-
Theranostics 2023Despite growing evidence for mitochondria's involvement in cancer, the roles of specific metabolic components outside the respiratory complex have been little explored....
Despite growing evidence for mitochondria's involvement in cancer, the roles of specific metabolic components outside the respiratory complex have been little explored. We conducted metabolomic studies on mitochondrial DNA (mtDNA)-deficient (ρ0) cancer cells with lower proliferation rates to clarify the undefined roles of mitochondria in cancer growth. Despite extensive metabolic downregulation, ρ0 cells exhibited high glycerol-3-phosphate (G3P) level, due to low activity of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2). Knockout (KO) of GPD2 resulted in cell growth suppression as well as inhibition of tumor progression Surprisingly, this was unrelated to the conventional bioenergetic function of GPD2. Instead, multi-omics results suggested major changes in ether lipid metabolism, for which GPD2 provides dihydroxyacetone phosphate (DHAP) in ether lipid biosynthesis. GPD2 KO cells exhibited significantly lower ether lipid level, and their slower growth was rescued by supplementation of a DHAP precursor or ether lipids. Mechanistically, ether lipid metabolism was associated with Akt pathway, and the downregulation of Akt/mTORC1 pathway due to GPD2 KO was rescued by DHAP supplementation. Overall, the GPD2-ether lipid-Akt axis is newly described for the control of cancer growth. DHAP supply, a non-bioenergetic process, may constitute an important role of mitochondria in cancer.
Topics: Energy Metabolism; Ethers; Glycerolphosphate Dehydrogenase; Mitochondria; Proto-Oncogene Proteins c-akt; Animals; Mice; Neoplasms; Humans
PubMed: 36632231
DOI: 10.7150/thno.75973 -
Scientific Reports Jan 2021Two putative methylglyoxal synthases, which catalyze the conversion of dihydroxyacetone phosphate to methylglyoxal, from Oceanithermus profundus DSM 14,977 and...
Two putative methylglyoxal synthases, which catalyze the conversion of dihydroxyacetone phosphate to methylglyoxal, from Oceanithermus profundus DSM 14,977 and Clostridium difficile 630 have been characterized for activity and thermal stability. The enzyme from O. profundus was found to be hyperthermophilic, with the optimum activity at 80 °C and the residual activity up to 59% after incubation of 15 min at 95 °C, whereas the enzyme from C. difficile was mesophilic with the optimum activity at 40 °C and the residual activity less than 50% after the incubation at 55 °C or higher temperatures for 15 min. The structural analysis of the enzymes with molecular dynamics simulation indicated that the hyperthermophilic methylglyoxal synthase has a rigid protein structure with a lower overall root-mean-square-deviation value compared with the mesophilic or thermophilic counterparts. In addition, the simulation results identified distinct regions with high fluctuations throughout those of the mesophilic or thermophilic counterparts via root-mean-square-fluctuation analysis. Specific molecular interactions focusing on the hydrogen bonds and salt bridges in the distinct regions were analyzed in terms of interatomic distances and positions of the individual residues with respect to the secondary structures of the enzyme. Key interactions including specific salt bridges and hydrogen bonds between a rigid beta-sheet core and surrounding alpha helices were found to contribute to the stabilisation of the hyperthermophilic enzyme by reducing the regional fluctuations in the protein structure. The structural information and analysis approach in this study can be further exploited for the engineering and industrial application of the enzyme.
Topics: Amino Acid Sequence; Carbon-Oxygen Lyases; Enzyme Stability; Hydrogen-Ion Concentration; Models, Molecular; Molecular Dynamics Simulation; Protein Conformation; Protein Engineering; Recombinant Proteins; Structure-Activity Relationship; Temperature; Thermodynamics
PubMed: 33510339
DOI: 10.1038/s41598-021-82078-7 -
Heliyon Nov 2023Aluminum phosphide (AlP), known as "rice tablet," is widely used as an effective pesticide. However, AlP poisoning is a common cause of mortality in many countries, such...
BACKGROUND AND OBJECTIVES
Aluminum phosphide (AlP), known as "rice tablet," is widely used as an effective pesticide. However, AlP poisoning is a common cause of mortality in many countries, such as Iran. Unfortunately, there is no specific antidote for AlP toxicity to date. AlP releases phosphine gas when it is exposed to moisture or acid. Phosphine is a potent mitochondrial toxin that could significantly inhibit cellular energy metabolism. AlP poisoning is an emergency condition that needs instant and effective intervention. Dihydroxyacetone (DHA) is a simple saccharide used for several pharmacological as well as cosmetic purposes. Previously, we found that DHA could significantly prevent mitochondrial impairment induced by toxic agents such as cyanide and phosphine in various and experimental models.
METHODS
Hospitalized patients (n = 111) were evaluated for eligibility criteria. Among these patients, n = 35 cases were excluded due to incomplete data (n = 11) and suspicion of poisoning with poisons other than AlP (n = 24). Meanwhile, n = 76 cases with confirmed AlP poisoning were included in the study. AlP-poisoned patients who did not receive DHA (n = 18) were used as the control group.Patients (n = 58) received at least one dose of DHA (500 ml of 5 % DHA solution w/v, i.v.) as an adjuvant therapy in addition to the routine treatment of AlP poisoning. Arterial blood gas (ABG), blood pH, bicarbonate levels, and other vital signs and biochemical measurements were monitored. Moreover, the mortality rate and hospitalization time were evaluated in DHA-treated and AlP-poisoned patients without DHA administration. Several biomarkers were assessed before (upon hospitalization) and after DHA treatment. The routine tests for AlP-poisoned patients in this study were the measurement of electrolytes (K and Na), WBC, RBC, hemoglobin, INR, carbonate (HCO), blood pH, PaCO, and PaO and SGPT, SGOT, BUN, Cr.
RESULTS
Upon patients' admission, significant decreases in blood pH (acidosis), blood PaO, and HCO levels were the hallmarks of AlP poisoning. It was found that DHA significantly alleviated biomarkers of AlP poisoning and tremendously enhanced patients' survival rate (65.52 % in DHA-treated 33.34 % in the control group) compared to patients treated based on hospital routine AlP poisoning protocols (no DHA). No significant adverse effects were evident in DHA-treated patients in the current study.
INTERPRETATION AND CONCLUSIONS
These data suggest that parenteral DHA is a novel and effective antidote against AlP poisoning to be used as an adjuvant in addition to routine supportive treatment.
TRIAL REGISTRATION
IR.SUMS.REC.1394.102.
PubMed: 38053886
DOI: 10.1016/j.heliyon.2023.e22165 -
PloS One 2020The main ingredient of sunless tanning products is dihydroxyacetone (DHA). DHA reacts with the protein and amino acid composition in the surface layers of the skin,...
The main ingredient of sunless tanning products is dihydroxyacetone (DHA). DHA reacts with the protein and amino acid composition in the surface layers of the skin, producing melanoidins, which changes the skin colour, imitating natural skin tan caused by melanin. The purpose of this study was to characterise DHA-induced skin colour changes and to test whether we can predict the outcome of DHA application on skin tone changes. To assess the DHA-induced skin colour shift quantitatively, colorimetric and spectral measurements of the inner forearm were obtained before, four hours and 24 hours after application of a 7.5% concentration DHA gel in the experimental group (n = 100). In a control group (n = 60), the same measurements were obtained on both the inner forearm (infrequently sun-exposed) and the outer forearm (frequently sun-exposed); the difference between these two areas was defined as the naturally occurring tan. Skin colour shifts caused by DHA tanning and by natural tanning were compared in terms of lightness (L*), redness (a*) and yellowness (b*) in the standard CIELAB colour space. Naturalness of the DHA-induced skin tan was evaluated by comparing the trajectory of the chromaticity distribution in (L*, b*) space with that of naturally occurring tan. Twenty-four hours after DHA application, approximately 20% of the skin colour samples became excessively yellow, with chromaticities outside the natural range in (L*, b*) space. A principal component analysis was used to characterise the tanning pathway. Skin colour shifts induced by DHA were predicted by a multiple regression on the chromaticities and the skin properties. The model explained up to 49% of variance in colorimetric components with a median error of less than 2 ΔE. We conclude that the control of both the magnitude and the direction of the colour shift is a critical factor to achieve a natural appearance.
Topics: Adult; Color; Colorimetry; Dihydroxyacetone; Female; Humans; Male; Skin; Skin Pigmentation; Sunbathing; Sunscreening Agents
PubMed: 33315862
DOI: 10.1371/journal.pone.0233816 -
ACS Central Science Jan 2023Metal-organic frameworks (MOFs) with Brønsted acidity are an alternative solid acid catalyst for many important chemical and fuel processes. However, the nature of the...
Metal-organic frameworks (MOFs) with Brønsted acidity are an alternative solid acid catalyst for many important chemical and fuel processes. However, the nature of the Brønsted acidity on the MOF's metal cluster or center is underexplored. To design and optimize the acid strength and density in these MOFs, it is important to understand the origin of their acidity at the molecular level. In the present work, isoreticular MOFs, ZrNDI and HfNDI (NDI = ,'-bis(5-isophthalate)naphthalenediimide), were prepared as a prototypical system to unravel and compare their Brønsted and Lewis acid sites through an array of spectroscopic, computational, and catalytic characterization techniques. With the aid of solid-state nuclear magnetic resonance and density functional calculations, Hf oxo-clusters on HfNDI are quantitatively proved to possess a higher density Brønsted acid site, while ZrNDI-based MOFs display stronger and higher-population Lewis acidity. HfNDI-based MOFs exhibit a superior catalytic performance in activating dihydroxyacetone (DHA) and converting DHA to ethyl lactate, with 71.1% selectivity at 54.7% conversion after 6 h. The turnover frequency of BAS-dominated Hf-MOF in DHA conversion is over 50 times higher than that of ZSM-5, a strong BAS-based zeolite. It is worth noting that HfNDI is reported for the first time in the literature, which is an alternative platform catalyst for biorefining and green chemistry. The present study furthermore highlights the uniqueness of Hf-based MOFs in this important biomass-to-chemical transformation.
PubMed: 36712491
DOI: 10.1021/acscentsci.2c01140 -
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 -
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 -
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