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RSC Chemical Biology Jun 2024The account attempts to substantiate the hypothesis that, from an evolutionary perspective, the coenzyme couple pyridoxal phosphate and pyridoxamine phosphate preceded... (Review)
Review
The account attempts to substantiate the hypothesis that, from an evolutionary perspective, the coenzyme couple pyridoxal phosphate and pyridoxamine phosphate preceded the coenzyme thiamine pyrophosphate and acted as its less efficient chemical analogue in some form of early metabolism. The analysis combines mechanism-based chemical reactivity with biosynthetic arguments and provides evidence that vestiges of "TPP-like reactivity" are still found for PLP today. From these thoughts, conclusions can be drawn about the key elements of a primordial form of metabolism, which includes the citric acid cycle, amino acid biosynthesis and the pentose phosphate pathway.
PubMed: 38846080
DOI: 10.1039/d4cb00016a -
Journal of Medicinal Chemistry Jun 2024Building on the preceding structural analysis and a structure-activity relationship (SAR) of 8-aryl-2-hexynyl nucleoside hAAR antagonist , we strategically inverted...
Structural Modification and Biological Evaluation of 2,8-Disubstituted Adenine and Its Nucleosides as A Adenosine Receptor Antagonists: Exploring the Roles of Ribose at Adenosine Receptors.
Building on the preceding structural analysis and a structure-activity relationship (SAR) of 8-aryl-2-hexynyl nucleoside hAAR antagonist , we strategically inverted C2/C8 substituents and eliminated the ribose moiety. These modifications aimed to mitigate potential steric interactions between ribose and adenosine receptors. The SAR findings indicated that such inversions significantly modulated hAAR binding affinities depending on the type of ribose, whereas removal of ribose altered the functional efficacy via hAAR. Among the synthesized derivatives, 2-aryl-8-hexynyl adenine demonstrated the highest selectivity for hAAR ( = 5.0 ± 0.5 nM, / = 86) and effectively blocked cAMP production and restored IL-2 secretion in PBMCs. Favorable pharmacokinetic properties and a notable enhancement of anticancer effects in combination with an mAb immune checkpoint blockade were observed upon oral administration of . These findings establish as a viable immune-oncology therapeutic candidate.
Topics: Humans; Structure-Activity Relationship; Animals; Adenine; Adenosine A2 Receptor Antagonists; Nucleosides; Ribose; Receptor, Adenosine A2A; Mice; Molecular Structure; Rats; Female; Cell Line, Tumor
PubMed: 38845345
DOI: 10.1021/acs.jmedchem.4c01003 -
International Journal of Biological... Jun 2024Mounting an active immune response is energy intensive and demands the reallocation of nutrients to maintain the body's resistance and tolerance against infections.... (Review)
Review
Mounting an active immune response is energy intensive and demands the reallocation of nutrients to maintain the body's resistance and tolerance against infections. Central to this metabolic adaptation is Glucose-6-phosphate dehydrogenase (G6PDH), a housekeeping enzyme involve in pentose phosphate pathway (PPP). PPP play an essential role in generating ribose, which is critical for nicotinamide adenine dinucleotide phosphate (NADPH). It is vital for physiological and cellular processes such as generating nucleotides, fatty acids and reducing oxidative stress. The G6PDH is extremely conserved enzyme across species in PP shunt. The deficiency of enzymes leads to serious consequences on organism, particularly on adaptation and development. Acute deficiency can lead to impaired cell development, halted embryonic growth, reduce sensitivity to insulin, hypertension and increase inflammation. Historically, research focusing on G6PDH and PPP have primarily targeted diseases on mammalian. However, our review has investigated the unique functions of the G6PDH enzyme in insects and greatly improved mechanistic understanding of its operations. This review explore how G6PDH in insects plays a crucial role in managing the redox balance and immune related metabolism. This study aims to investigate the enzyme's role in different metabolic adaptations.
PubMed: 38838892
DOI: 10.1016/j.ijbiomac.2024.132867 -
Bioresource Technology Jul 2024
Topics: Ethanol; Brazil; Xylose; Biofuels; Yeasts; Fermentation
PubMed: 38838833
DOI: 10.1016/j.biortech.2024.130930 -
Bioresource Technology Aug 2024The first comparative pre-treatment study of Miscanthus (Mxg) and sugarcane bagasse (SCB) using steam explosion (SE) and pressurised disc refining (PDR) pretreatment to...
Optimising parameters for pilot scale steam explosion and continuous pressurised disc refining of Miscanthus and sugarcane bagasse for xylose and xylo-oligosaccharide release.
The first comparative pre-treatment study of Miscanthus (Mxg) and sugarcane bagasse (SCB) using steam explosion (SE) and pressurised disc refining (PDR) pretreatment to optimise xylose and xylo-oligosaccharide release is described. The current investigation aimed to 1) Develop optimised batch-wise steam explosion parameters for Mxg and SCB, 2) Scale from static batch steam explosion to dynamic continuous pressurised disc refining, 3) Identify, understand, and circumvent scale-up production hurdles. Optimised SE parameters released 82% (Mxg) and 100% (SCB) of the available xylan. Scaling to PDR, Miscanthus yielded 85% xylan, highlighting how robust scouting assessments for boundary process parameters can result in successful technical transfer. In contrast, SCB technical transfer was not straightforward, with significant differences observed between the two processes, 100% (SE) and 58% (PDR). This report underlines the importance of feedstock-specific pretreatment strategies to underpin process development, scale-up, and optimisation of carbohydrate release from biomass.
Topics: Saccharum; Cellulose; Steam; Xylose; Oligosaccharides; Poaceae; Pilot Projects; Biotechnology; Xylans; Glucuronates
PubMed: 38838831
DOI: 10.1016/j.biortech.2024.130932 -
Carbohydrate Research Jul 2024It is well established that tumour cells undergo metabolic changes to acquire biological advantage over normal cells with activation of the glycolytic pathway, a process...
It is well established that tumour cells undergo metabolic changes to acquire biological advantage over normal cells with activation of the glycolytic pathway, a process termed "Warburg effect". Enzyme isoforms are alternative enzymatic forms with the same function but with different biochemical or epigenetic features. Moreover, isoforms may have varying impacts on different metabolic pathways. We challenge ourselves to analyse the glycolytic and gluconeogenic enzymes and isoforms in breast cancer, a complex and heterogeneous pathology, associated with high incidence and mortality rates especially among women. We analysed epithelial and tumour cell lines by RT-PCR and compared values to a publicly available database for the expression profile of normal and tumour tissues (Gepia) of enzymes and enzymatic isoforms from glycolytic and gluconeogenic pathways. Additionally, GeneMANIA was used to evaluate interactions, pathways, and attributes of each glycolytic/gluconeogenic steps. The findings reveal that the enzymes and enzymatic isoforms expressed in cell culture were somewhat different from those in breast tissue. We propose that the tumor microenvironment plays a crucial role in the expression of glycolytic and gluconeogenic enzymes and isoforms in tumour cells. Nonetheless, they not only participate in glycolytic and gluconeogenic enzymatic activities but may also influence other pathways, such as the Pentose-Phosphate-Pathway, TCA cycle, as well as other carbohydrate, lipid, and amino acid metabolism.
Topics: Humans; Breast Neoplasms; Gluconeogenesis; Female; Glycolysis; Cell Line, Tumor; Isoenzymes
PubMed: 38838492
DOI: 10.1016/j.carres.2024.109169 -
BioRxiv : the Preprint Server For... May 2024The adult mammalian heart has limited regenerative capacity following injury, leading to progressive heart failure and mortality. Recent studies have identified the...
The adult mammalian heart has limited regenerative capacity following injury, leading to progressive heart failure and mortality. Recent studies have identified the spiny mouse ( ) as a unique model for mammalian cardiac isch3emic resilience, exhibiting enhanced recovery after myocardial infarction (MI) compared to commonly used laboratory mouse strains. However, the underlying cellular and molecular mechanisms behind this unique response remain poorly understood. In this study, we comprehensively characterized the metabolic characteristics of cardiomyocytes in compared to the non-regenerative . We utilized single-nucleus RNA sequencing (snRNA-seq) in sham-operated animals and 1, 3, and 7 days post-myocardial infarction to investigate cardiomyocytes' transcriptomic and metabolomic profiles in response to myocardial infarction. Complementary targeted metabolomics, stable isotope-resolved metabolomics, and functional mitochondrial assays were performed on heart tissues from both species to validate the transcriptomic findings and elucidate the metabolic adaptations in cardiomyocytes following ischemic injury. Transcriptomic analysis revealed that cardiomyocytes inherently upregulate genes associated with glycolysis, the pentose phosphate pathway, and glutathione metabolism while downregulating genes involved in oxidative phosphorylation (OXPHOS). These metabolic characteristics are linked to decreased reactive oxygen species (ROS) production and increased antioxidant capacity. Our targeted metabolomic studies in heart tissue corroborated these findings, showing a shift from fatty acid oxidation to glycolysis and ancillary biosynthetic pathways in at baseline with adaptive changes post-MI. Functional mitochondrial studies indicated a higher reliance on glycolysis in compared to , underscoring the unique metabolic phenotype of hearts. Stable isotope tracing experiments confirmed a shift in glucose utilization from oxidative phosphorylation in . In conclusion, our study identifies unique metabolic characteristics of cardiomyocytes that contribute to their enhanced ischemic resilience following myocardial infarction. These findings provide novel insights into the role of metabolism in regulating cardiac repair in adult mammals. Our work highlights the importance of inherent and adaptive metabolic flexibility in determining cardiomyocyte ischemic responses and establishes as a valuable model for studying cardiac ischemic resilience in adult mammals.
PubMed: 38826249
DOI: 10.1101/2024.05.22.595229 -
Journal of Hepatology May 2024Crotonylation, a crotonyl-CoA-based non-enzymatic protein translational modification, affects diverse biological processes, such as spermatogenesis, tissue injury,...
BACKGROUND & AIMS
Crotonylation, a crotonyl-CoA-based non-enzymatic protein translational modification, affects diverse biological processes, such as spermatogenesis, tissue injury, inflammation, and neuropsychiatric diseases. Crotonylation shows decreased in hepatocellular carcinomas (HCCs), but the mechanism remains unknown. In this study, we aim to describe the role of glutaryl-CoA dehydrogenase (GCDH) in tumor suppression.
METHODS
Three cohorts containing 40, 248 and 17 pairs of samples were used to evaluate the link between GCDH expression levels and the HCC clinical characteristics as well as anti-PD-1 response. Subcutaneous xenograft, orthotopic xenograft, Trp53; MYC- as well as Ctnnb; MET- driven mouse models were adopted to validate GCDH effects on HCC suppression.
RESULTS
GCDH depletion promoted HCC growth and metastasis, whereas its overexpression reversed these processes. As GCDH converts glutaryl-CoA to crotonyl-CoA to increase crotonylation levels, we performed lysine crotonylome analysis and identified the pentose phosphate pathway (PPP) and glycolysis-related proteins PGD, TKT, and ALDOC as GCDH-induced crotonylation targets. Crotonyl-bound targets showed allosteric effects that controlled their enzymatic activities, leading to decreases in ribose 5-phosphate and lactate production, further limiting the Warburg effect. PPP blockade also stimulated peroxidation, synergizing with senescent modulators to induce senescence in GCDH cells. These cells induced the infiltration of immune cells by the senescence-associated secretory cell phenotype (SASP) to shape an anti-tumor immune microenvironment. Meanwhile, the GCDH population was sensitized to anti-programmed cell death protein 1 (PD-1) therapy.
CONCLUSION
GCDH inhibits HCC progression via crotonylation-induced suppression of the PPP and glycolysis, resulting in HCC cell senescence. The senescent cell further shapes an anti-tumor microenvironment by SASP. The GCDH population is vulnerable to anti-PD-1 therapy because more PD-1+CD8+ T cells are exhibited in GCDH population.
IMPACT AND IMPLICATIONS
GCDH is a favorable prognostic indicator in liver, lung, and renal cancers. In addition, most of GCDH depletion-induced toxic metabolites originate from the liver, accumulate locally, and cannot cross the blood-brain barrier. Therefore, studies on the correlation between GCDH and liver cancer would contribute to discovering the initiation and progression of hepatocellular carcinoma, of which over 70% of patients occupied >2-fold GCDH downregulation. Given that the GCDH and GCDH HCC population can be distinguished based on serum glucose and ammonia levels, it will be worthwhile to evaluate the curative effects of pro-senescent and immune-therapeutic strategies based on the expression levels of GCDH.
PubMed: 38825017
DOI: 10.1016/j.jhep.2024.05.034 -
Biomedicine & Pharmacotherapy =... Jul 2024Metabolic reprogramming plays critical roles in the development and progression of tumor by providing cancer cells with a sufficient supply of nutrients and other... (Review)
Review
Metabolic reprogramming plays critical roles in the development and progression of tumor by providing cancer cells with a sufficient supply of nutrients and other factors needed for fast-proliferating. Emerging evidence indicates that long noncoding RNAs (lncRNAs) are involved in the initiation of metastasis via regulating the metabolic reprogramming in various cancers. In this paper, we aim to summarize that lncRNAs could participate in intracellular nutrient metabolism including glucose, amino acid, lipid, and nucleotide, regardless of whether lncRNAs have tumor-promoting or tumor-suppressor function. Meanwhile, modulation of lncRNAs in glucose metabolic enzymes in glycolysis, pentose phosphate pathway and tricarboxylic acid cycle (TCA) in cancer is reviewed. We also discuss therapeutic strategies targeted at interfering with enzyme activity to decrease the utilization of glucoses, amino acid, nucleotide acid and lipid in tumor cells. This review focuses on our current understanding of lncRNAs participating in cancer cell metabolic reprogramming, paving the way for further investigation into the combination of such approaches with existing anti-cancer therapies.
Topics: Humans; RNA, Long Noncoding; Neoplasms; Animals; Metabolic Networks and Pathways; Gene Expression Regulation, Neoplastic
PubMed: 38824835
DOI: 10.1016/j.biopha.2024.116831 -
MSystems Jun 2024tools such as genome-scale metabolic models have shown to be powerful for metabolic engineering of microorganisms. is a complex aneuploid hybrid between the mesophilic...
UNLABELLED
tools such as genome-scale metabolic models have shown to be powerful for metabolic engineering of microorganisms. is a complex aneuploid hybrid between the mesophilic and the cold-tolerant . This species is of biotechnological importance because it is the primary yeast used in lager beer fermentation and is also a key model for studying the evolution of hybrid genomes, including expression pattern of ortholog genes, composition of protein complexes, and phenotypic plasticity. Here, we created the iSP_1513 GSMM for CBS1513 to allow top-down computational approaches to predict the evolution of metabolic pathways and to aid strain optimization in production processes. The iSP_1513 comprises 4,062 reactions, 1,808 alleles, and 2,747 metabolites, and takes into account the functional redundancy in the gene-protein-reaction rule caused by the presence of orthologous genes. Moreover, a universal algorithm to constrain GSMM reactions using transcriptome data was developed as a python library and enabled the integration of temperature as parameter. Essentiality data sets, growth data on various carbohydrates and volatile metabolites secretion were used to validate the model and showed the potential of media engineering to improve specific flavor compounds. The iSP_1513 also highlighted the different contributions of the parental sub-genomes to the oxidative and non-oxidative parts of the pentose phosphate pathway. Overall, the iSP_1513 GSMM represent an important step toward understanding the metabolic capabilities, evolutionary trajectories, and adaptation potential of in different industrial settings.
IMPORTANCE
Genome-scale metabolic models (GSMM) have been successfully applied to predict cellular behavior and design cell factories in several model organisms, but no models to date are currently available for hybrid species due to their more complex genetics and general lack of molecular data. In this study, we generated a bespoke GSMM, iSP_1513, for this industrial aneuploid hybrid , which takes into account the aneuploidy and functional redundancy from orthologous parental alleles. This model will (i) help understand the metabolic capabilities and adaptive potential of (domestication processes), (ii) aid top-down predictions for strain development (industrial biotechnology), and (iii) allow predictions of evolutionary trajectories of metabolic pathways in aneuploid hybrids (evolutionary genetics).
Topics: Saccharomyces; Metabolic Networks and Pathways; Genome, Fungal; Models, Biological; Metabolic Engineering; Saccharomyces cerevisiae; Evolution, Molecular; Industrial Microbiology
PubMed: 38819150
DOI: 10.1128/msystems.00429-24