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The Journal of Organic Chemistry Dec 2023The visible light-induced perfluoroalkyl (R) radical reactions on peracetylglycals derived from hexoses and pentoses (galactal, glucal, arabinal, and xylal derivatives)...
The visible light-induced perfluoroalkyl (R) radical reactions on peracetylglycals derived from hexoses and pentoses (galactal, glucal, arabinal, and xylal derivatives) were investigated. Various photocatalysts and perfluoroalkyl iodides (R-I) were employed as sources of R radicals with LEDs as the irradiation source. Particularly noteworthy was the use of an Iridium photocatalyst, Ir[dF(CF)ppy](dtbpy))PF, which yielded two distinct product types when applied to glucal. On the one hand, the 2-R-substituted glucal was formed, a trend observed even when utilizing organic dyes as photocatalysts. On the other hand, the unexpected addition product, namely the 1-R-2-iodo-α--configured -glycosyl derivative, was also obtained, as a result of a highly regioselective addition reaction of the R moiety into the anomeric carbon, followed by attachment of the iodine atom on C-2 in axial disposition. This result contrasted with other radical reactions carried out on 2-unsubstituted glycals, where the incipient radical adds to C-2, generating a stabilized 1-glycosyl radical. The photocatalyzed radical perfluoroalkylations of peracetyl glycals derived from galactose, arabinose, and xylose all afforded the 2-R-substituted glycals in good yields as a result of the expected vinylic substitution reaction. Mechanistic studies revealed that the 1-R-2-iodo-α--configured -glycosyl derivatives arise from a radical chain reaction, whereas the 2-R-substituted glycals proceed from inefficient chain processes.
PubMed: 38050850
DOI: 10.1021/acs.joc.3c01488 -
Biotechnology For Biofuels and... Oct 2023Mycosporine-like amino acids (MAAs), including shinorine and porphyra-334, are gaining attention as safe natural sunscreens. The production of MAAs has been achieved in...
BACKGROUND
Mycosporine-like amino acids (MAAs), including shinorine and porphyra-334, are gaining attention as safe natural sunscreens. The production of MAAs has been achieved in diverse microbial hosts, including Saccharomyces cerevisiae. While S. cerevisiae is the most extensively studied model yeast, the oleaginous yeast Yarrowia lipolytica has emerged as a promising candidate for the synthesis of valuable products. In this study, we explored the potential of Y. lipolytica as a host for producing MAAs, utilizing its advantages such as a robust pentose phosphate pathway flux and versatile carbon source utilization.
RESULTS
We produced MAAs in Y. lipolytica by introducing the MAA biosynthetic genes from cyanobacteria Nostoc punctiforme and Anabaena variabilis. These genes include mysA, mysB, and mysC responsible for producing mycosporine-glycine (MG) from sedoheptulose 7-phosphate (S7P). The two strains utilize different enzymes, D-Ala-D-Ala ligase homologue (MysD) in N. punctiforme and NRPS-like enzyme (MysE) in A. variabilis, for amino acid conjugation to MG. MysE specifically generated shinorine, a serine conjugate of MG, while MysD exhibited substrate promiscuity, yielding both shinorine and a small amount of porphyra-334, a threonine conjugate of MG. We enhanced MAAs production by selecting mysA, mysB, and mysC from A. variabilis and mysD from N. punctiforme based on their activities. We further improved production by strengthening promoters, increasing gene copies, and introducing the xylose utilization pathway. Co-utilization of xylose with glucose or glycerol increased MAAs production by boosting the S7P pool through the pentose phosphate pathway. Overexpressing GND1 and ZWF1, key genes in the pentose phosphate pathway, further enhanced MAAs production. The highest achieved MAAs level was 249.0 mg/L (207.4 mg/L shinorine and 41.6 mg/L of porphyra-334) in YP medium containing 10 g/L glucose and 10 g/L xylose.
CONCLUSIONS
Y. lipolytica was successfully engineered to produce MAAs, primarily shinorine. This achievement involved the introduction of MAA biosynthetic genes from cyanobacteria, establishing xylose utilizing pathway, and overexpressing the pentose phosphate pathway genes. These results highlight the potential of Y. lipolytica as a promising yeast chassis strain for MAAs production, notably attributed to its proficient expression of MysE enzyme, which remains non-functional in S. cerevisiae, and versatile utilization of carbon sources like glycerol.
PubMed: 37899467
DOI: 10.1186/s13068-023-02415-y -
Current Oncology (Toronto, Ont.) Dec 2023Preclinical and clinical studies have suggested potential synergies of combining poly (ADP-ribose) polymerase (PARP) inhibitors and novel hormonal therapies (NHT) for... (Review)
Review
Preclinical and clinical studies have suggested potential synergies of combining poly (ADP-ribose) polymerase (PARP) inhibitors and novel hormonal therapies (NHT) for patients with metastatic castration-resistant prostate cancer (mCRPC). We systematically searched PubMed, ClinicalTrials.gov and ASCO-GU annual meeting abstracts up to March 2023 to identify potential phase III trials reporting the use of combining PARP inhibitors with NHT in the first-line setting for mCRPC. A total of four phase III trials met the criteria for subsequent review. Emerging data suggested that the radiographic progression-free survival (rPFS) was significantly longer in the PARP inhibitor combined with NHT group versus the placebo plus NHT group for the first-line setting of biomarker-unselected mCRPC patients, especially for patients with homologous recombination repair (HRR) mutation (HRR m), and with the greatest benefit for BRCA1/2 mutation (BRCA1/2 m) populations. Final overall survival (OS) data of the PROpel trial indicated a significant improvement in median OS for mCRPC patients with HRR m and BRCA1/2 m receiving olaparib + abiraterone. Prior taxane-based chemotherapy might not influence the efficacy of the combination. Compared with the current standard-of-care therapies, combining NHT with PARP inhibitors could achieve a significant survival benefit in the first-line setting for mCRPC patients with HRR and BRCA1/2 mutations.
Topics: Male; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; BRCA1 Protein; Ribose; BRCA2 Protein; Antineoplastic Agents
PubMed: 38132385
DOI: 10.3390/curroncol30120751 -
Aging Cell Apr 2024Circadian cycles of sleep:wake and gene expression change with age in all organisms examined. Metabolism is also under robust circadian regulation, but little is known...
Circadian cycles of sleep:wake and gene expression change with age in all organisms examined. Metabolism is also under robust circadian regulation, but little is known about how metabolic cycles change with age and whether these contribute to the regulation of behavioral cycles. To address this gap, we compared cycling of metabolites in young and old Drosophila and found major age-related variations. A significant model separated the young metabolic profiles by circadian timepoint, but could not be defined for the old metabolic profiles due to the greater variation in this dataset. Of the 159 metabolites measured in fly heads, we found 17 that cycle by JTK analysis in young flies and 17 in aged. Only four metabolites overlapped in the two groups, suggesting that cycling metabolites are distinct in young and old animals. Among our top cyclers exclusive to young flies were components of the pentose phosphate pathway (PPP). As the PPP is important for buffering reactive oxygen species, and overexpression of glucose-6-phosphate dehydrogenase (G6PD), a key component of the PPP, was previously shown to extend lifespan in Drosophila, we asked if this manipulation also affects sleep:wake cycles. We found that overexpression in circadian clock neurons decreases sleep in association with an increase in cellular calcium and mitochondrial oxidation, suggesting that altering PPP activity affects neuronal activity. Our findings elucidate the importance of metabolic regulation in maintaining patterns of neural activity, and thereby sleep:wake cycles.
Topics: Animals; Drosophila; Sleep; Reactive Oxygen Species; Circadian Clocks; Pentose Phosphate Pathway; Circadian Rhythm
PubMed: 38204362
DOI: 10.1111/acel.14082 -
Neuro-oncology Nov 2023Nonstructural maintenance of chromatin condensin I complex subunit G (NCAPG), also known as non-structural maintenance of chromosomes condensin I complex subunit G, is...
Nonstructural maintenance of chromatin condensin I complex subunit G promotes the progression of glioblastoma by facilitating Poly (ADP-ribose) polymerase 1-mediated E2F1 transactivation.
BACKGROUND
Nonstructural maintenance of chromatin condensin I complex subunit G (NCAPG), also known as non-structural maintenance of chromosomes condensin I complex subunit G, is mitosis-related protein that widely existed in eukaryotic cells. Increasing evidence has demonstrated that aberrant NCAPG expression was strongly associated with various tumors. However, little is known about the function and mechanism of NCAPG in glioblastoma (GBM).
METHODS
The expression and prognostic value of NCAPG were detected in the clinical databases and tumor samples. The function effects of NCAPG downregulation or overexpression were evaluated in GBM cell proliferation, migration, invasion, and self-renewal in vitro and in tumor growth in vivo. The molecular mechanism of NCAPG was researched.
RESULTS
We identified that NCAPG was upregulated in GBM and associated with poor prognosis. Loss of NCAPG suppressed the progression of GBM cells in vitro and prolonged survival in mouse models of GBM in vivo. Mechanistically, we revealed that NCAPG positively regulated E2F transcription factor 1 (E2F1) pathway activity. By directly interacting with Poly (ADP-ribose) polymerase 1, a co-activator of E2F1, and facilitating the PARP1-E2F1 interaction to activate E2F1 target gene expression. Intriguingly, we also discovered that NCAPG functioned as a downstream target of E2F1, which was proved by the ChIP and Dual-Luciferase results. Comprehensive data mining and immunocytochemistry analysis revealed that NCAPG expression was positively associated with the PARP1/E2F1 signaling axis.
CONCLUSIONS
Our findings indicate that NCAPG promotes GBM progression by facilitating PARP1-mediated E2F1 transactivation, suggesting that NCAPG is a potential target for anticancer therapy.
Topics: Mice; Animals; Chromatin; Ribose; Glioblastoma; Transcriptional Activation; Cell Proliferation; Cell Line, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 37422706
DOI: 10.1093/neuonc/noad111 -
JCO Precision Oncology Aug 2023
Topics: Humans; Poly(ADP-ribose) Polymerases; Ribose; Carcinoma, Transitional Cell; Urinary Bladder Neoplasms
PubMed: 37535882
DOI: 10.1200/PO.23.00293 -
Frontiers in Physiology 2023Kidney injury and repair are accompanied by significant disruptions in metabolic pathways, leading to renal cell dysfunction and further contributing to the progression... (Review)
Review
Kidney injury and repair are accompanied by significant disruptions in metabolic pathways, leading to renal cell dysfunction and further contributing to the progression of renal pathology. This review outlines the complex involvement of various energy production pathways in glucose, lipid, amino acid, and ketone body metabolism within the kidney. We provide a comprehensive summary of the aberrant regulation of these metabolic pathways in kidney injury and repair. After acute kidney injury (AKI), there is notable mitochondrial damage and oxygen/nutrient deprivation, leading to reduced activity in glycolysis and mitochondrial bioenergetics. Additionally, disruptions occur in the pentose phosphate pathway (PPP), amino acid metabolism, and the supply of ketone bodies. The subsequent kidney repair phase is characterized by a metabolic shift toward glycolysis, along with decreased fatty acid β-oxidation and continued disturbances in amino acid metabolism. Furthermore, the impact of metabolism dysfunction on renal cell injury, regeneration, and the development of renal fibrosis is analyzed. Finally, we discuss the potential therapeutic strategies by targeting renal metabolic regulation to ameliorate kidney injury and fibrosis and promote kidney repair.
PubMed: 38283280
DOI: 10.3389/fphys.2023.1344271 -
International Immunology Jun 2024This review article delves into the complexities of granuloma formation, focusing on the metabolic reprogramming within these immune structures, especially in... (Review)
Review
This review article delves into the complexities of granuloma formation, focusing on the metabolic reprogramming within these immune structures, especially in tuberculosis and sarcoidosis. It underscores the role of the monocyte-macrophage lineage in granuloma formation and maintenance, emphasizing the adaptability of these cells to environmental cues and inflammatory stimuli. Key to the discussion is the macrophage polarization influenced by various cytokines, with a detailed exploration of the metabolic shifts towards glycolysis under hypoxic conditions and the utilization of the pentose phosphate pathway (PPP) for crucial biosynthetic processes. Significant attention is given to the metabolism of L-arginine in macrophages and its impact on immune response and granuloma function. The review also highlights the role of mechanistic target of rapamycin (mTOR) signaling in macrophage differentiation and its implications in granulomatous diseases. Discoveries such as elevated PPP activity in granuloma-associated macrophages and the protective role of NADPH against oxidative stress offer novel insights into granuloma biology. The review concludes by suggesting potential therapeutic targets within these metabolic pathways to modulate granuloma formation and function, proposing new treatment avenues for conditions characterized by chronic inflammation and granuloma formation. This work contributes significantly to the understanding of immune regulation and chronic inflammation, presenting avenues for future research and therapy in granulomatous diseases.
Topics: Humans; Macrophages; Granuloma; Animals; Pentose Phosphate Pathway; Signal Transduction; TOR Serine-Threonine Kinases; Macrophage Activation; Glycolysis; Metabolic Reprogramming
PubMed: 38441292
DOI: 10.1093/intimm/dxae013 -
Proceedings of the National Academy of... Apr 2024Many organisms that utilize the Calvin-Benson-Bassham (CBB) cycle for autotrophic growth harbor metabolic pathways to remove and/or salvage 2-phosphoglycolate, the...
Many organisms that utilize the Calvin-Benson-Bassham (CBB) cycle for autotrophic growth harbor metabolic pathways to remove and/or salvage 2-phosphoglycolate, the product of the oxygenase activity of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). It has been presumed that the occurrence of 2-phosphoglycolate salvage is linked to the CBB cycle, and in particular, the C2 pathway to the CBB cycle and oxygenic photosynthesis. Here, we examined 2-phosphoglycolate salvage in the hyperthermophilic archaeon , an obligate anaerobe that harbors a Rubisco that functions in the pentose bisphosphate pathway. harbors enzymes that have the potential to convert 2-phosphoglycolate to glycine and serine, and their genes were identified by biochemical and/or genetic analyses. 2-phosphoglycolate phosphatase activity increased 1.6-fold when cells were grown under microaerobic conditions compared to anaerobic conditions. Among two candidates, TK1734 encoded a phosphatase specific for 2-phosphoglycolate, and the enzyme was responsible for 80% of the 2-phosphoglycolate phosphatase activity in cells. The TK1734 disruption strain displayed growth impairment under microaerobic conditions, which was relieved upon addition of sodium sulfide. In addition, glycolate was detected in the medium when was grown under microaerobic conditions. The results suggest that removes 2-phosphoglycolate via a phosphatase reaction followed by secretion of glycolate to the medium. As the Rubisco in functions in the pentose bisphosphate pathway and not in the CBB cycle, mechanisms to remove 2-phosphoglycolate in this archaeon emerged independent of the CBB cycle.
Topics: Ribulose-Bisphosphate Carboxylase; Archaea; Photosynthesis; Glycolates; Phosphoric Monoester Hydrolases; Oxygenases; Pentoses
PubMed: 38593075
DOI: 10.1073/pnas.2311390121