Development of a vitamin B5 hyperproducer in Escherichia coli by multiple metabolic engineering.

Vitamin B5 [D-pantothenic acid (D-PA)] is an essential water-soluble vitamin that is widely used in the food and feed industries. Currently, the relatively low fermentation efficiency limits the industrial application of D-PA. Here, a plasmid-free D-PA hyperproducer was constructed using systematic metabolic engineering strategies. First, pyruvate was enriched by deleting the non-phosphotransferase system, inhibiting pyruvate competitive branches, and dynamically controlling the TCA cycle. Next, the (R)-pantoate pathway was enhanced by screening the rate-limiting enzyme PanBC and regulating the other enzymes of this pathway one by one. Then, to enhance NADPH sustainability, NADPH regeneration was achieved through the novel "PEACES" system by (1) expressing the NAD + kinase gene ppnk from Clostridium glutamicum and the NADP + -dependent gapCcae from Clostridium acetobutyricum and (2) knocking-out the endogenous sthA gene, which interacts with ilvC and panE in the D-PA biosynthesis pathway. Combined with transcriptome analysis, it was found that the membrane proteins OmpC and TolR promoted D-PA efflux by increasing membrane fluidity. Strain PA132 produced a D-PA titer of 83.26 g/L by two-stage fed-batch fermentation, which is the highest D-PA titer reported so far. This work established competitive producers for the industrial production of D-PA and provided an effective strategy for the production of related products.

Impaired coenzyme A homeostasis in cardiac dysfunction and benefits of boosting coenzyme A production with vitamin B5 and its derivatives in the management of heart failure.

Coenzyme A (CoA) is an essential cofactor required for over a hundred metabolic reactions in the human body. This cofactor is synthesized de novo in our cells from vitamin B5, also known as pantothenic acid, a water-soluble vitamin abundantly present in vegetables and animal-based foods. Neurodegenerative disorders, cancer, and infectious diseases have been linked to defects in de novo CoA biosynthesis or reduced levels of this coenzyme. There is now accumulating evidence that CoA limitation is a critical pathomechanism in cardiac dysfunction too. In the current review, we will summarize our current knowledge on CoA and heart failure, with emphasis on two primary cardiomyopathies, phosphopantothenoylcysteine synthetase and phosphopantothenoylcysteine decarboxylase deficiency disorders biochemically characterized by a decreased level of CoA in patients' samples. Hence, we will discuss the potential benefits of CoA restoration in these diseases and, more generally, in heart failure, by vitamin B5 and its derivatives pantethine and 4'-phosphopantetheine.

Comparative assessment of pantothenic, aspartic, ascorbic and tartaric acids assisted Pb-phytoextraction by sunflower (Helianthus annuus L.).

Phytoextraction of lead (Pb) is a challenging task due to its extremely low mobility within soil and plant systems. In this study, we tested the influence of some novel chelating agents for Pb-phytoextraction using sunflower. The Pb was applied at control (0.0278 mM) and 4.826 mM Pb as Pb(NO3)2 through soil-spiking. After 10 days of Pb addition, four different organic ligands (aspartic, ascorbic, tartaric, and pantothenic acids) were added to the soil at 1 mM concentration each. respectively. In the absence of any chelate, sunflower plants grown at 4.826 mM Pb level accumulated Pb concentrations up to 104 µg g-1 DW in roots, whereas 64 µg g-1 DW in shoot. By contrast, tartaric acid promoted significantly Pb accumulation in roots (191 µg g-1 DW; + 45.5%) and shoot (131.6 µg g-1 DW; + 51.3%). Pantothenic acid also resulted in a significant Pb-uptake in the sunflower shoots (123 µg g-1 DW; + 47.9%) and in roots (177.3 µg g-1 DW; + 41.3%). The least effective amongst the chelates tested was aspartic acid, but it still contributed to + 40.1% more Pb accumulation in the sunflower root and shoots. In addition, plant growth, biochemical, and ionomic parameters were positively regulated by the organic chelates used. Especially, an increase in leaf Ca, P, and S was evident in Pb-stressed plants in response to chelates. These results highlight that the use of biocompatible organic chelates positively alters plant physio-biochemical traits contributing to higher Pb-sequestration in sunflower plant parts.

Enhanced D-pantothenic acid biosynthesis by plasmid-free E. coli through sodium pyruvate addition combined with glucose and temperature control strategy.

AIMS: D-Pantothenic acid (D-PA) is an important vitamin widely used in the feed, pharmaceutical, and food industries. This study aims to enhance the D-PA production of a recombinant Escherichia coli without plasmid and inducer induction. METHODS AND RESULTS: The fermentation medium in shake flask was optimized, resulting in an 39.50% increased D-PA titer (3.32 g L-1). Subsequently, the fed-batch fermentation in a 5-L fermenter were specifically investigated. Firstly, a two-stage temperature control strategy led to a D-PA titer of 52.09 g L-1. Additionally, a two-stage glucose feeding was proposed and D-PA titer was increased to 65.29 g L-1. It was also found that appropriate amount of sodium pyruvate was beneficial to cell growth and D-PA synthesis. Finally, a two-stage glucose feeding combined with sodium pyruvate addition resulted in a substantially improved D-PA production with a titer of 72.90 g L-1. CONCLUSION: The D-PA synthesis was significantly improved through the fermentation process established in this work, that is sodium pyruvate addition combined with the temperature and glucose control strategy. The results of this study could provide significant reference for the industrial fermentation production of D-PA.

Microbial production of vitamin B5: current status and prospects.

Vitamin B5, also called D-pantothenic acid (D-PA), is a necessary micronutrient that plays an essential role in maintaining the physiological function of an organism. It is widely used in: food, medicine, feed, cosmetics, and other fields. Currently, the production of D-PA in industry heavily relies on chemical processes and enzymatic catalysis. With an increasing demand on the market, replacing chemical-based production of D-PA with microbial fermentation utilizing renewable resources is necessary. In this review, the physiological role and applications of D-PA were firstly introduced, after which the biosynthesis pathways and enzymes will be summarized. Subsequently, a series of cell factory development strategies for excessive D-PA production are analyzed and discussed. Finally, the prospect of microbial production of D-PA production has been prospected.

Enhanced supply of acetyl-CoA by exogenous pantothenate kinase promotes synthesis of poly(3-hydroxybutyrate).

BACKGROUND: Coenzyme A (CoA) is a carrier of acyl groups. This cofactor is synthesized from pantothenic acid in five steps. The phosphorylation of pantothenate is catalyzed by pantothenate kinase (CoaA), which is a key step in the CoA biosynthetic pathway. To determine whether the enhancement of the CoA biosynthetic pathway is effective for producing useful substances, the effect of elevated acetyl-CoA levels resulting from the introduction of the exogenous coaA gene on poly(3-hydroxybutyrate) [P(3HB)] synthesis was determined in Escherichia coli, which express the genes necessary for cyanobacterial polyhydroxyalkanoate synthesis (phaABEC). RESULTS: E. coli containing the coaA gene in addition to the pha genes accumulated more P(3HB) compared with the transformant containing the pha genes alone. P(3HB) production was enhanced by precursor addition, with P(3HB) content increasing from 18.4% (w/w) to 29.0% in the presence of 0.5 mM pantothenate and 16.3%-28.2% by adding 0.5 mM ß-alanine. Strains expressing the exogenous coaA in the presence of precursors contained acetyl-CoA in excess of 1 nmol/mg of dry cell wt, which promoted the reaction toward P(3HB) formation. The amount of acetate exported into the medium was three times lower in the cells carrying exogenous coaA and pha genes than in the cells carrying pha genes alone. This was attributed to significantly enlarging the intracellular pool size of CoA, which is the recipient of acetic acid and is advantageous for microbial production of value-added materials. CONCLUSIONS: Enhancing the CoA biosynthetic pathway with exogenous CoaA was effective at increasing P(3HB) production. Supplementing the medium with pantothenate facilitated the accumulation of P(3HB). ß-Alanine was able to replace the efficacy of adding pantothenate.

Brain CoA and Acetyl CoA Metabolism in Mechanisms of Neurodegeneration.

The processes of biotransformation of pantothenic acid (Pan) in the biosynthesis and hydrolysis of CoA, key role of pantothenate kinase (PANK) and CoA synthetase (CoASY) in the formation of the priority mitochondrial pool of CoA, with a high metabolic turnover of the coenzyme and limited transport of Pan across the blood-brain barrier are considered. The system of acetyl-CoA, a secondary messenger, which is the main substrate of acetylation processes including formation of N-acetyl aspartate and acetylcholine, post-translational modification of histones, predetermines protection of the neurons against degenerative signals and cholinergic neurotransmission. Biochemical mechanisms of neurodegenerative syndromes in the cases of PANK and CoASY defects, and the possibility of correcting of CoA biosynthesis in the models with knockouts of these enzymes have been described. The data of a post-mortem study of the brains from the patients with Huntington's and Alzheimer's diseases are presented, proving Pan deficiency in the CNS, which is especially pronounced in the pathognomonic neurostructures. In the frontal cortex of the patients with Parkinson's disease, combined immunofluorescence of anti-CoA- and anti-tau protein was detected, reflecting CoAlation during dimerization of the tau protein and its redox sensitivity. Redox activity and antioxidant properties of the precursors of CoA biosynthesis were confirmed in vitro with synaptosomal membranes and mitochondria during modeling of aluminum neurotoxicity accompanied by the decrease in the level of CoA in CNS. The ability of CoA biosynthesis precursors to stabilize glutathione pool in neurostructures, in particular, in the hippocampus, is considered as a pathogenetic protection mechanism during exposure to neurotoxins, development of neuroinflammation and neurodegeneration, and justifies the combined use of Pan derivatives (for example, D-panthenol) and glutathione precursors (N-acetylcysteine). Taking into account the discovery of new functions of CoA (redox-dependent processes of CoAlation of proteins, possible association of oxidative stress and deficiency of Pan (CoA) in neurodegenerative pathology), it seems promising to study bioavailability and biotransformation of Pan derivatives, in particular of D-panthenol, 4'-phospho-pantetheine, its acylated derivatives, and compositions with redox pharmacological compounds, are promising for their potential use as etiopathogenetic agents.

Motor and somatosensory degenerative myelopathy responsive to pantothenic acid in piglets.

This report describes 2 events of degenerative myelopathy in 4- to 27-day-old piglets, with mortality rates reaching 40%. Sows were fed rations containing low levels of pantothenic acid. Piglets presented with severe depression, weakness, ataxia, and paresis, which were more pronounced in the pelvic limbs. No significant gross lesions were observed. Histologically, there were degeneration and necrosis of neurons in the spinal cord, primarily in the thoracic nucleus in the thoracic and lumbar segments, and motor neurons in nucleus IX of the ventral horn in the cervical and lumbar intumescence. Minimal-to-moderate axonal and myelin degeneration was observed in the dorsal funiculus of the spinal cord and in the dorsal and ventral nerve roots. Immunohistochemistry demonstrated depletion of acetylcholine neurotransmitters in motor neurons and accumulation of neurofilaments in the perikaryon of neurons in the thoracic nucleus and motor neurons. Ultrastructurally, the thoracic nucleus neurons and motor neurons showed dissolution of Nissl granulation. The topographical distribution of the lesions indicates damage to the second-order neurons of the spinocerebellar tract, first-order axon cuneocerebellar tract, and dorsal column-medial lemniscus pathway as the cause of the conscious and unconscious proprioceptive deficit, and damage to the alpha motor neuron as the cause of the motor deficit. Clinical signs reversed and no new cases occurred after pantothenic acid levels were corrected in the ration, and piglets received parenteral administration of pantothenic acid. This study highlights the important and practical use of detailed neuropathological analysis to refine differential diagnosis.

Metabolomics and Transcriptomics Analyses of Curcumin Alleviation of Ochratoxin A-Induced Hepatotoxicity.

Ochratoxin A (OTA) is one of the mycotoxins that poses a serious threat to human and animal health. Curcumin (CUR) is a major bioactive component of turmeric that provides multiple health benefits. CUR can reduce the toxicities induced by mycotoxins, but the underlying molecular mechanisms remain largely unknown. To explore the effects of CUR on OTA toxicity and identify the key regulators and metabolites involved in the biological processes, we performed metabolomic and transcriptomic analyses of livers from OTA-exposed mice. We found that CUR can alleviate the toxic effects of OTA on body growth and liver functions. In addition, CUR supplementation significantly affects the expressions of 1584 genes and 97 metabolites. Integrated analyses of transcriptomic and metabolomic data showed that the pathways including Arachidonic acid metabolism, Purine metabolism, and Cholesterol metabolism were significantly enriched. Pantothenic acid (PA) was identified as a key metabolite, the exogenous supplementation of which was observed to significantly alleviate the OTA-induced accumulation of reactive oxygen species and cell apoptosis. Further mechanistical analyses revealed that PA can downregulate the expression level of proapoptotic protein BAX, enhance the expression level of apoptosis inhibitory protein BCL2, and decrease the level of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2). This study demonstrated that CUR can alleviate the adverse effects of OTA by influencing the transcriptomic and metabolomic profiles of livers, which may contribute to the application of CUR in food and feed products for the prevention of OTA toxicity.

[Analysis of Free Pantothenic Acid in Foods by HPLC and LC-MS/MS].

A simple and reliable analytical method has been developed for the determination of pantothenic acid in food. For the high-protein food, 20 mL of water was added to 2 g of sample, and after homogenization extraction, 1 mL of 15% zinc sulfate solution was added, mixed well, centrifuged, and the supernatant was filtered to make the test solution. For the low-protein food, 20 mL of 1% formic acid solution was added to 2 g of sample, homogenized, extracted, centrifuged, and the supernatant was filtered to make the test solution. The HPLC separation was carried out on a L-column2 ODS column with 0.02 mol/L phosphate solution (pH 3.0)- acetonitrile (95 : 5) as the mobile phase, and detected at 200 nm. The LC-MS/MS conditions were L-column2 ODS as the separation column, 5 mmol/L ammonium formate (containing 0.01% formic acid)-methanol (85 : 15) as the mobile phase, and multiple reaction monitoring (MRM) was used for detection. The recoveries of pantothenic acid in milk powder and nutritional food products were more than 88% with high precision. As a result of analyzing commetrcially available foods labeled as containing pantothenic acid, analytical values almost identical to the labeled values were obtained, and a high correlation was observed between the values obtained by HPLC and LC-MS/MS.

[Use of dexpanthenol in corneal damage]. / Primenenie dekspantenola pri povrezhdenii rogovitsy.

Issues of regeneration of the cornea, which is the most vulnerable structure of the eyeball, suffering from various diseases and injuries, burns, when wearing contact lenses and glaucoma, are highly relevant for ophthalmologists. It is also necessary to minimize damage and stimulate corneal epithelization during and after the use of steroidal and non-steroidal anti-inflammatory drugs, antibacterial drugs and antiseptics, which have a cytotoxic effect and often inhibit regeneration processes, potentially even leading to the development of corneal epithelial defects. This review analyzes the effectiveness of a promising drug 5% dexpanthenol in terms of improving the reparative processes and the function of epithelial cells.

Pantothenate protects against obesity via brown adipose tissue activation.

Brown adipose tissue (BAT) is the primary site of adaptive thermogenesis, which is involved in energy expenditure and has received much attention in the field of obesity treatment. By screening a small-molecule compound library of drugs approved by the Food and Drug Administration, pantothenic acid was identified as being able to significantly upregulate the expression of uncoupling protein 1 (UCP1), a key thermogenic protein found in BAT. Pantothenate (PA) treatment decreased adiposity, reversed hepatic steatosis, and improved glucose homeostasis by increasing energy expenditure in C57BL/6J mice fed a high-fat diet. PA also significantly increased BAT activity and induced beige adipocytes formation. Mechanistically, the beneficial effects were mediated by UCP1 because PA treatment was unable to ameliorate obesity in UCP1 knockout mice. In conclusion, we identified PA as an effective BAT activator that can prevent obesity and may represent a promising strategy for the clinical treatment of obesity and related metabolic diseases.NEW & NOTEWORTHY PA treatment effectively and safely protected against obesity via the BAT-UCP1 axis. PA has therapeutic potential for treating obesity and type II diabetes.

Safety Assessment of Panthenol, Pantothenic Acid, and Derivatives as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of Panthenol, Pantothenic Acid, and 5 derivatives as used in cosmetics. These ingredients named in this report are reported to function in cosmetics as hair conditioning agents, and Panthenol also is reported to function as a skin-conditioning agent-humectant and a solvent. The Panel reviewed relevant data for these ingredients, and concluded that these 7 ingredients are safe in cosmetics in the present practices of use concentration described in this safety assessment.

Engineering precursor and co-factor supply to enhance D-pantothenic acid production in Bacillus megaterium.

High-yielding chemical and chemo-enzymatic methods of D-pantothenic acid (DPA) synthesis are limited by using poisonous chemicals and DL-pantolactone racemic mixture formation. Alternatively, the safe microbial fermentative route of DPA production was found promising but suffered from low productivity and precursor supplementation. In this study, Bacillus megaterium was metabolically engineered to produce DPA without precursor supplementation. In order to provide a higher supply of precursor D-pantoic acid, key genes involved in its synthesis are overexpressed, resulting strain was produced 0.53 ± 0.08 g/L DPA was attained in shake flasks. Cofactor CH2-THF was found to be vital for DPA biosynthesis and was regenerated through the serine-glycine degradation pathway. Enhanced supply of another precursor, ß-alanine was achieved by codon optimization and dosing of the limiting L-asparate-1-decarboxylase (ADC). Co-expression of Pantoate-ß-alanine ligase, ADC, phosphoenolpyruvate carboxylase, aspartate aminotransferase and aspartate ammonia-lyase enhanced DPA concentration to 2.56 ± 0.05 g/L at shake flasks level. Fed-batch fermentation in a bioreactor with and without the supplementation of ß-alanine increased DPA concentration to 19.52 ± 0.26 and 4.78 ± 0.53 g/L, respectively. This present study successfully demonstrated a rational approach combining precursor supply engineering with cofactor regeneration for the enhancement of DPA titer in recombinant B. megaterium.

Evidence for a Conserved Function of Eukaryotic Pantothenate Kinases in the Regulation of Mitochondrial Homeostasis and Oxidative Stress.

Human PANK1, PANK2, and PANK3 genes encode several pantothenate kinase isoforms that catalyze the phosphorylation of vitamin B5 (pantothenic acid) to phosphopantothenate, a critical step in the biosynthesis of the major cellular cofactor, Coenzyme A (CoA). Mutations in the PANK2 gene, which encodes the mitochondrial pantothenate kinase (PanK) isoform, have been linked to pantothenate-kinase associated neurodegeneration (PKAN), a debilitating and often fatal progressive neurodegeneration of children and young adults. While the biochemical properties of these enzymes have been well-characterized in vitro, their expression in a model organism such as yeast in order to probe their function under cellular conditions have never been achieved. Here we used three yeast mutants carrying missense mutations in the yeast PanK gene, CAB1, which are associated with defective growth at high temperature and iron, mitochondrial dysfunction, increased iron content, and oxidative stress, to assess the cellular function of human PANK genes and functional conservation of the CoA-controlled processes between humans and yeast. Overexpression of human PANK1 and PANK3 in these mutants restored normal cellular activity whereas complementation with PANK2 was partial and could only be achieved with an isoform, PanK2mtmΔ, lacking the mitochondrial transit peptide. These data, which demonstrate functional conservation of PanK activity between humans and yeast, set the stage for the use of yeast as a model system to investigate the impact of PKAN-associated mutations on the metabolic pathways altered in this disease.

High-level expression and optimization of pantoate-ß-alanine ligase in Bacillus megaterium for the enhanced biocatalytic production of D-pantothenic acid.

D-Pantothenic acid (DPA), also known as vitamin B5 is associated with several biological functions and its deficiency causes metabolic and energetic disorders in humans. Fortification of foods with DPA is the viable option to address this risk. DPA biological production route employs pantoate-ß-alanine ligase (PBL) as the key enzyme, which avoids the tedious and time-consuming optical resolution process. The selection of an efficient PBL enzyme is vital for the biological production of DPA. In this study, the panC gene encoding PBL from Escherichia coli, Bacillus megaterium, Corynebacterium glutamicum and Bacillus subtilis was expressed in B. megaterium. B. subtilis derived panC exhibited high PBL activity 61.62 ± 2.15 U/mL. Co-expression of phosphoenolpyruvate carboxykinase (pckA) did not improve the DPA production in B. megaterium. Biocatalytic fed-batch fermentation with externally supplemented precursor substrates (D-pantoic acid and ß-alanine) improved DPA titer to 45.56 ± 0.53 g/L. Daily dietary requirements of DPA for different age groups (including babies, small children, athletes and elderly people) is steadily increasing and the improved DPA production addressed in this study offers advantage for its application in fortification of food products meeting the emerging nutritional demand. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13197-021-05093-6.

Severe pantothenic acid deficiency induces alterations in the intestinal mucosal proteome of starter Pekin ducks.

BACKGROUND: Pantothenic acid deficiency (PAD) results in growth depression and intestinal hypofunction of animals. However, the underlying molecular mechanisms remain to be elucidated. Mucosal proteome might reflect dietary influences on physiological processes. RESULTS: A total of 128 white Pekin ducks of one-day-old were randomly assigned to two groups, fed either a PAD or a pantothenic acid adequate (control, CON) diet. After a 16-day feeding period, two ducks from each replicate were sampled to measure plasma parameters, intestinal morphology, and mucosal proteome. Compared to the CON group, high mortality, growth retardation, fasting hypoglycemia, reduced plasma insulin, and oxidative stress were observed in the PAD group. Furthermore, PAD induced morphological alterations of the small intestine indicated by reduced villus height and villus surface area of duodenum, jejunum, and ileum. The duodenum mucosal proteome of ducks showed that 198 proteins were up-regulated and 223 proteins were down-regulated (> 1.5-fold change) in the PAD group compared to those in the CON group. Selected proteins were confirmed by Western blotting. Pathway analysis of these proteins exhibited the suppression of glycolysis and gluconeogenesis, fatty acid beta oxidation, tricarboxylic acid cycle, oxidative phosphorylation, oxidative stress, and intestinal absorption in the PAD group, indicating impaired energy generation and abnormal intestinal absorption. We also show that nine out of eleven proteins involved in regulation of actin cytoskeleton were up-regulated by PAD, probably indicates reduced intestinal integrity. CONCLUSION: PAD leads to growth depression and intestinal hypofunction of ducks, which are associated with impaired energy generation, abnormal intestinal absorption, and regulation of actin cytoskeleton processes. These findings provide insights into the mechanisms of intestinal hypofunction induced by PAD.

High-level production of d-pantothenic acid from glucose by fed-batch cultivation of Escherichia coli.

d-Pantothenic acid (D-PA) is an essential vitamin widely used in food, feed, chemical, and pharmaceutical industries. An Escherichia coli platform was developed for the high-level production of D-PA from glucose through fed-batch cultivation. Initially, the effects of different glucose feeding strategies D-PA synthesis were studied. It was found that D-PA production in glucose control (5 g/L) fed-batch culture reached 24.3 g/L, which was 4.09 times that in the batch culture. Next, the effect of auxotrophic amino acid (isoleucine)-limited feeding on D-PA production was investigated. The results revealed that isoleucine feeding decreased the accumulation of by-product acetic acid and promoted D-PA production significantly. Furthermore, an isoleucine feeding embedded multistage glucose supply strategy was established, and a maximum titer of 39.1 g/L was achieved. To the best of our knowledge, this levels are the highest reported so far in engineered E. coli for the D-PA production. The developed fed-batch feeding strategy may be useful for the industrial D-PA production by E. coli.

Calcium pantothenate is present in cosmetics and may cause allergic contact dermatitis.

Calcium pantothenate (CAS no. 137-08-6) is the calcium salt of pantothenic acid (vitamin B5). It is used in cosmetics due to its anti-static and hair conditioning properties. A 53-year-old female nurse's aide presented with intermittent facial eruptions (Figure S1). Patch tests were positive to calcium pantothenate, an ingredient of two of her products (a cleansing milk and a facial tonic). To our knowledge, no previous cases of sensitization from calcium pantothenate have been reported except for one case of systemic dermatitis from a nutritional supplement in a dexpanthenol-sensitized patient.

The yeast pantothenate kinase Cab1 is a master regulator of sterol metabolism and of susceptibility to ergosterol biosynthesis inhibitors.

In fungi, ergosterol is an essential component of the plasma membrane. Its biosynthesis from acetyl-CoA is the primary target of the most commonly used antifungal drugs. Here, we show that the pantothenate kinase Cab1p, which catalyzes the first step in the metabolism of pantothenic acid for CoA biosynthesis in budding yeast (Saccharomyces cerevisiae), significantly regulates the levels of sterol intermediates and the activities of ergosterol biosynthesis-targeting antifungals. Using genetic and pharmacological analyses, we show that altered pantothenate utilization dramatically alters the susceptibility of yeast cells to ergosterol biosynthesis inhibitors. Genome-wide transcription and MS-based analyses revealed that this regulation is mediated by changes both in the expression of ergosterol biosynthesis genes and in the levels of sterol intermediates. Consistent with these findings, drug interaction experiments indicated that inhibition of pantothenic acid utilization synergizes with the activity of the ergosterol molecule-targeting antifungal amphotericin B and antagonizes that of the ergosterol pathway-targeting antifungal drug terbinafine. Our finding that CoA metabolism controls ergosterol biosynthesis and susceptibility to antifungals could set the stage for the development of new strategies to manage fungal infections and to modulate the potency of current drugs against drug-sensitive and -resistant fungal pathogens.