FAMIN is a multifunctional purine enzyme enabling the purine nucleotide cycle (Macrophage RNA Seq dataset)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA522787 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8582380.fastq.gz | Fastqsanger.gz | |||
| SRR8582390.fastq.gz | Fastqsanger.gz | |||
| SRR8582400.fastq.gz | Fastqsanger.gz | |||
| SRR8582410.fastq.gz | Fastqsanger.gz | |||
| SRR8582371.fastq.gz | Fastqsanger.gz |
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Project description:FAMIN (LACC1, C13orf31) loss-of-function causes systemic juvenile idiopathic arthritis and very early-onset inflammatory bowel disease, while a common I254V substitution results in hypomorphic function and increases susceptibility to Crohn’s disease and leprosy. In this study, we compare the mRNA transcriptional profiles of M0, M1 and M2-polarised bone marrow-derived macrophages from mice engineered at their endogenous locus to express human non-risk (Faminp.254I), risk (Faminp.254V) and monogenic (Faminp.284R) disease variants.
2020-01-28 | GSE126641 | GEO
Project description:Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases the risk for Crohn's disease and leprosy. We developed an unbiased liquid chromatography-mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic orthologs additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activity, hence, combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronizes mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.
| S-EPMC6978800 | biostudies-literature
Project description:Tumor-specific metabolic rewiring, intended to confer a survival advantage over non-transformed cells, often offers an opportunity to target cancers. Here, we identify deregulated expression of purine biosynthetic enzymes as a metabolic hallmark in human hepatocellular carcinomas (HCC), with the extent of enzyme upregulation a predictor of clinical outcome. We demonstrate in HCC cell lines, patient-derived xenograft (PDX) organoids and mouse models that inhibition of purine biosynthesis abrogated cancer cell proliferation and tumor growth. Mechanistically, a PI3K-E2F1 axis coordinated purine biosynthetic enzyme expression. Clinically approved inhibitors against PI3K and the purine biosynthetic rate-limiting enzyme IMPDH synergistically reduced the tumor burden in a PDX mouse model. Collectively, our results support targeting purine metabolic reprogramming as a precision therapeutic strategy for HCC patients.
2020-07-06 | GSE145988 | GEO
Project description:Enterococcus faecalis is commonly isolated from different wound types. However, despite its prevalence, the pathogenic mechanisms of E. faecalis during wound infections remain poorly understood. We adopted an in vivo E. faecalis transposon sequencing and RNA sequencing approach to identify fitness determinants that are crucial for replication and persistence of E. faecalis during wound infections in a mouse model. We demonstrated that E. faecalis purine biosynthesis genes are important for replication as purine metabolites are low in wounds during the early phase of wound infections. Furthermore, we found that the E. faecalis MptABCD phosphotransferase system (PTS) involved in the uptake of galactose and mannose, is crucial for E. faecalis persistence in wounds, and that carbohydrate availability changes as the infection progresses. To understand how MptABCD PTS contributes to the reduced fitness observed during E. faecalis wound persistence, we performed an in vitro transcriptomic analysis using the galactose/mannose PTS gene deletion mutant (∆mptD). When mannose was the sole carbohydrate source, shikimate and purine biosynthesis genes in the ∆mptD mutant were downregulated compared to the isogenic wild-type strain, indicating that mannose transport is interconnected with shikimate and purine biosynthesis. Together, our results suggest that dynamic and temporal microenvironment changes at the wound site affects pathogenic requirements and mechanisms of E. faecalis during infections and raise the possibility of inhibiting purine biosynthesis and/or MptABCD PTS to control wound infections.
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Project description:Enterococcus faecalis is commonly isolated from different wound types. However, despite its prevalence, the pathogenic mechanisms of E. faecalis during wound infections remain poorly understood. We adopted an in vivo E. faecalis transposon sequencing and RNA sequencing approach to identify fitness determinants that are crucial for replication and persistence of E. faecalis during wound infections in a mouse model. We demonstrated that E. faecalis purine biosynthesis genes are important for replication as purine metabolites are low in wounds during the early phase of wound infections. Furthermore, we found that the E. faecalis MptABCD phosphotransferase system (PTS) involved in the uptake of galactose and mannose, is crucial for E. faecalis persistence in wounds, and that carbohydrate availability changes as the infection progresses. To understand how MptABCD PTS contributes to the reduced fitness observed during E. faecalis wound persistence, we performed an in vitro transcriptomic analysis using the galactose/mannose PTS gene deletion mutant (∆mptD). When mannose was the sole carbohydrate source, shikimate and purine biosynthesis genes in the ∆mptD mutant were downregulated compared to the isogenic wild-type strain, indicating that mannose transport is interconnected with shikimate and purine biosynthesis. Together, our results suggest that dynamic and temporal microenvironment changes at the wound site affects pathogenic requirements and mechanisms of E. faecalis during infections and raise the possibility of inhibiting purine biosynthesis and/or MptABCD PTS to control wound infections.
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Project description:Cancer immunotherapy has reshaped the landscape of cancer treatment, but its effectiveness is limited by tumor immunosuppression caused by excessive lactate production by cancer cells. While efforts to reduce lactate levels through lactate dehydrogenase inhibition have been made, such inhibitors can disrupt the metabolism of healthy cells and cause severe non-specific toxicity. Based on lactate oxidase, we report herein an enzyme therapeutic, which reduces lactate levels, releases an immunostimulatory molecule-hydrogen peroxide, averts tumor immunosuppression, and synergistically improves the efficacy of immune checkpoint blockades, as demonstrated in a murine melanoma model and a humanized mouse model of triple-negative breast cancer.
2024-05-10 | GSE230896 | GEO
Project description:Macroautophagy (hereafter, autophagy) is a process that directs the degradation of cytoplasmic material in lysosomes. In addition to its homeostatic roles, autophagy undergoes dynamic positive and negative regulation in response to multiple forms of cellular stress, thus enabling the survival of cells. However, the precise mechanisms of autophagy regulation are not fully understood. To identify potential negative regulators of autophagy, we performed a genome-wide CRISPR screen using the quantitative autophagic flux reporter GFP-LC3-RFP. We identified phosphoribosylformylglycinamidine synthase (PFAS), a component of the de novo purine synthesis pathway, as one such negative regulator of autophagy. Autophagy was activated in cells lacking PFAS or phosphoribosyl pyrophosphate amidotransferase (PPAT), another de novo purine synthesis enzyme, or treated with methotrexate when exogenous levels of purines were insufficient. Purine starvation-induced autophagy activation was concomitant with mTORC1 suppression, and was profoundly suppressed in cells deficient for TSC2, which negatively regulates mTORC1 through inhibition of RHEB, suggesting that purines regulate autophagy through the TSC-RHEB-mTORC1 signaling axis. Moreover, depletion of the pyrimidine synthesis enzymes carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) and dihydroorotate dehydrogenase (DHODH) activated autophagy as well, although mTORC1 activity was not altered by pyrimidine shortage. These results suggest a different mechanism of autophagy induction between purine and pyrimidine starvation. These findings provide novel insights into the regulation of autophagy by nucleotides and possibly the role of autophagy in nucleotide metabolism, leading to further developing anticancer strategies involving nucleotide synthesis and autophagy.
2021-05-11 | GSE164778 | GEO
Project description:The ability of Leishmania to survive in their insect or mammalian host is dependent upon an ability to sense and adapt to changes in the microenvironment. However, little is known about the molecular mechanisms underlying the parasite response to environmental changes, such as nutrient availability. To elucidate nutrient stress response pathways in Leishmania donovani, we have used purine starvation as the paradigm. The salvage of purines from the host milieu is obligatory for parasite replication; nevertheless, purine-starved parasites can persist in culture without supplementary purine for over 3 months, indicating that the response to purine starvation is robust and engenders parasite survival under conditions of extreme scarcity. To understand metabolic reprogramming during purine starvation we have employed global approaches. Whole proteome comparisons between purine-starved and purine-replete parasites over a 6-48 h span have revealed a temporal and coordinated response to purine starvation. Purine transporters and enzymes involved in acquisition at the cell surface are upregulated within a few hours of purine removal from the media, while other key purine salvage components are upregulated later in the time-course and more modestly. After 48 h, the proteome of purine-starved parasites is extensively remodeled and adaptations to purine stress appear tailored to deal with both purine deprivation and general stress. To probe the molecular mechanisms affecting proteome remodeling in response to purine starvation, comparative RNA-seq analyses, qRT-PCR, and luciferase reporter assays were performed on purine-starved versus purine-replete parasites. While the regulation of a minority of proteins tracked with changes at the mRNA level, for many regulated proteins it appears that proteome remodeling during purine stress occurs primarily via translational and post-translational mechanisms. One mRNA sample from each of Purine-Starved and Purine-Replete cells were analyzed using SL RNA-Seq methodology
2014-02-01 | E-GEOD-48394 | biostudies-arrayexpress
Project description:The ability of Leishmania to survive in their insect or mammalian host is dependent upon an ability to sense and adapt to changes in the microenvironment. However, little is known about the molecular mechanisms underlying the parasite response to environmental changes, such as nutrient availability. To elucidate nutrient stress response pathways in Leishmania donovani, we have used purine starvation as the paradigm. The salvage of purines from the host milieu is obligatory for parasite replication; nevertheless, purine-starved parasites can persist in culture without supplementary purine for over 3 months, indicating that the response to purine starvation is robust and engenders parasite survival under conditions of extreme scarcity. To understand metabolic reprogramming during purine starvation we have employed global approaches. Whole proteome comparisons between purine-starved and purine-replete parasites over a 6-48 h span have revealed a temporal and coordinated response to purine starvation. Purine transporters and enzymes involved in acquisition at the cell surface are upregulated within a few hours of purine removal from the media, while other key purine salvage components are upregulated later in the time-course and more modestly. After 48 h, the proteome of purine-starved parasites is extensively remodeled and adaptations to purine stress appear tailored to deal with both purine deprivation and general stress. To probe the molecular mechanisms affecting proteome remodeling in response to purine starvation, comparative RNA-seq analyses, qRT-PCR, and luciferase reporter assays were performed on purine-starved versus purine-replete parasites. While the regulation of a minority of proteins tracked with changes at the mRNA level, for many regulated proteins it appears that proteome remodeling during purine stress occurs primarily via translational and post-translational mechanisms.
2014-02-01 | GSE48394 | GEO
Project description:Curto1998 - purine metabolism
This is a purine metabolism model that is geared toward studies of gout.
The model uses Generalized Mass Action (GMA; i.e. power law) descriptions of reaction rate laws.
Such descriptions are local approximations that assume independent substrate binding.
This model is described in the article:
Mathematical models of
purine metabolism in man.
Curto R, Voit EO, Sorribas A,
Cascante M.
Math Biosci 1998 Jul; 151(1):
1-49
Abstract:
Experimental and clinical data on purine metabolism are
collated and analyzed with three mathematical models. The first
model is the result of an attempt to construct a traditional
kinetic model based on Michaelis-Menten rate laws. This attempt
is only partially successful, since kinetic information, while
extensive, is not complete, and since qualitative information
is difficult to incorporate into this type of model. The data
gaps necessitate the complementation of the Michaelis-Menten
model with other functional forms that can incorporate
different types of data. The most convenient and established
representations for this purpose are rate laws formulated as
power-law functions, and these are used to construct a
Complemented Michaelis-Menten (CMM) model. The other two models
are pure power-law-representations, one in the form of a
Generalized Mass Action (GMA) system, and the other one in the
form of an S-system. The first part of the paper contains a
compendium of experimental data necessary for any model of
purine metabolism. This is followed by the formulation of the
three models and a comparative analysis. For physiological and
moderately pathological perturbations in metabolites or
enzymes, the results of the three models are very similar and
consistent with clinical findings. This is an encouraging
result since the three models have different structures and
data requirements and are based on different mathematical
assumptions. Significant enzyme deficiencies are not so well
modeled by the S-system model. The CMM model captures the
dynamics better, but judging by comparisons with clinical
observations, the best model in this case is the GMA model. The
model results are discussed in some detail, along with
advantages and disadvantages of each modeling strategy.
This model is hosted on
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BIOMD0000000015.
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2024-09-02 | BIOMD0000000015 | BioModels