-
Nature Communications Apr 2022Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class...
Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission.
Topics: Animals; Antimalarials; Folic Acid Antagonists; Malaria; Malaria, Falciparum; Malaria, Vivax; Mice; Pantothenic Acid; Plasmodium falciparum; Rats
PubMed: 35444200
DOI: 10.1038/s41467-022-29688-5 -
Yeast (Chichester, England) Apr 2020Chemically defined media for yeast cultivation (CDMY) were developed to support fast growth, experimental reproducibility, and quantitative analysis of growth rates and... (Review)
Review
Chemically defined media for yeast cultivation (CDMY) were developed to support fast growth, experimental reproducibility, and quantitative analysis of growth rates and biomass yields. In addition to mineral salts and a carbon substrate, popular CDMYs contain seven to nine B-group vitamins, which are either enzyme cofactors or precursors for their synthesis. Despite the widespread use of CDMY in fundamental and applied yeast research, the relation of their design and composition to the actual vitamin requirements of yeasts has not been subjected to critical review since their first development in the 1940s. Vitamins are formally defined as essential organic molecules that cannot be synthesized by an organism. In yeast physiology, use of the term "vitamin" is primarily based on essentiality for humans, but the genome of the Saccharomyces cerevisiae reference strain S288C harbours most of the structural genes required for synthesis of the vitamins included in popular CDMY. Here, we review the biochemistry and genetics of the biosynthesis of these compounds by S. cerevisiae and, based on a comparative genomics analysis, assess the diversity within the Saccharomyces genus with respect to vitamin prototrophy.
Topics: Biomass; Biotin; Inositol; Niacin; Pantothenic Acid; Pyridoxine; Reproducibility of Results; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Thiamine; Vitamins
PubMed: 31972058
DOI: 10.1002/yea.3461 -
Cell Reports Nov 2022Metabolic rewiring is essential for Th17 cells' functional identity to sense and interpret environmental cues. However, the environmental metabolic checkpoints with...
Metabolic rewiring is essential for Th17 cells' functional identity to sense and interpret environmental cues. However, the environmental metabolic checkpoints with specific regulation of Th17 cells, manifesting potential therapeutic opportunities to autoimmune diseases, remain largely unknown. Here, by screening more than one hundred compounds derived from intestinal microbes or diet, we found that vitamin B5 (VB5) restrains Th17 cell differentiation as well as related autoimmune diseases such as experimental autoimmune encephalomyelitis and colitis. Mechanistically, VB5 is catabolized into coenzyme A (CoA) in a pantothenate kinase (PANK)-dependent manner, and in turn, CoA binds to pyruvate kinase isoform 2 (PKM2) to impede its phosphorylation and nuclear translocation, thus inhibiting glycolysis and STAT3 phosphorylation. In humans, reduced serum VB5 levels are found in both IBD and MS patients. Collectively, our study demonstrates a role of VB5 in Th17 cell metabolic reprograming, thus providing a potential therapeutic intervention for Th17 cell-associated autoimmune diseases.
Topics: Humans; Animals; Pyruvate Kinase; Pantothenic Acid; Th17 Cells; Protein Isoforms; Coenzyme A; Encephalomyelitis, Autoimmune, Experimental
PubMed: 36450257
DOI: 10.1016/j.celrep.2022.111741 -
Nutrients Jul 2019L. is a well-known fruit worldwide, and its highest production occurs in tropical and subtropical regions. The pulp contains vitamins A, C, and E, B complex vitamins,... (Review)
Review
L. is a well-known fruit worldwide, and its highest production occurs in tropical and subtropical regions. The pulp contains vitamins A, C, and E, B complex vitamins, such as pantothenic acid and folate, and minerals, such as magnesium and potassium, as well as food fibers. Phenolic compounds, such as benzyl isothiocyanate, glucosinolates, tocopherols (α and δ), β-cryptoxanthin, β-carotene and carotenoids, are found in the seeds. The oil extracted from the seed principally presents oleic fatty acid followed by palmitic, linoleic and stearic acids, whereas the leaves have high contents of food fibers and polyphenolic compounds, flavonoids, saponins, pro-anthocyanins, tocopherol, and benzyl isothiocyanate. Studies demonstrated that the nutrients present in its composition have beneficial effects on the cardiovascular system, protecting it against cardiovascular illnesses and preventing harm caused by free radicals. It has also been reported that it aids in the treatment of diabetes mellitus and in the reduction of cholesterol levels. Thus, both the pulp and the other parts of the plant (leaves and seeds) present antioxidant, anti-hypertensive, hypoglycemic, and hypolipidemic actions, which, in turn, can contribute to the prevention and treatment of obesity and associated metabolic disorders.
Topics: Carica; Dietary Supplements; Fruit; Humans; Metabolic Syndrome; Nutritive Value; Phytochemicals
PubMed: 31315213
DOI: 10.3390/nu11071608 -
Molecular Neurodegeneration Dec 2023Untargeted high-resolution metabolomic profiling provides simultaneous measurement of thousands of metabolites. Metabolic networks based on these data can help uncover...
BACKGROUND
Untargeted high-resolution metabolomic profiling provides simultaneous measurement of thousands of metabolites. Metabolic networks based on these data can help uncover disease-related perturbations across interconnected pathways.
OBJECTIVE
Identify metabolic disturbances associated with Parkinson's disease (PD) in two population-based studies using untargeted metabolomics.
METHODS
We performed a metabolome-wide association study (MWAS) of PD using serum-based untargeted metabolomics data derived from liquid chromatography with high-resolution mass spectrometry (LC-HRMS) using two distinct population-based case-control populations. We also combined our results with a previous publication of 34 metabolites linked to PD in a large-scale, untargeted MWAS to assess external validation.
RESULTS
LC-HRMS detected 4,762 metabolites for analysis (HILIC: 2716 metabolites; C18: 2046 metabolites). We identified 296 features associated with PD at FDR<0.05, 134 having a log fold change (FC) beyond ±0.5 (228 beyond ±0.25). Of these, 104 were independently associated with PD in both discovery and replication studies at p<0.05 (170 at p<0.10), while 27 were associated with levodopa-equivalent dose among the PD patients. Intriguingly, among the externally validated features were the microbial-related metabolites, p-cresol glucuronide (FC=2.52, 95% CI=1.67, 3.81, FDR=7.8e-04) and p-cresol sulfate. P-cresol glucuronide was also associated with motor symptoms among patients. Additional externally validated metabolites associated with PD include phenylacetyl-L-glutamine, trigonelline, kynurenine, biliverdin, and pantothenic acid. Novel associations include the anti-inflammatory metabolite itaconate (FC=0.79, 95% CI=0.73, 0.86; FDR=2.17E-06) and cysteine-S-sulfate (FC=1.56, 95% CI=1.39, 1.75; FDR=3.43E-11). Seventeen pathways were enriched, including several related to amino acid and lipid metabolism.
CONCLUSIONS
Our results revealed PD-associated metabolites, confirming several previous observations, including for p-cresol glucuronide, and newly implicating interesting metabolites, such as itaconate. Our data also suggests metabolic disturbances in amino acid and lipid metabolism and inflammatory processes in PD.
Topics: Humans; Amino Acids; Parkinson Disease; Lipid Metabolism; Glucuronides
PubMed: 38115046
DOI: 10.1186/s13024-023-00694-5 -
Biomedicines Apr 2023The number of people living with chronic kidney disease (CKD) is growing as our global population continues to expand. With aging, diabetes, and cardiovascular disease... (Review)
Review
The number of people living with chronic kidney disease (CKD) is growing as our global population continues to expand. With aging, diabetes, and cardiovascular disease being major harbingers of kidney disease, the number of people diagnosed with diabetic kidney disease (DKD) has grown concurrently. Poor clinical outcomes in DKD could be influenced by an array of factors-inadequate glycemic control, obesity, metabolic acidosis, anemia, cellular senescence, infection and inflammation, cognitive impairment, reduced physical exercise threshold, and, importantly, malnutrition contributing to protein-energy wasting, sarcopenia, and frailty. Amongst the various causes of malnutrition in DKD, the metabolic mechanisms of vitamin B (B1 (Thiamine), B2 (Riboflavin), B3 (Niacin/Nicotinamide), B5 (Pantothenic Acid), B6 (Pyridoxine), B8 (Biotin), B9 (Folate), and B12 (Cobalamin)) deficiency and its clinical impact has garnered greater scientific interest over the past decade. There remains extensive debate on the biochemical intricacies of vitamin B metabolic pathways and how their deficiencies may affect the development of CKD, diabetes, and subsequently DKD, and vice-versa. Our article provides a review of updated evidence on the biochemical and physiological properties of the vitamin B sub-forms in normal states, and how vitamin B deficiency and defects in their metabolic pathways may influence CKD/DKD pathophysiology, and in reverse how CKD/DKD progression may affect vitamin B metabolism. We hope our article increases awareness of vitamin B deficiency in DKD and the complex physiological associations that exist between vitamin B deficiency, diabetes, and CKD. Further research efforts are needed going forward to address the knowledge gaps on this topic.
PubMed: 37189771
DOI: 10.3390/biomedicines11041153 -
Food Science & Nutrition Nov 2021Fermented foods are an essential source of nutrition for the communities living in developing areas of the world. Additionally, traditional fermented products are a rich... (Review)
Review
Fermented foods are an essential source of nutrition for the communities living in developing areas of the world. Additionally, traditional fermented products are a rich source of various bioactive components. Experimental research regarding the functional exploration of these products is a way forward for better human health. Among fermented foods, Koumiss is rich in vitamins especially vitamin C and minerals, i.e., phosphorus and calcium. In addition, it is also rich in vitamins A, E, B2, B12, and pantothenic acid. High concentrations of lactose in milk favor bacterial fermentation, as the original cultures decompose it into lactic acid. Koumiss contains essential fatty acids such as linoleic and linolenic acid. Koumiss offers many health benefits including boosting the immune system and maintains blood pressure, good effect on the kidneys, endocrine glands, gut system, liver, and nervous and vascular system. The rich microflora from the fermented product has a pivotal role in maintaining gut health and treating various digestive diseases. The core focus of the current review paper is to highlight the nutritional and therapeutic potential, i.e., anticarcinogenic, hypocholesterolemia effect, antioxidative properties, antibacterial properties, antibacterial spectrum, intestinal enlargement, and β-galactosidase activity, of Koumiss as a traditional fermented product. Moreover, history and production technology of the Koumiss are also the main part of this review paper.
PubMed: 34760271
DOI: 10.1002/fsn3.2595 -
Frontiers in Chemistry 2021The main effect of Vanin-1/VNN1 is related to its pantetheinase sulfhydrylase activity, which can hydrolyze pantetheine into pantothenic acid and cysteamine. In recent...
The main effect of Vanin-1/VNN1 is related to its pantetheinase sulfhydrylase activity, which can hydrolyze pantetheine into pantothenic acid and cysteamine. In recent studies, the enzymatic activity of vanin-1/VNN1 has been found to be essential in the development of many diseases. The study of specific vanin-1/VNN1 inhibitors can give us a deeper understanding of its role in the disease process. In this study, different skeletal inhibitors were designed and synthesized using pyrimidine amide compounds as lead compounds. In order to screen inhibitors intuitively, a fluorescent probe PA-AFC for evaluation of inhibitors was designed and synthesized in this study, which has good sensitivity and specificity. The bioluminescent probe PA-AL was then used for cellular level and inhibitor evaluation. This screening method was convenient, economical and highly accurate. Finally, these inhibitors were applied to a mouse colitis model, confirming that vanin-1 is useful in IBD and providing a new therapeutic direction.
PubMed: 35155380
DOI: 10.3389/fchem.2021.809495 -
Oncoimmunology 2022Vitamin B5 (panthotenic acid), the precursor of coenzyme A (CoA), is contained in most food items and is produced by the intestinal microbiota. A recent study published...
Vitamin B5 (panthotenic acid), the precursor of coenzyme A (CoA), is contained in most food items and is produced by the intestinal microbiota. A recent study published in reports that vitamin B5 and CoA favor the differentiation of CD8 cytotoxic T cells into interleukin-22 (IL-22)-producing Tc22 cells, likely through fueling mitochondrial metabolism. Importantly, in a small cohort of melanoma patients, the plasma levels of vitamin B5 positively correlate with responses to PD-1-targeted immunotherapy. Moreover, in mice, supplementation with vitamin B5 increases the efficacy of PD-L1-targeted cancer immunotherapy, and culture of T cells with CoA enhances their antitumor activity upon adoptive transfer into mice. These finding suggest that vitamin B5 is yet another B vitamin that stimulates anti-cancer immunosurveillance.
Topics: Animals; Coenzyme A; Gastrointestinal Microbiome; Humans; Immunologic Factors; Immunotherapy; Melanoma; Mice; Pantothenic Acid
PubMed: 35096488
DOI: 10.1080/2162402X.2022.2031500