scholarly journals Fatty Acid Synthesis and Pyruvate Metabolism Pathways Remain Active in Dihydroartemisinin-Induced Dormant Ring Stages of Plasmodium falciparum

2014 ◽  
Vol 58 (8) ◽  
pp. 4773-4781 ◽  
Author(s):  
Nanhua Chen ◽  
Alexis N. LaCrue ◽  
Franka Teuscher ◽  
Norman C. Waters ◽  
Michelle L. Gatton ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Metabolic Pathways ◽  
Acid Synthesis ◽  
High Rate ◽  
Mitochondrial Proteins ◽  
Pyruvate Metabolism ◽  
Transcription Analysis ◽  
Recent Emergence ◽  
Genes Encoding

ABSTRACTArtemisinin (ART)-based combination therapy (ACT) is used as the first-line treatment of uncomplicated falciparum malaria worldwide. However, despite high potency and rapid action, there is a high rate of recrudescence associated with ART monotherapy or ACT long before the recent emergence of ART resistance. ART-induced ring-stage dormancy and recovery have been implicated as possible causes of recrudescence; however, little is known about the characteristics of dormant parasites, including whether dormant parasites are metabolically active. We investigated the transcription of 12 genes encoding key enzymes in various metabolic pathways inP. falciparumduring dihydroartemisinin (DHA)-induced dormancy and recovery. Transcription analysis showed an immediate downregulation for 10 genes following exposure to DHA but continued transcription of 2 genes encoding apicoplast and mitochondrial proteins. Transcription of several additional genes encoding apicoplast and mitochondrial proteins, particularly of genes encoding enzymes in pyruvate metabolism and fatty acid synthesis pathways, was also maintained. Additions of inhibitors for biotin acetyl-coenzyme A (CoA) carboxylase and enoyl-acyl carrier reductase of the fatty acid synthesis pathways delayed the recovery of dormant parasites by 6 and 4 days, respectively, following DHA treatment. Our results demonstrate that most metabolic pathways are downregulated in DHA-induced dormant parasites. In contrast, fatty acid and pyruvate metabolic pathways remain active. These findings highlight new targets to interrupt recovery of parasites from ART-induced dormancy and to reduce the rate of recrudescence following ART treatment.

IDENTIFYING RELEVANT PATHWAYS AND BIOMARKERS IN CROHN’S DISEASE USING CONTEXTUALIZED METABOLIC NETWORK MODEL

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S9-S10
Author(s):  
Brooklyn McGrew ◽  
Aman Shrivastava ◽  
Philip Fernandes ◽  
Lubaina Ehsan ◽  
Yash Sharma ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Fatty Acid ◽  
Crohn's Disease ◽  
Fatty Acid Synthesis ◽  
Metabolic Pathway ◽  
Metabolic Pathways ◽  
Acid Synthesis ◽  
Transcriptomic Data ◽  
Context Specific

Abstract Background Candidate markers for Crohn’s Disease (CD) may be identified via gene expression-based construction of metabolic networks (MN). These can computationally describe gene-protein-reaction associations for entire tissues and also predict the flux of reactions (rate of turnover of specific molecules via a metabolic pathway). Recon3D is the most comprehensive human MN to date. We used publicly available CD transcriptomic data along with Recon3D to identify metabolites as potential diagnostic and prognostic biomarkers. Methods Terminal ileal gene expression profiles (36,372 genes; 218 CD. 42 controls) from the RISK cohort (Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn’s Disease) and their transcriptomic abundances were used. Recon3D was pruned to only include RISK dataset transcripts which determined metabolic reaction linkage with transcriptionally active genes. Flux balance analysis (FBA) was then run using RiPTiDe with context specific transcriptomic data to further constrain genes (Figure 1). RiPTiDe was independently run on transcriptomic data from both CD and controls. From the pruned and constricted MN obtained, reactions were extracted for further analysis. Results After applying the necessary constraints to modify Recon3D, 527 CD and 537 control reactions were obtained. Reaction comparison with a publicly available list of healthy small intestinal epithelial reactions (n=1282) showed an overlap of 80 CD and 84 control reactions. These were then further grouped based on their metabolic pathways. RiPTiDe identified context specific metabolic pathway activity without supervision and the percentage of forward, backward, and balanced reactions for each metabolic pathway (Figure 2). The metabolite concentrations in the small intestine was altered among CD patients. Notably, the citric acid cycle and malate-aspartate shuttle were affected, highlighting changes in mitochondrial metabolic pathways. This is illustrated by changes in the number of reactions at equilibrium between CD and control. Conclusions The results are relevant as cytosolic acetyl-CoA is needed for fatty acid synthesis and is obtained by removing citrate from the citric acid cycle. An intermediate removal from the cycle has significant cataplerotic effects. The malate-aspartate shuttle also allows electrons to move across the impermeable membrane in the mitochondria (fatty acid synthesis location). These findings are reported by previously published studies where gene expression for fatty acid synthesis is altered in CD patients along with mitochondrial metabolic pathway changes, resulting in altered cell homeostasis. In-depth analysis is currently underway with our work supporting the utility of potential metabolic biomarkers for CD diagnosis, management and improved care.

scholarly journals Glycolysis, Glutaminolysis, and Fatty Acid Synthesis Are Required for Distinct Stages of Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication

2017 ◽  
Vol 91 (10) ◽  
Author(s):  
Erica L. Sanchez ◽  
Thomas H. Pulliam ◽  
Terri A. Dimaio ◽  
Angel B. Thalhofer ◽  
Tracie Delgado ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Metabolic Pathways ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Acid Synthesis ◽  
Lytic Replication ◽  
Early Gene ◽  
Latently Infected ◽  
Infected Cells

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS). KSHV infection induces and requires multiple metabolic pathways, including the glycolysis, glutaminolysis, and fatty acid synthesis (FAS) pathways, for the survival of latently infected endothelial cells. To determine the metabolic requirements for productive KSHV infection, we induced lytic replication in the presence of inhibitors of different metabolic pathways. We found that glycolysis, glutaminolysis, and FAS are all required for maximal KSHV virus production and that these pathways appear to participate in virus production at different stages of the viral life cycle. Glycolysis and glutaminolysis, but not FAS, inhibit viral genome replication and, interestingly, are required for different early steps of lytic gene expression. Glycolysis is necessary for early gene transcription, while glutaminolysis is necessary for early gene translation but not transcription. Inhibition of FAS resulted in decreased production of extracellular virions but did not reduce intracellular genome levels or block intracellular virion production. However, in the presence of FAS inhibitors, the intracellular virions are noninfectious, indicating that FAS is required for virion assembly or maturation. KS tumors support both latent and lytic KSHV replication. Previous work has shown that multiple cellular metabolic pathways are required for latency, and we now show that these metabolic pathways are required for efficient lytic replication, providing novel therapeutic avenues for KS tumors. IMPORTANCE KSHV is the etiologic agent of Kaposi's sarcoma, the most common tumor of AIDS patients. KS spindle cells, the main tumor cells, all contain KSHV, mostly in the latent state, during which there is limited viral gene expression. However, a percentage of spindle cells support lytic replication and production of virus and these cells are thought to contribute to overall tumor formation. Our previous findings showed that latently infected cells are sensitive to inhibitors of cellular metabolic pathways, including glycolysis, glutaminolysis, and fatty acid synthesis. Here we found that these same inhibitors block the production of infectious virus from lytically infected cells, each at a different stage of viral replication. Therefore, inhibition of specific cellular metabolic pathways can both eliminate latently infected cells and block lytic replication, thereby inhibiting infection of new cells. Inhibition of metabolic pathways provides novel therapeutic approaches for KS tumors.

scholarly journals Synthesis of Dolichols in Candida albicans Is Co-Regulated with Elongation of Fatty Acids

2021 ◽  
Vol 23 (1) ◽  
pp. 409
Author(s):  
Anna Janik ◽  
Urszula Perlińska-Lenart ◽  
Katarzyna Gawarecka ◽  
Justyna Augustyniak ◽  
Ewelina Bratek-Gerej ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Mevalonate Pathway ◽  
Acid Synthesis ◽  
Cellular Level ◽  
Protein Glycosylation ◽  
Acetyl Coa ◽  
Gene Encoding ◽  
Expression Of Genes ◽  
Genes Encoding

Protein glycosylation requires dolichyl phosphate as a carbohydrate carrier. Dolichols are α-saturated polyprenols, and their saturation in S. cerevisiae is catalyzed by polyprenyl reductase Dfg10 together with some other unknown enzymes. The aim of this study was to identify such enzymes in Candida. The Dfg10 polyprenyl reductase from S. cerevisiae comprises a C-terminal 3-oxo-5-alpha-steroid 4-dehydrogenase domain. Alignment analysis revealed such a domain in two ORFs (orf19.209 and orf19.3293) from C. albicans, which were similar, respectively, to Dfg10 polyprenyl reductase and Tsc13 enoyl-transferase from S. cerevisiae. Deletion of orf19.209 in Candida impaired saturation of polyprenols. The Tsc13 homologue turned out not to be capable of saturating polyprenols, but limiting its expression reduce the cellular level of dolichols and polyprenols. This reduction was not due to a decreased expression of genes encoding cis-prenyltransferases from the dolichol branch but to a lower expression of genes encoding enzymes of the early stages of the mevalonate pathway. Despite the resulting lower consumption of acetyl-CoA, the sole precursor of the mevalonate pathway, it was not redirected towards fatty acid synthesis or elongation. Lowering the expression of TSC13 decreased the expression of the ACC1 gene encoding acetyl-CoA carboxylase, the key regulatory enzyme of fatty acid synthesis and elongation.

scholarly journals Effect of propionate on fatty acid and cholesterol synthesis and on acetate metabolism in isolated rat hepatocytes

1995 ◽  
Vol 74 (2) ◽  
pp. 209-219 ◽  
Author(s):  
Christian Demigné ◽  
Christine Morand ◽  
Marie-Anne Levrat ◽  
Catherine Besson ◽  
Corinne Moundras ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Cholesterol Synthesis ◽  
Rat Hepatocytes ◽  
Acid Synthesis ◽  
High Rate ◽  
Acetate Metabolism ◽  
Effective Inhibitor ◽  
Isolated Rat Hepatocytes

In the present study the actual role of propionic acid in the control of fatty acid and cholesterol synthesis was investigated in isolated liver cells from fed rats maintained in the presence of near-physiological concentrations of glucose, glutamine and acetate. Using 3H2O for lipid labelling, propionate appears as an effective inhibitor of fatty acid synthesis and to a lesser extent of cholesterol synthesis, even at the lowest concentration used (0·6 mmol/l). Butyrate is a potent activator of both synthetic pathways, and the activating effect was not counteracted by propionate. Using 1-[14C]acetate, it was observed that propionate at a moderate concentration, or 1 mmol oleate/l, are both very effective inhibitors of 14C incorporation into fatty acid and cholesterol. This incorporation was drastically inhibited when propionate and oleate were present together in the incubation medium. The net utilization of acetate by rat hepatocytes was impaired by propionate, in contrast to oleate. 1-[14C]butyrate was utilized at a high rate for fatty acid synthesis, but to a lesser extent for cholesterol synthesis; both processes were unaffected by propionate. Intracellular citrate concentration was not markedly depressed by propionate, whereas it was strongly elevated by butyrate. In conclusion, propionate may represent an effective inhibitor of lipid synthesis when acetate is a major source of acetyl-CoA, a situation which is encountered with diets rich in readily-fermentable fibres. The present findings also suggest that propionate may be effective at concentrations close to values measured in vivo in the portal vein.

scholarly journals Multiple Triclosan Targets in Trypanosoma brucei

2004 ◽  
Vol 3 (4) ◽  
pp. 855-861 ◽  
Author(s):  
Kimberly S. Paul ◽  
Cyrus J. Bacchi ◽  
Paul T. Englund
Keyword(s):  
Fatty Acid ◽  
Trypanosoma Brucei ◽  
Fatty Acid Synthesis ◽  
Acyl Carrier Protein ◽  
Acid Synthesis ◽  
Bloodstream Form ◽  
Type Ii ◽  
Subcellular Compartment ◽  
Genes Encoding ◽  
Enoyl Acp Reductase

ABSTRACT Trypanosoma brucei genes encoding putative fatty acid synthesis enzymes are homologous to those encoding type II enzymes found in bacteria and organelles such as chloroplasts and mitochondria. It was therefore not surprising that triclosan, an inhibitor of type II enoyl-acyl carrier protein (enoyl-ACP) reductase, killed both procyclic forms and bloodstream forms of T. brucei in culture with 50% effective concentrations (EC50s) of 10 and 13 μM, respectively. Triclosan also inhibited cell-free fatty acid synthesis, though much higher concentrations were required (EC50s of 100 to 200 μM). Unexpectedly, 100 μM triclosan did not affect the elongation of [3H]laurate (C12:0) to myristate (C14:0) in cultured bloodstream form parasites, suggesting that triclosan killing of trypanosomes may not be through specific inhibition of enoyl-ACP reductase but through some other mechanism. Interestingly, 100 μM triclosan did reduce the level of incorporation of [3H]myristate into glycosyl phosphatidylinositol species (GPIs). Furthermore, we found that triclosan inhibited fatty acid remodeling in a cell-free assay in the same concentration range required for killing T. brucei in culture. In addition, we found that a similar concentration of triclosan also inhibited the myristate exchange pathway, which resides in a distinct subcellular compartment. However, GPI myristoylation and myristate exchange are specific to the bloodstream form parasite, yet triclosan kills both the bloodstream and procyclic forms. Therefore, triclosan killing may be due to a nonspecific perturbation of subcellular membrane structure leading to dysfunction in sensitive membrane-resident biochemical pathways.

scholarly journals Inhibition by long-chain acyl-CoAs of glucose 6-phosphate metabolism in plastids isolated from developing embryos of oilseed rape (Brassica napus L.)

2000 ◽  
Vol 348 (1) ◽  
pp. 145-150 ◽  
Author(s):  
Philip E. JOHNSON ◽  
Simon R. FOX ◽  
Matthew J. HILLS ◽  
Stephen RAWSTHORNE
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Starch Synthesis ◽  
Acid Synthesis ◽  
Pentose Phosphate ◽  
Pyruvate Metabolism ◽  
Brassica Napus L ◽  
Chain Acyl ◽  
Long Chain

The effects of long-chain acyl-CoA (lcACoA) esters (both added exogenously and synthesized de novo) and acyl-CoA binding protein (ACBP) on plastidial glucose 6-phosphate (Glc6P) and pyruvate metabolism were examined using isolated plastids. The binding of lcACoA esters by ACBP stimulated the utilization of Glc6P for fatty acid synthesis, starch synthesis and reductant supply via the oxidative pentose phosphate (OPP) pathway. Stimulation occurred at low (1-10 μM) concentrations of ACBP. Pyruvate-dependent fatty acid synthesis was not directly affected by ACBP. However, addition of ACBP did increase the Glc6P-dependent stimulation of pyruvate utilization mediated through the OPP pathway. On the basis of these experiments, we conclude that lcACoA esters may inhibit Glc6P uptake into plastids, and that this inhibition is relieved by ACBP. We also suggest that utilization of other substrates for fatty acid synthesis may be affected by lcACoA/ACBP via their effects on the OPP pathway.

scholarly journals Delayed Feeding Alters Transcriptional and Post-Transcriptional Regulation of Hepatic Metabolic Pathways in Peri-Hatch Broiler Chicks

Genes ◽  
2019 ◽  
Vol 10 (4) ◽  
pp. 272 ◽  
Author(s):  
Julie A. Hicks ◽  
Tom E. Porter ◽  
Nishanth E. Sunny ◽  
Hsiao-Ching Liu
Keyword(s):  
Oxidative Stress ◽  
Energy Source ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Metabolic Pathways ◽  
Acid Synthesis ◽  
Feed Consumption ◽  
Acid Oxidation ◽  
Metabolic Switch ◽  
Hepatic Expression

Hepatic fatty acid oxidation of yolk lipoproteins provides the main energy source for chick embryos. Post-hatching these yolk lipids are rapidly exhausted and metabolism switches to a carbohydrate-based energy source. We recently demonstrated that many microRNAs (miRNAs) are key regulators of hepatic metabolic pathways during this metabolic switching. MiRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression in most eukaryotes. To further elucidate the roles of miRNAs in the metabolic switch, we used delayed feeding for 48 h to impede the hepatic metabolic switch. We found that hepatic expression of several miRNAs including miR-33, miR-20b, miR-34a, and miR-454 was affected by delaying feed consumption for 48 h. For example, we found that delayed feeding resulted in increased miR-20b expression and conversely reduced expression of its target FADS1, an enzyme involved in fatty acid synthesis. Interestingly, the expression of a previously identified miR-20b regulator FOXO3 was also higher in delayed fed chicks. FOXO3 also functions in protection of cells from oxidative stress. Delayed fed chicks also had much higher levels of plasma ketone bodies than their normal fed counterparts. This suggests that delayed fed chicks rely almost exclusively on lipid oxidation for energy production and are likely under higher oxidative stress. Thus, it is possible that FOXO3 may function to both limit lipogenesis as well as to help protect against oxidative stress in peri-hatch chicks until the initiation of feed consumption. This is further supported by evidence that the FOXO3-regulated histone deacetylase (HDAC2) was found to recognize the FASN (involved in fatty acid synthesis) chicken promoter in a yeast one-hybrid assay. Expression of FASN mRNA was lower in delayed fed chicks until feed consumption. The present study demonstrated that many transcriptional and post-transcriptional mechanisms, including miRNA, form a complex interconnected regulatory network that is involved in controlling lipid and glucose molecular pathways during the metabolic transition in peri-hatch chicks.

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