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Angewandte Chemie (International Ed. in... Jun 2022Unprecedented bacterial targets are urgently needed to overcome the resistance crisis. Herein we systematically mine pyridoxal phosphate-dependent enzymes (PLP-DEs) in...
Unprecedented bacterial targets are urgently needed to overcome the resistance crisis. Herein we systematically mine pyridoxal phosphate-dependent enzymes (PLP-DEs) in bacteria to focus on a target class which is involved in crucial metabolic processes. For this, we tailored eight pyridoxal (PL) probes bearing modifications at various positions. Overall, the probes exceeded the performance of a previous generation and provided a detailed map of PLP-DEs in clinically relevant pathogens including challenging Gram-negative strains. Putative PLP-DEs with unknown function were exemplarily characterized via in-depth enzymatic assays. Finally, we screened a panel of PLP binders for antibiotic activity and unravelled the targets of hit molecules. Here, an uncharacterized enzyme, essential for bacterial growth, was assigned as PLP-dependent cysteine desulfurase and confirmed to be inhibited by the marketed drug phenelzine. Our approach provides a basis for deciphering novel PLP-DEs as essential antibiotic targets along with corresponding ways to decipher small molecule inhibitors.
Topics: Anti-Bacterial Agents; Bacteria; Pyridoxal; Pyridoxal Phosphate
PubMed: 35199904
DOI: 10.1002/anie.202117724 -
Journal of Bacteriology May 2020Pyridoxal 5'-phosphate (PLP) is the biologically active form of vitamin B and an essential cofactor in all organisms. In , PLP is synthesized via the deoxyxylulose...
Pyridoxal 5'-phosphate (PLP) is the biologically active form of vitamin B and an essential cofactor in all organisms. In , PLP is synthesized via the deoxyxylulose 5-phosphate (DXP)-dependent pathway that includes seven enzymatic steps and generates pyridoxine 5'-phosphate as an intermediate. Additionally, is able to salvage pyridoxal, pyridoxine, and pyridoxamine B vitamers to produce PLP using kinases PdxK/PdxY and pyridox(am)ine phosphate oxidase (PdxH). We found that strains blocked in PLP synthesis prior to the formation of pyridoxine 5'-phosphate (PNP) required significantly less exogenous pyridoxal (PL) than strains lacking and identified the conversion of PL to pyridoxine (PN) during cultivation to be the cause. Our data showed that PdxI, shown to have PL reductase activity , was required for the efficient salvage of PL in The strains converted exogenous PL to PN during growth, while mutants did not. In total, the data herein demonstrated that PdxI is a critical enzyme in the salvage of PL by The biosynthetic pathway of pyridoxal 5'-phosphate (PLP) has extensively been studied in , yet limited information is available about the vitamin B salvage pathway. We show that the protein PdxI (YdbC) is the primary pyridoxal (PL) reductase in and is involved in the salvage of PL. The orthologs of PdxI occur in a wide range of bacteria and plants, suggesting that PL reductase in the B salvage pathway is more widely distributed than previously expected.
Topics: Biosynthetic Pathways; Escherichia coli; Oxidoreductases; Pyridoxal; Pyridoxal Phosphate
PubMed: 32253339
DOI: 10.1128/JB.00056-20 -
Chemical & Pharmaceutical Bulletin 2024Amine-free phosphorylation of various alcohols was developed with 4-methylpyridine N-oxide in the presence of 4 Å molecular sieves at room temperature. This mild...
Amine-free phosphorylation of various alcohols was developed with 4-methylpyridine N-oxide in the presence of 4 Å molecular sieves at room temperature. This mild method gave various phosphorylated products in high yield and could be applied to acid- or base-sensitive substrates. Furthermore, this method was also effective for the chemoselective phosphorylation of diols or polyols.
Topics: Alcohols; Oxides; Amines; Phosphorylation; Catalysis; Picolines
PubMed: 38479853
DOI: 10.1248/cpb.c24-00029 -
Nature Communications Dec 2020Protein N-phosphorylation plays a critical role in central metabolism and two/multicomponent signaling of prokaryotes. However, the current enrichment methods for...
Protein N-phosphorylation plays a critical role in central metabolism and two/multicomponent signaling of prokaryotes. However, the current enrichment methods for O-phosphopeptides are not preferred for N-phosphopeptides due to the intrinsic lability of P-N bond under acidic conditions. Therefore, the effective N-phosphoproteome analysis remains challenging. Herein, bis(zinc(II)-dipicolylamine)-functionalized sub-2 μm core-shell silica microspheres (SiO@DpaZn) are tailored for rapid and effective N-phosphopeptides enrichment. Due to the coordination of phosphate groups to Zn(II), N-phosphopeptides can be effectively captured under neutral conditions. Moreover, the method is successfully applied to an E.coli and HeLa N-phosphoproteome study. These results further broaden the range of methods for the discovery of N-phosphoproteins with significant biological functions.
Topics: Escherichia coli Proteins; HeLa Cells; Hep G2 Cells; Humans; Microspheres; Neoplasm Proteins; Organometallic Compounds; Particle Size; Phosphopeptides; Phosphoproteins; Picolines; Proteome; Proteomics; Reproducibility of Results; Silicon Dioxide; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 33277485
DOI: 10.1038/s41467-020-20026-1 -
Revista Do Colegio Brasileiro de... 2022This prospective, randomized and double-blind study aims to compare two different protocols used for bowel preparation in patients scheduled for colonoscopy. The... (Comparative Study)
Comparative Study Randomized Controlled Trial
This prospective, randomized and double-blind study aims to compare two different protocols used for bowel preparation in patients scheduled for colonoscopy. The protocols were composed by solutions of Mannitol or sodium picosulfate combined with magnesium oxide. Patients from the proctology outpatient clinic of the General Surgery Unit of the Regional Hospital of Asa Norte (HRAN) comprised the sample of this study. Both the patients and the colonoscopist had no prior knowledge of the substance used to prepare bowel, which was randomly distributed among the participants. Both protocols demonstrated good and similar results regarding the efficiency of colon preparation, although the review of literature shows a difference in favor of preparation made with Mannitol solution regarding the colon neatness during the exam. In line with the literature, patients who used Mannitol solution had more side effects, highlighting the significant difference found for vomiting and sleep impairment. The preparation with Sodium Picosulfate with Magnesium Oxide was significantly superior in relation to the ease of ingestion perceived by the patients.
Topics: Cathartics; Citrates; Colonoscopy; Humans; Magnesium Oxide; Mannitol; Organometallic Compounds; Picolines; Prospective Studies
PubMed: 35584529
DOI: 10.1590/0100-6991e-20222476-en -
The Journal of Biological Chemistry Jan 1947
Topics: Amino Acids; Pyridoxine; Transaminases; Vitamin B 6 Deficiency
PubMed: 20281632
DOI: No ID Found -
Molecules (Basel, Switzerland) Feb 2023Picolinic acid and picolinate compounds are a remarkable class of synthetic auxin herbicides. In recent years, two new picolinate compounds, halauxifen-methyl (Arylex...
Picolinic acid and picolinate compounds are a remarkable class of synthetic auxin herbicides. In recent years, two new picolinate compounds, halauxifen-methyl (Arylex active) and florpyrauxifen-benzyl (Rinskor active), have been launched as novel herbicides. Using their structural skeleton as a template, 33 4-amino-3,5-dicholor-6-(5-aryl-substituted-1-pytazolyl)-2-picolinic acid compounds were designed and synthesized for the discovery of compounds with potent herbicidal activity. The compounds were tested for inhibitory activity against the growth of roots, and the results demonstrated that the IC value of compound was 45 times lower than that of the halauxifen-methyl commercial herbicide. Molecular docking analyses revealed that compound docked with the receptor auxin-signaling F-box protein 5 (AFB5) more intensively than picloram. An adaptive three-dimensional quantitative structure-activity relationship model was constructed from these IC values to guide the next step of the synthetic strategy. Herbicidal tests of the new compounds indicated that compound exhibited better post-emergence herbicidal activity than picloram at a dosage of 300 gha, and it was also safe for corn, wheat, and sorghum at this dosage. These results demonstrated that 6-(5-aryl-substituted-1-pyrazolyl)-2-picolinic acid compounds could be used as potential lead structures in the discovery of novel synthetic auxin herbicides.
Topics: Herbicides; Picloram; Molecular Docking Simulation; Structure-Activity Relationship; Arabidopsis; Indoleacetic Acids
PubMed: 36771096
DOI: 10.3390/molecules28031431 -
Molecules (Basel, Switzerland) Feb 2024Diabetic osteoporosis (DOP) is an abnormal metabolic disease caused by long-term hyperglycemia. In this study, a model rat of streptozotocin (STZ)-induced diabetes was...
Diabetic osteoporosis (DOP) is an abnormal metabolic disease caused by long-term hyperglycemia. In this study, a model rat of streptozotocin (STZ)-induced diabetes was established, and chromium picolinate (5 mg·kg) was given; the changes in blood glucose and body weight were detected before and after administration; and bone mineral density (BMD), bone morphology, bone turnover markers, inflammatory cytokines, and oxidative stress indicators were observed in each group. We found that after chromium picolinate (CP) intervention for 8 weeks, the blood glucose level was decreased; the BMD, the bone histomorphology parameters, and the pathological structure were improved; the expression of bone resorption-related proteins was downregulated; and the expression of bone formation-related proteins was upregulated. Meanwhile, serum antioxidant activity was increased, and inflammatory cytokine levels were decreased. In conclusion, CP could alleviate DOP by anti-oxidation, inhibition of bone turnover, anti-inflammation, and regulation of the OPG/RANKL/RANK signaling pathway. Therefore, CP has important application values for further development as a functional food or active medicine in DOP treatment.
Topics: Rats; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Bone Diseases, Metabolic; Bone Density; Osteoporosis; RANK Ligand; Picolinic Acids
PubMed: 38474436
DOI: 10.3390/molecules29050924 -
European Journal of Vascular and... Mar 1998Iso-osmotic bowel preparation (Klean Prep) improves the accuracy of iliac duplex examination and reduces the time of each examination. Full-dose Klean Prep entails 4 l... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
OBJECTIVES
Iso-osmotic bowel preparation (Klean Prep) improves the accuracy of iliac duplex examination and reduces the time of each examination. Full-dose Klean Prep entails 4 l of fluid. We studied the effect of 2 l of Klean Prep (half-dose) and Picolax on image quality.
DESIGN
Prospective study comparing clarity of duplex examination after three different bowel preparation regimes with that after 12 h starvation.
MATERIALS AND METHODS
Thirty patients underwent iliac duplex examination after 12 h starvation. Scans were scored subjectively for grey scale and colour image quality, and Doppler signal-to-noise ratio. Patients were allocated blindly to: (a) full-dose Klean Prep, (b) half-dose Klean Prep, or (c) Picolax. After out-patient preparation, the scan was repeated and scored by the same observer, blinded to the preparation.
RESULTS
Both full- and half-dose Klean Prep produced significant improvements in image quality for all three modalities; Picolax produced minimal change. There was minimal advantage of full-dose over half-dose Klean Prep. Patients preferred half-dose Klean Prep to full-dose.
CONCLUSION
Klean Prep significantly improves the image obtained by iliac duplex examination; Picolax does not. Half-dose Klean Prep is an acceptable preparation to patients.
Topics: Aged; Aged, 80 and over; Arterial Occlusive Diseases; Cathartics; Citrates; Female; Humans; Iliac Artery; Isotonic Solutions; Male; Middle Aged; Organometallic Compounds; Patient Satisfaction; Picolines; Prospective Studies; Single-Blind Method; Ultrasonography, Doppler, Duplex
PubMed: 9587343
DOI: 10.1016/s1078-5884(98)80188-3 -
PloS One 2015Over the past years, the essential role of vitamin B6 in brain development and functioning has been recognized and genetic metabolic disorders resulting in functional...
BACKGROUND
Over the past years, the essential role of vitamin B6 in brain development and functioning has been recognized and genetic metabolic disorders resulting in functional vitamin B6 deficiency have been identified. However, data on B6 vitamers in children are scarce.
MATERIALS AND METHODS
B6 vitamer concentrations in simultaneously sampled plasma and cerebrospinal fluid (CSF) of 70 children with intellectual disability were determined by ultra performance liquid chromatography-tandem mass spectrometry. For ethical reasons, CSF samples could not be obtained from healthy children. The influence of sex, age, epilepsy and treatment with anti-epileptic drugs, were investigated.
RESULTS
The B6 vitamer composition of plasma (pyridoxal phosphate (PLP) > pyridoxic acid > pyridoxal (PL)) differed from that of CSF (PL > PLP > pyridoxic acid > pyridoxamine). Strong correlations were found for B6 vitamers in and between plasma and CSF. Treatment with anti-epileptic drugs resulted in decreased concentrations of PL and PLP in CSF.
CONCLUSION
We provide concentrations of all B6 vitamers in plasma and CSF of children with intellectual disability (±epilepsy), which can be used in the investigation of known and novel disorders associated with vitamin B6 metabolism as well as in monitoring of the biochemical effects of treatment with vitamin B6.
Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Chromatography, Liquid; Cross-Sectional Studies; Female; Humans; Infant; Intellectual Disability; Male; Pyridoxal; Pyridoxal Phosphate; Pyridoxamine; Pyridoxic Acid; Tandem Mass Spectrometry; Vitamin B 6
PubMed: 25760040
DOI: 10.1371/journal.pone.0120972