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International Journal of Molecular... Dec 2023Androgen receptor pathway inhibitors (ARPI) and polyadenosine diphosphate-ribose inhibitors (PARPi) are part of the standard of care in patients with metastatic... (Review)
Review
Androgen receptor pathway inhibitors (ARPI) and polyadenosine diphosphate-ribose inhibitors (PARPi) are part of the standard of care in patients with metastatic castration-resistant prostate cancer (mCRPC). There is biological evidence that the association of ARPI and PARPi could have a synergistic effect; therefore, several ongoing clinical trials are investigating the efficacy of this combination with preliminary results that are not perfectly concordant in identifying patients who can obtain the most benefit from this therapeutic option. The purpose of this review is to describe the PARPi mechanisms of action and to analyze the biological mechanisms behind the interplay between the androgen receptor and the PARPi system to better understand the rationale of the ARPI + PARPi combinations. Furthermore, we will summarize the preliminary results of the ongoing studies on these combinations, trying to understand in which patients to apply. Finally, we will discuss the clinical implications of this combination and its possible future perspectives.
Topics: Male; Humans; Receptors, Androgen; Synthetic Lethal Mutations; Diphosphates; Ribose; Prostatic Neoplasms; Androgen Receptor Antagonists; Adenosine; Polymers
PubMed: 38203248
DOI: 10.3390/ijms25010078 -
Biomolecules May 2023Obesity and nonalcoholic fatty liver disease (NAFLD) are global health concerns, and thus, drugs for the long-term treatment of these diseases are urgently needed. We...
Obesity and nonalcoholic fatty liver disease (NAFLD) are global health concerns, and thus, drugs for the long-term treatment of these diseases are urgently needed. We previously discovered that the inositol pyrophosphate biosynthetic enzyme IP6K1 is a target in diet-induced obesity (DIO), insulin resistance, and NAFLD. Moreover, high-throughput screening (HTS) assays and structure-activity relationship (SAR) studies identified LI-2242 as a potent IP6K inhibitor compound. Here, we tested the efficacy of LI-2242 in DIO C57/BL6J mice. LI-2242 (20 mg/kg/BW daily, i.p.) reduced body weight in DIO mice by specifically reducing the accumulation of body fat. It also improved glycemic parameters and reduced hyperinsulinemia. LI-2242-treated mice displayed reduced the weight of various adipose tissue depots and an increased expression of metabolism- and mitochondrial-energy-oxidation-inducing genes in these tissues. LI-2242 also ameliorated hepatic steatosis by reducing the expression of genes that enhance lipid uptake, lipid stabilization, and lipogenesis. Furthermore, LI-2242 enhances the mitochondrial oxygen consumption rate (OCR) and insulin signaling in adipocytes and hepatocytes in vitro. In conclusion, the pharmacologic inhibition of the inositol pyrophosphate pathway by LI-2242 has therapeutic potential in obesity and NAFLD.
Topics: Mice; Animals; Non-alcoholic Fatty Liver Disease; Diphosphates; Insulin; Obesity; Diet; Insulin Resistance; Hyperglycemia; Lipids; Inositol; Mice, Inbred C57BL; Liver; Lipid Metabolism
PubMed: 37238737
DOI: 10.3390/biom13050868 -
Drug Development Research Feb 2022The pyrophosphate mimicking groups offer rational modification of the pyrophosphate-bearing natural substrates of the overexpressed enzymes that cause the onset of... (Review)
Review
The pyrophosphate mimicking groups offer rational modification of the pyrophosphate-bearing natural substrates of the overexpressed enzymes that cause the onset of disease progression. Mainly, the modified substrate interacts differently with the enzyme active site eventually causing its deactivation, or provides the therapeutically active products at the completion of the catalytic cycle that contribute toward the inhibition of the target enzyme. Many of the pyrophosphate mimic-containing molecules serve as competitive or allosteric inhibitors of the target enzyme to achieve the desirable properties for the mitigation of the target enzyme's pathophysiology. This review presents an epigrammatic overview of the pyrophosphate mimics in medicinal chemistry.
Topics: Catalytic Domain; Chemistry, Pharmaceutical; Diphosphates
PubMed: 34506652
DOI: 10.1002/ddr.21877 -
FEMS Microbiology Letters Jan 2023Polyphosphate kinase 1 (Ppk1) generates polyphosphates (polyPs) by catalyzing phosphate transfer from ATP. In the presence of ATP, Myxococcus xanthus Ppk1 showed the...
Polyphosphate kinase 1 (Ppk1) generates polyphosphates (polyPs) by catalyzing phosphate transfer from ATP. In the presence of ATP, Myxococcus xanthus Ppk1 showed the highest activity with polyP60-70 but also showed high activity with orthophosphate and pyrophosphate. Ppk1 synthesizes long-chain polyPs with >1 000 phosphate residues from orthophosphate or pyrophosphate present in high concentrations, suggesting that in M. xanthus, Ppk1 uses intracellular ortho/pyrophosphate as an initial primer for polyP production. During M. xanthus starvation-induced development, the specific activity of Ppk1 peaked at 12 h (300-800 nmol/min/mg) and then gradually decreased. The polyP concentration was highest during mound formation (45 nmol phosphate/mg protein); then, the level of long-chain polyPs decreased and that of short-chain polyPs increased during fruiting body and spore formation. Myxococcus xanthus expresses two exopolyphosphatases, Ppx1 and Ppx2, which mainly degrade short- and long-chain polyPs, respectively, both of which were highest in vegetative cells and were detected during starvation, which may account for the degradation of polyPs. Thus, polyPs synthesized by Ppk1 early in starvation-induced development could be degraded by exopolyphosphatases and may also be used as substrates by polyP:AMP phosphotransferases and polyphosphate/ATP-NAD kinases to generate ADP and NADP+, respectively.
Topics: Polyphosphates; Diphosphates; Myxococcus xanthus; Adenosine Triphosphate
PubMed: 36731866
DOI: 10.1093/femsle/fnad007 -
Molecules (Basel, Switzerland) Sep 2022Carotenoids are isoprenoid-derived natural products produced in plants, algae, fungi, and photosynthetic bacteria. Most animals cannot synthesize carotenoids because the... (Review)
Review
Carotenoids are isoprenoid-derived natural products produced in plants, algae, fungi, and photosynthetic bacteria. Most animals cannot synthesize carotenoids because the biosynthetic machinery to create carotenoids de novo is absent in animals, except arthropods. Carotenoids are biosynthesized from two C20 geranylgeranyl pyrophosphate (GGPP) molecules made from isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) via the methylerythritol 4-phosphate (MEP) route. Carotenoids can be extracted by a variety of methods, including maceration, Soxhlet extraction, supercritical fluid extraction (SFE), microwave-assisted extraction (MAE), accelerated solvent extraction (ASE), ultrasound-assisted extraction (UAE), pulsed electric field (PEF)-assisted extraction, and enzyme-assisted extraction (EAE). Carotenoids have been reported to exert various biochemical actions, including the inhibition of the Akt/mTOR, Bcl-2, SAPK/JNK, JAK/STAT, MAPK, Nrf2/Keap1, and NF-κB signaling pathways and the ability to increase cholesterol efflux to HDL. Carotenoids are absorbed in the intestine. A handful of carotenoids and carotenoid-based compounds are in clinical trials, while some are currently used as medicines. The application of metabolic engineering techniques for carotenoid production, whole-genome sequencing, and the use of plants as cell factories to produce specialty carotenoids presents a promising future for carotenoid research. In this review, we discussed the biosynthesis and extraction of carotenoids, the roles of carotenoids in human health, the metabolism of carotenoids, and carotenoids as a source of drugs and supplements.
Topics: Animals; Biological Products; Carotenoids; Cholesterol; Diphosphates; Drug Discovery; Humans; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; NF-kappa B; Plants; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Solvents; TOR Serine-Threonine Kinases; Terpenes
PubMed: 36144741
DOI: 10.3390/molecules27186005 -
The Plant Journal : For Cell and... Sep 2022The THIAMIN REQUIRING2 (TH2) protein comprising a mitochondrial targeting peptide followed by a transcription enhancement A and a haloacid dehalogenase domain is a...
The THIAMIN REQUIRING2 (TH2) protein comprising a mitochondrial targeting peptide followed by a transcription enhancement A and a haloacid dehalogenase domain is a thiamin monophosphate (TMP) phosphatase in the vitamin B1 biosynthetic pathway. The Arabidopsis th2-3 T-DNA insertion mutant was chlorotic and deficient in thiamin diphosphate (TDP). Complementation assays confirmed that haloacid dehalogenase domain alone was sufficient to rescue the th2-3 mutant. In pTH2:TH2-GFP/th2-3 complemented plants, the TH2-GFP was localized to the cytosol, mitochondrion, and nucleus, indicating that the vitamin B1 biosynthetic pathway extended across multi-subcellular compartments. Engineered TH2-GFP localized to the cytosol, mitochondrion, nucleus, and chloroplast, could complement the th2 mutant. Together, these results highlight the importance of intracellular TMP and thiamin trafficking in vitamin B1 biosynthesis. In an attempt to enhance the production of thiamin, we created various constructs to overexpress TH2-GFP in the cytosol, mitochondrion, chloroplast, and nucleus. Unexpectedly, overexpressing TH2-GFP resulted in an increase rather than a decrease in TMP. While studies on th2 mutants support TH2 as a TMP phosphatase, analyses of TH2-GFP overexpression lines implicating TH2 may also function as a TDP phosphatase in planta. We propose a working model that the TMP/TDP phosphatase activity of TH2 connects TMP, thiamin, and TDP into a metabolic cycle. The TMP phosphatase activity of TH2 is required for TDP biosynthesis, and the TDP phosphatase activity of TH2 may modulate TDP homeostasis in Arabidopsis.
Topics: Arabidopsis; DNA-Binding Proteins; Diphosphates; Homeostasis; Phosphoric Monoester Hydrolases; Thiamine; Thiamine Pyrophosphate
PubMed: 35791282
DOI: 10.1111/tpj.15895 -
RNA (New York, N.Y.) Nov 2022(Pho) RtcB exemplifies a family of binuclear transition metal- and GTP-dependent RNA ligases that join 3'-phosphate and 5'-OH ends via RtcB-(histidinyl-N)-GMP and...
(Pho) RtcB exemplifies a family of binuclear transition metal- and GTP-dependent RNA ligases that join 3'-phosphate and 5'-OH ends via RtcB-(histidinyl-N)-GMP and RNAppG intermediates. We find that guanylylation of PhoRtcB is optimal with manganese and less effective with cobalt and nickel. Zinc and copper are inactive and potently inhibit manganese-dependent guanylylation. We report crystal structures of PhoRtcB in complexes with GTP and permissive (Mn, Co, Ni) or inhibitory (Zn, Cu) metals. Zinc and copper occupy the M1 and M2 sites adjacent to the GTP phosphates, as do manganese, cobalt, and nickel. The identity/positions of enzymic ligands for M1 (His234, His329, Cys98) and M2 (Cys98, Asp95, His203) are the same for permissive and inhibitory metals. The differences pertain to: (i) the coordination geometries and phosphate contacts of the metals; and (ii) the orientation of the His404 nucleophile with respect to the GTP α-phosphate and pyrophosphate leaving group. M2 metal coordination geometry correlates with metal cofactor activity, whereby inhibitory Zn2 and Cu2 assume a tetrahedral configuration and contact only the GTP γ-phosphate, whereas Mn2, Co2, and Ni2 coordination complexes are pentahedral and contact the β- and γ-phosphates. The His404-Nε-Pα-O(α-β) angle is closer to apical in Mn (179°), Co (171°), and Ni (169°) structures than in Zn (160°) and Cu (155°) structures. The octahedral Mn1 geometry in our RtcB•GTP•Mn structure, in which Mn1 contacts α-, β-, and γ-phosphates, transitions to a tetrahedral configuration after formation of RtcB•(His404)-GMP•Mn and departure of pyrophosphate.
Topics: Diphosphates; Manganese; Cations, Divalent; Nickel; Copper; Guanosine Triphosphate; RNA Ligase (ATP); RNA; Zinc; Cobalt
PubMed: 36130078
DOI: 10.1261/rna.079327.122 -
Plant Biology (Stuttgart, Germany) Nov 2019Cellular pyrophosphate (PPi) homeostasis is vital for normal plant growth and development. Plant proton-pumping pyrophosphatases (H -PPases) are enzymes with different... (Review)
Review
Cellular pyrophosphate (PPi) homeostasis is vital for normal plant growth and development. Plant proton-pumping pyrophosphatases (H -PPases) are enzymes with different tissue-specific functions related to the regulation of PPi homeostasis. Enhanced expression of plant H -PPases increases biomass and yield in different crop species. Here, we emphasise emerging studies utilising heterologous expression in yeast and plant vacuole electrophysiology approaches, as well as phylogenetic relationships and structural analysis, to showcase that the H -PPases possess a PPi synthesis function. We postulate this synthase activity contributes to modulating and promoting plant growth both in H -PPase-engineered crops and in wild-type plants. We propose a model where the PPi synthase activity of H -PPases maintains the PPi pool when cells adopt PPi-dependent glycolysis during high energy demands and/or low oxygen environments. We conclude by proposing experiments to further investigate the H -PPase-mediated PPi synthase role in plant growth.
Topics: Arabidopsis; Arabidopsis Proteins; Diphosphates; Inorganic Pyrophosphatase; Pyrophosphatases
PubMed: 31081197
DOI: 10.1111/plb.13007 -
Organic & Biomolecular Chemistry Oct 2022New homo-sesquiterpenes are accessible after conversion of presilphiperfolan-8β-ol synthase (BcBOT2) with cyclopropylmethyl analogs of farnesyl diphosphate, and this...
New homo-sesquiterpenes are accessible after conversion of presilphiperfolan-8β-ol synthase (BcBOT2) with cyclopropylmethyl analogs of farnesyl diphosphate, and this biotransformation is dependent on subtle structural refinements. Two of the three cyclisation products are homo variants of germacrene D and germacrene D-4-ol while the third product reported contains a new bicyclic backbone for which no analogue in nature has been described so far. The findings on diphosphate activation are discussed and rationalised by relaxed force constants and dissociation energies computed at the DFT level of theory.
Topics: Alkyl and Aryl Transferases; Diphosphates; Sesquiterpenes; Sesquiterpenes, Germacrane
PubMed: 36169604
DOI: 10.1039/d2ob01279k -
Biochemistry Sep 2019The inositol pyrophosphates (PP-InsPs) are an important group of cellular messengers that influence a broad range of biological processes. To elucidate the functions of...
The inositol pyrophosphates (PP-InsPs) are an important group of cellular messengers that influence a broad range of biological processes. To elucidate the functions of these high-energy metabolites at the biochemical level, access to the purified molecules is required. Here, a robust and scalable strategy for the synthesis of various PP-InsPs [5PP-InsP, 1PP-InsP, and 1,5(PP)-InsP] is reported, relying on the highly active inositol hexakisphosphate kinase A from and the kinase domain of human diphosphoinositol pentakisphosphate kinase 2. A facile purification procedure using precipitation with Mg ions and an optional strong anion exchange chromatography on an FPLC system afforded PP-InsPs in high purity. Furthermore, the newly developed protocol could be applied to simplify the synthesis of radiolabeled 5PP-InsP-βP, which is a valuable tool for studying protein pyrophosphorylation. The chemoenzymatic method for obtaining PP-InsPs is readily amenable to both chemists and biologists and will thus foster future research on the multiple signaling functions of PP-InsP molecules.
Topics: Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Diphosphates; Entamoeba histolytica; Inositol Phosphates; Phosphotransferases (Phosphate Group Acceptor); Protein Domains; Protozoan Proteins; Recombinant Proteins
PubMed: 31461621
DOI: 10.1021/acs.biochem.9b00587