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Frontiers in Veterinary Science 2024Brucellosis is a worldwide extended zoonosis caused by pathogens of the genus . While most , , and biovars grow slowly in complex media, they multiply intensely in...
Brucellosis is a worldwide extended zoonosis caused by pathogens of the genus . While most , , and biovars grow slowly in complex media, they multiply intensely in livestock genitals and placenta indicating high metabolic capacities. Mutant analyses and in infection models emphasize that erythritol (abundant in placenta and genitals) is a preferred substrate of brucellae, and suggest hexoses, pentoses, and gluconeogenic substrates use in host cells. While sugar and erythritol catabolic pathways are known, growth on 3-4 carbon substrates persists in Fbp- and GlpX-deleted mutants, the canonical gluconeogenic fructose 1,6-bisphosphate (F1,6bP) bisphosphatases. Exploiting the prototrophic and fast-growing properties of biovar 5, we show that gluconeogenesis requires fructose-bisphosphate aldolase (Fba); the existence of a novel broad substrate bisphosphatase (Bbp) active on sedoheptulose 1,7-bisphosphate (S1,7bP), F1,6bP, and other phosphorylated substrates; that Fbp unexpectedly acts on S1,7bP and F1,6bP; and that, while active in and , GlpX is disabled in biovar 5. Thus, two Fba-dependent reactions (dihydroxyacetone-phosphate + glyceraldehyde 3-phosphate ⇌ F1,6bP; and dihydroxyacetone-phosphate + erythrose 4-phosphate ⇌ S1,7bP) can, respectively, yield fructose 6-phosphate and sedoheptulose 7-phosphate for classical gluconeogenesis and the Pentose Phosphate Shunt (PPS), the latter reaction opening a new gluconeogenic route. Since erythritol generates the PPS-intermediate erythrose 4-phosphate, and the Fba/Fbp-Bbp route predicts sedoheptulose 7-phosphate generation from erythrose 4-phosphate, we re-examined the erythritol connections with PPS. Growth on erythritol required transaldolase or the Fba/Fbp-Bbp pathway, strongly suggesting that Fba/Fbp-Bbp works as a PPS entry for both erythritol and gluconeogenic substrates in . We propose that, by increasing erythritol channeling into PPS through these peculiar routes, brucellae proliferate in livestock genitals and placenta in the high numbers that cause abortion and infertility, and make brucellosis highly contagious. These findings could be the basis for developing attenuated brucellosis vaccines safer in pregnant animals.
PubMed: 38601913
DOI: 10.3389/fvets.2024.1328293 -
Microbiology Spectrum Apr 2024All organisms utilize -adenosyl-l-methionine (SAM) as a key co-substrate for the methylation of biological molecules, the synthesis of polyamines, and radical SAM...
UNLABELLED
All organisms utilize -adenosyl-l-methionine (SAM) as a key co-substrate for the methylation of biological molecules, the synthesis of polyamines, and radical SAM reactions. When these processes occur, 5'-deoxy-nucleosides are formed as byproducts such as -adenosyl-l-homocysteine, 5'-methylthioadenosine (MTA), and 5'-deoxyadenosine (5dAdo). A prevalent pathway found in bacteria for the metabolism of MTA and 5dAdo is the dihydroxyacetone phosphate (DHAP) shunt, which converts these compounds into dihydroxyacetone phosphate and 2-methylthioacetaldehyde or acetaldehyde, respectively. Previous work in other organisms has shown that the DHAP shunt can enable methionine synthesis from MTA or serve as an MTA and 5dAdo detoxification pathway. Rather, the DHAP shunt in ATCC 25922, when introduced into K-12, enables the use of 5dAdo and MTA as a carbon source for growth. When MTA is the substrate, the sulfur component is not significantly recycled back to methionine but rather accumulates as 2-methylthioethanol, which is slowly oxidized non-enzymatically under aerobic conditions. The DHAP shunt in ATCC 25922 is active under oxic and anoxic conditions. Growth using 5-deoxy-d-ribose was observed during aerobic respiration and anaerobic respiration with Trimethylamine N-oxide (TMAO), but not during fermentation or respiration with nitrate. This suggests the DHAP shunt may only be relevant for extraintestinal pathogenic lineages with the DHAP shunt that inhabit oxic or TMAO-rich extraintestinal environments. This reveals a heretofore overlooked role of the DHAP shunt in carbon and energy metabolism from ubiquitous SAM utilization byproducts and suggests a similar role may occur in other pathogenic and non-pathogenic bacteria with the DHAP shunt.
IMPORTANCE
The acquisition and utilization of organic compounds that serve as growth substrates are essential for to grow and multiply. Ubiquitous enzymatic reactions involving S-adenosyl-l-methionine as a co-substrate by all organisms result in the formation of the 5'-deoxy-nucleoside byproducts, 5'-methylthioadenosine and 5'-deoxyadenosine. All possess a conserved nucleosidase that cleaves these 5'-deoxy-nucleosides into 5-deoxy-pentose sugars for adenine salvage. The DHAP shunt pathway is found in some extraintestinal pathogenic , but its function in possessing it has remained unknown. This study reveals that the DHAP shunt enables the utilization of 5'-deoxy-nucleosides and 5-deoxy-pentose sugars as growth substrates in strains with the pathway during aerobic respiration and anaerobic respiration with TMAO, but not fermentative growth. This provides an insight into the diversity of sugar compounds accessible by with the DHAP shunt and suggests that the DHAP shunt is primarily relevant in oxic or TMAO-rich extraintestinal environments.
Topics: S-Adenosylmethionine; Escherichia coli; Dihydroxyacetone Phosphate; Methionine; Bacteria; Pentoses; Carbon; Sugars; Deoxyadenosines; Methylamines; Thionucleosides
PubMed: 38441472
DOI: 10.1128/spectrum.03086-23 -
Biomedicine & Pharmacotherapy =... Feb 2023Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by skin photosensitivity caused by accumulation of protoporphyrin IX. We aimed to... (Review)
Review
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by skin photosensitivity caused by accumulation of protoporphyrin IX. We aimed to review the clinical evidence of efficacy and safety of skin photosensitivity treatments in individuals with EPP or XLP. We systematically searched MEDLINE, Embase, the Cochrane Library, and ClinicalTrials.gov. A total of 40 studies with data on 18 treatment modalities were included. Comprehensive treatment safety data were obtained from the European Medicines Agency and the United States Food and Drug Administration. The studies used different outcome measures to evaluate the sensitivity without a generally accepted method to assess treatment effect on skin photosensitivity. Of the included studies, 13 were controlled trials. Gathered, the trials showed moderate positive effect of inorganic sunscreen application and subcutaneous implant of afamelanotide and no effect of organic sunscreen application, or oral treatment with beta-carotene, cysteine, N-acetylcysteine, vitamin C, or warfarin. Studies without control groups suggested treatment effect of foundation cream, dihydroxyacetone/lawsone cream, narrow-band ultraviolet B phototherapy, erythrocyte transfusion, extracorporeal erythrocyte photodynamic therapy, or oral treatment with zinc sulphate, terfenadine, cimetidine, or canthaxanthin, but the real effect is uncertain. Assessment of treatment effect on photosensitivity in patients with EPP or XLP carries a high risk of bias since experienced photosensitivity varies with both weather conditions, exposure pattern, and pigmentation. Controlled trials of promising treatment options are important although challenging in this small patient population.
Topics: United States; Humans; Protoporphyria, Erythropoietic; Sunscreening Agents; Photosensitivity Disorders; Genetic Diseases, X-Linked; Protoporphyrins
PubMed: 36525819
DOI: 10.1016/j.biopha.2022.114132 -
Nature Communications Oct 2022Many biomass intermediates are polyols and selectively oxidizing only a primary or secondary alcohol group is beneficial for the valorization of these intermediates. For...
Many biomass intermediates are polyols and selectively oxidizing only a primary or secondary alcohol group is beneficial for the valorization of these intermediates. For example, production of 1,3-dihydroxyacetone, a highly valuable oxidation product of glycerol, requires selective secondary alcohol oxidation. However, selective secondary alcohol oxidation is challenging due to its steric disadvantage. This study demonstrates that NiOOH, which oxidizes alcohols via two dehydrogenation mechanisms, hydrogen atom transfer and hydride transfer, can convert glycerol to 1,3-dihydroxyacetone with high selectivity when the conditions are controlled to promote hydrogen atom transfer, favoring secondary alcohol oxidation. This rational production of 1,3-dihydroxyacetone achieved by selectively enabling one desired dehydrogenation pathway, without requiring alteration of catalyst composition, demonstrates how comprehensive mechanistic understanding can enable predictive control over selectivity.
Topics: Catalysis; Dihydroxyacetone; Ethanol; Glycerol; Hydrogen
PubMed: 36195626
DOI: 10.1038/s41467-022-33637-7 -
Dermatology Online Journal Jul 2020Vitiligo is a depigmenting skin disorder that can cause significant patient distress. Treatment of vitiligo is challenging and should address patient's concern for...
Vitiligo is a depigmenting skin disorder that can cause significant patient distress. Treatment of vitiligo is challenging and should address patient's concern for cosmetic treatment. Herein, we report the case of a 60-year-old patient who achieved temporary improvement in pigmentation using a spray tan. Camouflaging vitiligo using a spray-tan is a reasonable, safe, and effective mechanism for management of vitiligo.
Topics: Administration, Cutaneous; Cosmetics; Dihydroxyacetone; Humans; Male; Middle Aged; Vitiligo
PubMed: 32898413
DOI: No ID Found -
Structure (London, England : 1993) Mar 2023Sulfoquinovose (SQ) is a key component of plant sulfolipids (sulfoquinovosyl diacylglycerols) and a major environmental reservoir of biological sulfur. Breakdown of SQ...
Sulfoquinovose (SQ) is a key component of plant sulfolipids (sulfoquinovosyl diacylglycerols) and a major environmental reservoir of biological sulfur. Breakdown of SQ is achieved by bacteria through the pathways of sulfoglycolysis. The sulfoglycolytic sulfofructose transaldolase (sulfo-SFT) pathway is used by gut-resident firmicutes and soil saprophytes. After isomerization of SQ to sulfofructose (SF), the namesake enzyme catalyzes the transaldol reaction of SF transferring dihydroxyacetone to 3C/4C acceptors to give sulfolactaldehyde and fructose-6-phosphate or sedoheptulose-7-phosphate. We report the 3D cryo-EM structure of SF transaldolase from Bacillus megaterium in apo and ligand bound forms, revealing a decameric structure formed from two pentameric rings of the protomer. We demonstrate a covalent "Schiff base" intermediate formed by reaction of SF with Lys89 within a conserved Asp-Lys-Glu catalytic triad and defined by an Arg-Trp-Arg sulfonate recognition triad. The structural characterization of the signature enzyme of the sulfo-SFT pathway provides key insights into molecular recognition of the sulfonate group of sulfosugars.
Topics: Transaldolase; Fructose-Bisphosphate Aldolase; Methylglucosides
PubMed: 36805128
DOI: 10.1016/j.str.2023.01.010 -
Effect of sugar metabolite methylglyoxal on equine lamellar explants: An ex vivo model of laminitis.PloS One 2021Laminitis is one of the most devastating diseases in equine medicine, and although several etiopathogenetic mechanisms have been proposed, few clear answers have been...
Laminitis is one of the most devastating diseases in equine medicine, and although several etiopathogenetic mechanisms have been proposed, few clear answers have been identified to date. Several lines of evidence point towards its underlying pathology as being metabolism-related. In the carbonyl stress pathway, sugars are converted to methylglyoxal (MG)-a highly reactive α-oxoaldehyde, mainly derived during glycolysis in eukaryotic cells from the triose phosphates: D-glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. One common hypothesis is that MG could be synthesized during the digestive process in horses, and excessive levels absorbed into peripheral blood could be delivered to the foot and lead to alterations in the hoof lamellar structure. In the present study, employing an ex vivo experimental design, different concentrations of MG were applied to hoof explants (HE), which were then incubated and maintained in a specific medium for 24 and 48 h. Macroscopic and histological analyses and a separation force test were performed at 24 and 48 h post-MG application. Gene expression levels of matrix metalloproteinase (MMP)-2 and -14 and tissue inhibitor of metalloproteinase (TIMP)-2 were also measured at each time point for all experimental conditions. High concentrations of MG induced macroscopic and histological changes mimicking laminitis. The separation force test revealed that hoof tissue samples incubated for 24 h in a high concentration of MG, or with lower doses but for a longer period (48 h), demonstrated significant weaknesses, and samples were easily separated. All results support that high levels of MG could induce irreversible damage in HEs, mimicking laminitis in an ex vivo model.
Topics: Animals; Gene Expression; Hoof and Claw; Horses; Male; Matrix Metalloproteinase 14; Matrix Metalloproteinase 2; Models, Biological; Pyruvaldehyde; Sugars; Tissue Inhibitor of Metalloproteinase-2
PubMed: 34314429
DOI: 10.1371/journal.pone.0253840 -
Microbial Biotechnology Jul 2021Since methylotrophic yeasts such as Ogataea methanolica can use methanol as a sole carbon feedstock, they could be applied to produce valuable products from methanol, a...
Since methylotrophic yeasts such as Ogataea methanolica can use methanol as a sole carbon feedstock, they could be applied to produce valuable products from methanol, a next-generation energy source synthesized from natural gases, using genetic engineering tools. In this study, metabolite profiling of O. methanolica was conducted under glucose (Glc) and low and high methanol (L- and H-MeOH) conditions to show the adaptation mechanism to a H-MeOH environment. The yeast strain responded not only to the presence of methanol but also to its concentration based on the growth condition. Under H-MeOH conditions, O. methanolica downregulated the methanol utilization, glycolytic pathway and alcohol oxidase (AOD) isozymes and dihydroxyacetone synthase (DAS) expression compared with L-MeOH-grown cells. However, levels of energy carriers, such as ATP, were maintained to support cell survival. In H-MeOH-grown cells, reactive oxygen species (ROS) levels were significantly elevated. Along with increasing ROS levels, ROS scavenging system expression was significantly increased in H-MeOH-grown cells. Thus, we concluded that formaldehyde and H O , which are products of methanol oxidation by AOD isozymes in the peroxisome, are overproduced in H-MeOH-grown cells, and excessive ROS derived from these cells is generated in the cytosol, resulting in upregulation of the antioxidant system and downregulation of the methanol-utilizing pathway to suppress overproduction of toxic intermediates.
Topics: Gene Expression Regulation, Fungal; Methanol; Pichia; Saccharomycetales
PubMed: 33939325
DOI: 10.1111/1751-7915.13811 -
Signal Transduction and Targeted Therapy Nov 2020
Review
Topics: Animals; Dihydroxyacetone Phosphate; Glucose; Glycolysis; Humans; Mechanistic Target of Rapamycin Complex 1; Neoplasm Proteins; Neoplasms; Second Messenger Systems
PubMed: 33144567
DOI: 10.1038/s41392-020-00371-9 -
NPJ Science of Food Jul 2021This study examined the effects of oral administration of water extract of chlorella (WEC) (100 mg/kg bodyweight) and phenethylamine (10 μg/kg bodyweight) on...
This study examined the effects of oral administration of water extract of chlorella (WEC) (100 mg/kg bodyweight) and phenethylamine (10 μg/kg bodyweight) on high-fat diet (HFD)-induced liver damage in mice. Phenethylamine significantly mitigated HFD-induced lipid oxidation (generation of malondialdehyde) and liver damage without markedly decreasing hepatic lipid accumulation. WEC exerted similar effects although with decreased efficacy. In addition, WEC and phenethylamine decreased the methylglyoxal levels and increased the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) protein levels in the liver. Methylglyoxal is generated from substrates of GAPDH, dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. These facts indicate that methylglyoxal triggers oxidation of accumulated lipid, which generates malondialdehyde and consequently induces liver damage. Suppression of generation of toxic aldehydes by WEC and phenethylamine was also confirmed by maintaining hepatic cysteine, highly reactive to aldehydes. Thus, trace amounts of phenethylamine alleviate HFD-induced liver damage by regulating methylglyoxal via increase of GAPDH.
PubMed: 34301957
DOI: 10.1038/s41538-021-00105-3