotide prodrug systems: (i) nucleoside triphosphate analogues in which the γ-phosph(on)ate has two...
We report on the synthesis and evaluation of three different nucleotide prodrug systems: (i) nucleoside triphosphate analogues in which the γ-phosph(on)ate has two different lipophilic nonbioreversible alkyl residues with d4TDP as the released nucleotide analogue; (ii) nucleoside diphosphate analogues bearing a bioreversible and a stable β-alkyl group; or (iii) nucleoside diphosphate analogues bearing two nonhydrolysable lipophilic alkyl moieties. The delivery of d4TDP (for the triphosphate precursor) and d4TMP (for the diphosphate precursor) was demonstrated in CD4 T-lymphocyte CEM cell extracts as well as in phosphate buffer saline (PBS). In primer extension assay, we found that γ-dialkylated d4TTP derivatives and d4TDP were accepted as substrates by HIV-RT. Several of these compounds were observed to be extremely active against HIV-1/2 replication in HIV-infected cells. A more than 45,000-fold increase in the anti-HIV activity was detected for compound as compared to the parent d4T which results in a selectivity index value of 37,000.
Topics: Diphosphates; Nucleosides; Polyphosphates; Nucleotides
PubMed: 37647547
DOI: 10.1021/acs.jmedchem.3c00755 -
Antiviral Chemistry & Chemotherapy Dec 2017In this review, our recent advances in the development of nucleoside di- and nucleoside triphosphate prodrugs is summarized. Previously, we had developed a successful... (Review)
Review
In this review, our recent advances in the development of nucleoside di- and nucleoside triphosphate prodrugs is summarized. Previously, we had developed a successful membrane-permeable pronucleotide system for the intracellular delivery of nucleoside monophosphates as well, the so-called cycloSal-approach. In contrast to that work in which the delivery is initiated by a chemically driven hydrolysis reaction, for the di- and triphosphate delivery, an enzymatic trigger mechanism involving (carboxy)esterases had to be used. The other features of the new pronucleotide approaches are: (i) lipophilic modification was restricted to the terminal phosphate group leaving charges at the internal phosphate moieties and (ii) appropriate lipophilicity is introduced by long aliphatic residues within the bipartite prodrug moiety. The conceptional design of the di- and triphosphate prodrug systems will be described and the chemical synthesis, the hydrolysis properties, a structure-activity relationship and antiviral activity data will be discussed as well. The advantage of these new approaches is that all phosphorylation steps from the nucleoside analogue into the bioactive nucleoside triphosphate form can be bypassed in the case of the triphosphate prodrugs. Moreover, enzymatic processes like the deamination of nucleosides or nucleoside monophosphates which lead to catabolic clearance of the potential antivirally active compound can be avoided by the delivery of the higher phosphorylated nucleotides.
Topics: Antiviral Agents; Diphosphates; Humans; Microbial Sensitivity Tests; Nucleosides; Polyphosphates; Prodrugs; Viruses
PubMed: 29096525
DOI: 10.1177/2040206617738656 -
The Journal of Antibiotics Jul 2016Terpenoid cyclases catalyze the most complex reactions in biology, in that more than half of the substrate carbon atoms often undergo changes in bonding during the... (Review)
Review
Terpenoid cyclases catalyze the most complex reactions in biology, in that more than half of the substrate carbon atoms often undergo changes in bonding during the course of a multistep cyclization cascade that proceeds through multiple carbocation intermediates. Many cyclization mechanisms require stereospecific deprotonation and reprotonation steps, and most cyclization cascades are terminated by deprotonation to yield an olefin product. The first bacterial terpenoid cyclase to yield a crystal structure was pentalenene synthase from Streptomyces exfoliatus UC5319. This cyclase generates the hydrocarbon precursor of the pentalenolactone family of antibiotics. The structures of pentalenene synthase and other terpenoid cyclases reveal predominantly nonpolar active sites typically lacking amino acid side chains capable of serving general base-general acid functions. What chemical species, then, enables the Brønsted acid-base chemistry required in the catalytic mechanisms of these enzymes? The most likely candidate for such general base-general acid chemistry is the co-product inorganic pyrophosphate. Here, we briefly review biological and nonbiological systems in which phosphate and its derivatives serve general base and general acid functions in catalysis. These examples highlight the fact that the Brønsted acid-base activities of phosphate derivatives are comparable to the Brønsted acid-base activities of amino acid side chains.
Topics: Aspartate Carbamoyltransferase; Biocatalysis; Cyclization; Diphosphates; Geranyltranstransferase; Hydrolases; Intramolecular Lyases; Isomerases; L-Serine Dehydratase; Phosphates; Terpenes
PubMed: 27072285
DOI: 10.1038/ja.2016.39 -
Chemical Society Reviews Apr 2015Pyrophosphate anions play key roles in various biological and chemical processes. During the last few years, many exciting results have emerged regarding the development... (Review)
Review
Pyrophosphate anions play key roles in various biological and chemical processes. During the last few years, many exciting results have emerged regarding the development of fluorescent and colorimetric sensors for this biologically important species. In this review, we will cover the fluorescent and colorimetric chemosensors developed for the detection of pyrophosphate (PPi) since 2010.
Topics: Colorimetry; Diphosphates; Metals; Spectrometry, Fluorescence
PubMed: 25578599
DOI: 10.1039/c4cs00353e -
Annales de Biologie Clinique 2015Vascular calcification is a marker of cardiovascular risk increase. Age and specific disease such as diabetes or chronic kidney disease are important factors for... (Review)
Review
Vascular calcification is a marker of cardiovascular risk increase. Age and specific disease such as diabetes or chronic kidney disease are important factors for calcification genesis. Vascular calcification process is a complex phenomenon, involving several activators and inhibitors factors. Indeed, recent works related to in vitro and in vivo experimental studies have led to a better understanding of calcification process and identification of molecules able to modulate this system. This revue will summarize some of these molecules with a particular interest of those with therapeutic relevance. We will present: i) calcium sensing receptor and its modulation by cinacalcet; ii) pyrophosphate supplementation; iii) fetuin A and overall propensity serum test for calcification and finally; iv) matrix-Gla-protein and the use of vitamin K to prevent vascular calcification progression.
Topics: Calcium-Binding Proteins; Cardiovascular Diseases; Diphosphates; Extracellular Matrix Proteins; Humans; Vascular Calcification; alpha-2-HS-Glycoprotein; Matrix Gla Protein
PubMed: 26069068
DOI: 10.1684/abc.2015.1047 -
Methods in Enzymology 2023Isoprenoids in plants are synthesized following the plastidial methylerythritol-4-phosphate (MEP) pathway or the mevalonate pathway localized to the cytosol and...
Isoprenoids in plants are synthesized following the plastidial methylerythritol-4-phosphate (MEP) pathway or the mevalonate pathway localized to the cytosol and peroxisomes. Isoprenyl-diphosphates (isoprenyl-PP) are important intermediates for the synthesis of chlorophyll, carotenoids, sterols, and other isoprenoids in plants. The quantification of isoprenyl-PP is challenging due to the amphipathic structure, the low abundance, and the susceptibility to hydrolysis during extraction and storage. Different methods for the measurement of isoprenyl-phosphates have been developed. Isoprenyl-phosphates can be measured after radioactive labeling or after derivatization. Liquid chromatography-mass spectrometry (LC-MS) methods provide enhanced sensitivity, but still require the extraction from large amounts of sample material. In the protocol presented here, the monophosphates and diphosphates of farnesol, geranylgeraniol and phytol are isolated from plant material with an isopropanol-containing buffer and quantified by LC-MS using citronellyl-P and citronellyl-PP as internal standards. With a low limit of detection for phytyl-P, geranylgeranyl-P, phytyl-PP, and geranylgeranyl-PP, isoprenyl-phosphates can be accurately measured in Arabidopsis leaves or seeds starting with only 20mg of fresh weight.
Topics: Diphosphates; Mass Spectrometry; Terpenes; Chromatography, Liquid; Plants; Arabidopsis
PubMed: 37087186
DOI: 10.1016/bs.mie.2022.08.026 -
Virulence Jan 2018Inositol pyrophosphates (PP-IPs) are energy-rich small molecules that are omnipresent in eukaryotic cells, from yeast to mammals, playing central roles in overall...
Inositol pyrophosphates (PP-IPs) are energy-rich small molecules that are omnipresent in eukaryotic cells, from yeast to mammals, playing central roles in overall cellular homeostasis as a diverse and multifaceted class of intracellular messengers. Recent studies of the metabolic pathways and physiological roles of PP-IPs in the human pathogenic fungus Cryptococcus neoformans have revealed that the PP-IP (IP) is a key metabolite essential for fungal metabolic adaptation to the host environment, immune recognition, and pathogenicity. This suggests the PP-IP biosynthesis pathway, comprising phospholipase C1 (Plc1) and a series of sequentially acting inositol polyphosphate kinases (IPKs), as a new virulence-related signaling pathway in C. neoformans. Given that fungal species have a reduced array of the kinases required for the synthesis of PP-IPs and that the homology between human and fungal IPKs is restricted to a few catalytically important residues, identification of IPK inhibitors specifically targeting the kinases of pathogenic fungi has emerged as a desirable and achievable strategy for antifungal drug development.
Topics: Animals; Cryptococcosis; Cryptococcus neoformans; Diphosphates; Fungal Proteins; Humans; Inositol Phosphates; Virulence
PubMed: 29338603
DOI: 10.1080/21505594.2017.1421832