-
Applied and Environmental Microbiology Aug 2019In this work, we shed light on the metabolism of dihydroxyacetone (DHA), a versatile, ubiquitous, and important intermediate for various chemicals in industry, by...
In this work, we shed light on the metabolism of dihydroxyacetone (DHA), a versatile, ubiquitous, and important intermediate for various chemicals in industry, by analyzing its metabolism at the system level in Using constraint-based modeling, we show that the growth of on DHA is suboptimal and identify the potential causes. Nuclear magnetic resonance analysis shows that DHA is degraded nonenzymatically into substrates known to be unfavorable to high growth rates. Transcriptomic analysis reveals that DHA promotes genes involved in biofilm formation, which may reduce the bacterial growth rate. Functional analysis of the genes involved in DHA metabolism proves that under the aerobic conditions used in this study, DHA is mainly assimilated via the dihydroxyacetone kinase pathway. In addition, these results show that the alternative routes of DHA assimilation (i.e., the glycerol and fructose-6-phosphate aldolase pathways) are not fully activated under our conditions because of anaerobically mediated hierarchical control. These pathways are therefore certainly unable to sustain fluxes as high as the ones predicted for optimal aerobic growth on DHA. Overexpressing some of the genes in these pathways releases these constraints and restores the predicted optimal growth on DHA. DHA is an attractive triose molecule with a wide range of applications, notably in cosmetics and the food and pharmaceutical industries. DHA is found in many species, from microorganisms to humans, and can be used by as a growth substrate. However, knowledge about the mechanisms and regulation of this process is currently lacking, motivating our investigation of DHA metabolism in We show that under aerobic conditions, growth on DHA is far from optimal and is hindered by chemical, hierarchical, and possibly allosteric constraints. We show that optimal growth on DHA can be restored by releasing the hierarchical constraint. These results improve our understanding of DHA metabolism and are likely to help unlock biotechnological applications involving DHA as an intermediate, such as the bioconversion of glycerol or C substrates into value-added chemicals.
Topics: Bacterial Proteins; Dihydroxyacetone; Escherichia coli; Glycerol
PubMed: 31126940
DOI: 10.1128/AEM.00768-19 -
The Journal of Biological Chemistry Jun 2015Nicotinamide phosphoribosyltransferase (NAMPT) has been extensively studied due to its essential role in NAD(+) biosynthesis in cancer cells and the prospect of...
Nicotinamide phosphoribosyltransferase (NAMPT) has been extensively studied due to its essential role in NAD(+) biosynthesis in cancer cells and the prospect of developing novel therapeutics. To understand how NAMPT regulates cellular metabolism, we have shown that the treatment with FK866, a specific NAMPT inhibitor, leads to attenuation of glycolysis by blocking the glyceraldehyde 3-phosphate dehydrogenase step (Tan, B., Young, D. A., Lu, Z. H., Wang, T., Meier, T. I., Shepard, R. L., Roth, K., Zhai, Y., Huss, K., Kuo, M. S., Gillig, J., Parthasarathy, S., Burkholder, T. P., Smith, M. C., Geeganage, S., and Zhao, G. (2013) Pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), an enzyme essential for NAD(+) biosynthesis, in human cancer cells: metabolic basis and potential clinical implications. J. Biol. Chem. 288, 3500-3511). Due to technical limitations, we failed to separate isotopomers of phosphorylated sugars. In this study, we developed an enabling LC-MS methodology. Using this, we confirmed the previous findings and also showed that NAMPT inhibition led to accumulation of fructose 1-phosphate and sedoheptulose 1-phosphate but not glucose 6-phosphate, fructose 6-phosphate, and sedoheptulose 7-phosphate as previously thought. To investigate the metabolic basis of the metabolite formation, we carried out biochemical and cellular studies and established the following. First, glucose-labeling studies indicated that fructose 1-phosphate was derived from dihydroxyacetone phosphate and glyceraldehyde, and sedoheptulose 1-phosphate was derived from dihydroxyacetone phosphate and erythrose via an aldolase reaction. Second, biochemical studies showed that aldolase indeed catalyzed these reactions. Third, glyceraldehyde- and erythrose-labeling studies showed increased incorporation of corresponding labels into fructose 1-phosphate and sedoheptulose 1-phosphate in FK866-treated cells. Fourth, NAMPT inhibition led to increased glyceraldehyde and erythrose levels in the cell. Finally, glucose-labeling studies showed accumulated fructose 1,6-bisphosphate in FK866-treated cells mainly derived from dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. Taken together, this study shows that NAMPT inhibition leads to attenuation of glycolysis, resulting in further perturbation of carbohydrate metabolism in cancer cells. The potential clinical implications of these findings are also discussed.
Topics: Acrylamides; Carbohydrate Metabolism; Cytokines; Enzyme Inhibitors; Humans; Mass Spectrometry; NAD; Neoplasm Proteins; Neoplasms; Nicotinamide Phosphoribosyltransferase; Piperidines; Sugar Phosphates
PubMed: 25944913
DOI: 10.1074/jbc.M114.632141 -
Brain, Behavior, and Immunity Mar 2018Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11β-hydroxysteroid dehydrogenase type-1...
Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11β-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11β-HSD1 deficiency upon hippocampal energy metabolism. Inflammation was induced in 11β-HSD1 deficient (Hsd11b1) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1 mice, suggesting a similar peripheral inflammatory response. However, the induction of pro-inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1 mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1 mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1 mice. Consistent with increased glycolytic flux, levels of 3-phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1 mice. Expression of Sdha and Sdhb, encoding subunits of succinate dehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1 mice, together with increased levels of its product, fumarate. These data suggest 11β-HSD1 deficiency attenuates the hippocampal pro-inflammatory response to LPS, associated with increased capacity for aerobic glycolysis and mitochondrial ATP generation. This may provide better metabolic support and be neuroprotective during systemic inflammation or aging.
Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Behavior, Animal; Corticosterone; Energy Metabolism; Hippocampus; Illness Behavior; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Monocytes; Neutrophils
PubMed: 29162555
DOI: 10.1016/j.bbi.2017.11.015 -
Molecular Microbiology May 2020S-adenosyl-l-methionine (SAM) is a necessary cosubstrate for numerous essential enzymatic reactions including protein and nucleotide methylations, secondary metabolite...
S-adenosyl-l-methionine (SAM) is a necessary cosubstrate for numerous essential enzymatic reactions including protein and nucleotide methylations, secondary metabolite synthesis and radical-mediated processes. Radical SAM enzymes produce 5'-deoxyadenosine, and SAM-dependent enzymes for polyamine, neurotransmitter and quorum sensing compound synthesis produce 5'-methylthioadenosine as by-products. Both are inhibitory and must be addressed by all cells. This work establishes a bifunctional oxygen-independent salvage pathway for 5'-deoxyadenosine and 5'-methylthioadenosine in both Rhodospirillum rubrum and Extraintestinal Pathogenic Escherichia coli. Homologous genes for this pathway are widespread in bacteria, notably pathogenic strains within several families. A phosphorylase (Rhodospirillum rubrum) or separate nucleoside and kinase (Escherichia coli) followed by an isomerase and aldolase sequentially function to salvage these two wasteful and inhibitory compounds into adenine, dihydroxyacetone phosphate and acetaldehyde or (2-methylthio)acetaldehyde during both aerobic and anaerobic growth. Both SAM by-products are metabolized with equal affinity during aerobic and anaerobic growth conditions, suggesting that the dual-purpose salvage pathway plays a central role in numerous environments, notably the human body during infection. Our newly discovered bifunctional oxygen-independent pathway, widespread in bacteria, salvages at least two by-products of SAM-dependent enzymes for carbon and sulfur salvage, contributing to cell growth.
Topics: Bacterial Proteins; Carbon; Deoxyadenosines; Dihydroxyacetone Phosphate; Escherichia coli; Fructose-Bisphosphate Aldolase; Isomerases; Metabolic Networks and Pathways; Methionine; N-Glycosyl Hydrolases; Oxygen; Phosphorylases; Phosphotransferases; Rhodospirillum rubrum; S-Adenosylmethionine; Thionucleosides
PubMed: 31950558
DOI: 10.1111/mmi.14459 -
The New Phytologist Nov 2021Current models of floral nectar production do not include a contribution from photosynthesis by green nectary tissue, even though many species have green nectaries....
Current models of floral nectar production do not include a contribution from photosynthesis by green nectary tissue, even though many species have green nectaries. Mānuka (Leptospermum scoparium) floral nectaries are green, and in addition to sugars, their nectar contains dihydroxyacetone (DHA), the precursor of the antimicrobial agent in the honey. We investigated causes of variation in mānuka floral nectar production, particularly the effect of light incident on the nectary. Flower gas exchange, chlorophyll fluorescence, and the effects on nectar of age, temperature, light, sucrose, 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), pyridoxal phosphate, and CO , were measured for attached and excised flowers. Flower age affected all nectar traits, whilst temperature affected total nectar sugar only. Increased light reduced floral CO efflux, increased nectar sugar production, and affected the ratio of DHA to other nectar sugars. DCMU, an inhibitor of photosystem II, reduced nectar sugar production. Pyridoxal phosphate, an inhibitor of the chloroplast envelope triose phosphate transporter, reduced nectar DHA content. Incubation of excised flowers with CO in the light resulted in enrichment of nectar sugars, including DHA. Photosynthesis within green nectaries contributes to nectar sugars and influences nectar composition. Mānuka nectar DHA arises from pools of triose phosphate that are modulated by nectary photosynthesis.
Topics: Dihydroxyacetone; Flowers; Leptospermum; Photosynthesis; Plant Nectar
PubMed: 34287899
DOI: 10.1111/nph.17632 -
Arhiv Za Higijenu Rada I Toksikologiju Jun 2018Aluminium phosphide (AlP), a very toxic pesticide also known as the rice tablet, releases phosphine gas upon contact with water, moisture, or gastric acid. Its mortality...
Aluminium phosphide (AlP), a very toxic pesticide also known as the rice tablet, releases phosphine gas upon contact with water, moisture, or gastric acid. Its mortality rate in humans is 70-100 % due to cardiogenic shock and refractory hypotension. Dihydroxyacetone (DHA) is a simple ketonic carbohydrate, mainly used for sunless skin tanning. It also plays a beneficial role in the treatment of hypotension and cardiogenic shock by restoring blood volume and cellular respiration. The aim of this study was to investigate the its effect on the haemodynamics and electrocardiogram (ECG) in male rats poisoned with AlP. The animals were divided into the following groups: control (received 1 mL corn oil, orally), AlP (received 15 mg kg-1 AlP solved in corn oil, orally), AlP plus DHA (treated with 50 mg kg-1 of DHA 30 min after receiving AlP), and AlP plus N-acetyl cysteine (NAC) (treated with 200 mg kg-1 of NAC 30 min after receiving AlP). The animals were then anaesthetised and ECG, blood pressure, and heart rate were recorded for 120 min. Treatment with AlP alone and in combination with NAC was associated with progressive hypotension, tachycardia, and ECG disturbances in rats, resulting in 100 % mortality 3 h after poisoning. However, DHA achieved 100 % survival in the poisoned rats and prevented AlP-induced ECG and haemodynamic abnormalities. The main mechanism of DHA in the treatment of AlP poisoning is unclear, but the findings suggest the promising therapeutic potential of DHA against AlP poisoning.
Topics: Aluminum Compounds; Animals; Dihydroxyacetone; Male; Pesticides; Phosphines; Poisoning; Rats; Shock, Cardiogenic
PubMed: 29990298
DOI: 10.2478/aiht-2018-69-3106 -
PloS One 2016The efficient use of hemicellulose in the plant cell wall is critical for the economic conversion of plant biomass to renewable fuels and chemicals. Previously, the...
The efficient use of hemicellulose in the plant cell wall is critical for the economic conversion of plant biomass to renewable fuels and chemicals. Previously, the yeast Saccharomyces cerevisiae has been engineered to convert the hemicellulose-derived pentose sugars xylose and arabinose to d-xylulose-5-phosphate for conversion via the pentose phosphate pathway (PPP). However, efficient pentose utilization requires PPP optimization and may interfere with its roles in NADPH and pentose production. Here, we developed an alternative xylose utilization pathway that largely bypasses the PPP. In the new pathway, d-xylulose is converted to d-xylulose-1-phosphate, a novel metabolite to S. cerevisiae, which is then cleaved to glycolaldehyde and dihydroxyacetone phosphate. This synthetic pathway served as a platform for the biosynthesis of ethanol and ethylene glycol. The use of d-xylulose-1-phosphate as an entry point for xylose metabolism opens the way for optimizing chemical conversion of pentose sugars in S. cerevisiae in a modular fashion.
Topics: Fermentation; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Fungal; Metabolic Networks and Pathways; Mutation; Pentose Phosphate Pathway; Pentoses; Phosphotransferases (Alcohol Group Acceptor); Saccharomyces cerevisiae; Xylose
PubMed: 27336308
DOI: 10.1371/journal.pone.0158111 -
Analytical Biochemistry Sep 2022For many years, Shiliu Buxue Syrup (SLBXS) has been used in the treatment of anemia in Xinjiang, China. However, the potential therapeutic mechanism of SLBXS in the...
For many years, Shiliu Buxue Syrup (SLBXS) has been used in the treatment of anemia in Xinjiang, China. However, the potential therapeutic mechanism of SLBXS in the treatment of anemia remains unclear. We qualitatively analyzed the ingredients of SLBXS and predicted the underlying mechanisms by network pharmacology. A mice model of anemia was established by subcutaneous injection of 1-Acetyl-2-phenylhydrazine (APH). Spleen metabolomics was performed to screen potential biomarkers and pathways related to anemia. Furthermore, core targets of crucial pathways were experimentally validated. Finally, molecular docking was used for predicting interactions between compositions and targets. Network pharmacology indicated that the 230 SLBXS ingredients may affect 141 target proteins to regulate the PI3K/AKT and HIF-1 signaling pathways. Metabolomics revealed that SLBXS could mediate 30 biomarkers, such as phosphoric acid, l-pyroglutamic acid, alpha-Tocopherol, 1-stearoyl-rac-glycerol, and dihydroxyacetone phosphate, to regulate drug metabolism-other enzymes, glutathione metabolism, glycolysis or gluconeogenesis, nicotinate and nicotinamide metabolism, nitrogen metabolism, and purine metabolism. Western blot indicated that SLBXS can regulate the protein expression levels of AKT1, Bcl2, Caspase3, HIF-1α, VEGF-A, and NOS2. The molecular docking revealed that most of the compositions had a good binding ability to the core targets. Based on these findings, we speculate that SLBXS treats anemia mainly by modulating the PI3K/AKT and HIF-1 pathways and glutathione and glycolytic metabolisms.
Topics: Anemia; Animals; Biomarkers; Drugs, Chinese Herbal; Glutathione; Metabolomics; Mice; Molecular Docking Simulation; Network Pharmacology; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt
PubMed: 35690102
DOI: 10.1016/j.ab.2022.114774 -
Scientific Reports Oct 2022In vitro and in vivo studies have established the organic anion transporters OAT1 (SLC22A6, NKT) and OAT3 (SLC22A8) among the main multi-specific "drug" transporters....
In vitro and in vivo studies have established the organic anion transporters OAT1 (SLC22A6, NKT) and OAT3 (SLC22A8) among the main multi-specific "drug" transporters. They also transport numerous endogenous metabolites, raising the possibility of drug-metabolite interactions (DMI). To help understand the role of these drug transporters on metabolism across scales ranging from organ systems to organelles, a formal multi-scale analysis was performed. Metabolic network reconstructions of the omics-alterations resulting from Oat1 and Oat3 gene knockouts revealed links between the microbiome and human metabolism including reactions involving small organic molecules such as dihydroxyacetone, alanine, xanthine, and p-cresol-key metabolites in independent pathways. Interestingly, pairwise organ-organ interactions were also disrupted in the two Oat knockouts, with altered liver, intestine, microbiome, and skin-related metabolism. Compared to older models focused on the "one transporter-one organ" concept, these more sophisticated reconstructions, combined with integration of a multi-microbial model and more comprehensive metabolomics data for the two transporters, provide a considerably more complex picture of how renal "drug" transporters regulate metabolism across the organelle (e.g. endoplasmic reticulum, Golgi, peroxisome), cellular, organ, inter-organ, and inter-organismal scales. The results suggest that drugs interacting with OAT1 and OAT3 can have far reaching consequences on metabolism in organs (e.g. skin) beyond the kidney. Consistent with the Remote Sensing and Signaling Theory (RSST), the analysis demonstrates how transporter-dependent metabolic signals mediate organ crosstalk (e.g., gut-liver-kidney) and inter-organismal communication (e.g., gut microbiome-host).
Topics: Humans; Gastrointestinal Microbiome; Metabolic Networks and Pathways; Metabolomics; Organic Anion Transport Protein 1; Organic Anion Transporters, Sodium-Independent
PubMed: 36316339
DOI: 10.1038/s41598-022-21091-w -
Journal of the Dermatology Nurses'... 2023The use of indoor UV tanning devices (also known as "indoor tanning") has declined in recent years. Less is known about use of dihydroxyacetone-containing products used...
The use of indoor UV tanning devices (also known as "indoor tanning") has declined in recent years. Less is known about use of dihydroxyacetone-containing products used for tanning (also known as "sunless tanning"). We analyzed data from the 2015 National Health Interview Survey. Analysis was limited to non-Hispanic White women ages 18-49 years. We estimated the proportion of women reporting spray tanning, self-applied lotion tanning, and indoor tanning and used weighted multivariable logistic regression models to examine the relationships between socio-demographic characteristics, skin cancer risk factors, and other cancer risk factors with sunless and indoor tanning. Overall, 17.7% of women reported sunless tanning. Lotion tanning was more common (15.3%) than spray tanning (6.8%), while 12.0% of women engaged in indoor tanning. Among sunless tanners, 23.7% also engaged in indoor tanning. Younger age, ever having a skin exam, skin reactions to the sun, binge drinking, and being at a healthy weight were associated with sunless tanning. While sunless tanning may be less harmful for skin cancer risk than indoor tanning, the frequency with which the two behaviors co-occur suggests that efforts to address societal pressures for women to alter their skin color may have important public health benefits.
PubMed: 38463180
DOI: 10.1097/jdn.0000000000000736