Prebiotic syntheses of vitamin coenzymes: II. Pantoic acid, pantothenic acid, and the composition of coenzyme A

Miller, Stanley L.; Schlesinger, G.

doi:10.1007/bf00182178

Cited by 22 publications

(12 citation statements)

References 37 publications

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“…In the membrane fraction of the proteomic approach, a putative pantothenate transporter (PanT) showed high abundance at all sample time points reaching its maximum in the early stationary phase (stat1). Pantothenate is a precursor of CoA, which is used in the Stickland reactions as well as the central carbon metabolism ( Miller and Schlesinger, 1993 ). The biosynthesis of CoA was induced before the onset of the stationary phase.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Reprogramming of Clostridioides difficile During the Stationary Phase With the Induction of Toxin Production

et al. 2018

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The obligate anaerobe, spore forming bacterium Clostridioides difficile (formerly Clostridium difficile) causes nosocomial and community acquired diarrhea often associated with antibiotic therapy. Major virulence factors of the bacterium are the two large clostridial toxins TcdA and TcdB. The production of both toxins was found strongly connected to the metabolism and the nutritional status of the growth environment. Here, we systematically investigated the changes of the gene regulatory, proteomic and metabolic networks of C. difficile 630Δerm underlying the adaptation to the non-growing state in the stationary phase. Integrated data from time-resolved transcriptome, proteome and metabolome investigations performed under defined growth conditions uncovered multiple adaptation strategies. Overall changes in the cellular processes included the downregulation of ribosome production, lipid metabolism, cold shock proteins, spermine biosynthesis, and glycolysis and in the later stages of riboflavin and coenzyme A (CoA) biosynthesis. In contrast, different chaperones, several fermentation pathways, and cysteine, serine, and pantothenate biosynthesis were found upregulated. Focusing on the Stickland amino acid fermentation and the central carbon metabolism, we discovered the ability of C. difficile to replenish its favored amino acid cysteine by a pathway starting from the glycolytic 3-phosphoglycerate via L-serine as intermediate. Following the growth course, the reductive equivalent pathways used were sequentially shifted from proline via leucine/phenylalanine to the central carbon metabolism first to butanoate fermentation and then further to lactate fermentation. The toxin production was found correlated mainly to fluxes of the central carbon metabolism. Toxin formation in the supernatant was detected when the flux changed from butanoate to lactate synthesis in the late stationary phase. The holistic view derived from the combination of transcriptome, proteome and metabolome data allowed us to uncover the major metabolic strategies that are used by the clostridial cells to maintain its cellular homeostasis and ensure survival under starvation conditions.

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Section: Discussionmentioning

confidence: 99%

Metabolic Reprogramming of Clostridioides difficile During the Stationary Phase With the Induction of Toxin Production

et al. 2018

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“…CoA is an essential cofactor for cell growth and is involved in many metabolic reactions, including the synthesis of phospholipids, synthesis and degradation of fatty acids, and the operation of the tricarboxylic acid cycle. The prebiotic formation and stability of pantothenate precursors suggests that CoA function was important in the earliest metabolic pathways (87). From genetic footprinting experiments in E. coli, all five biosynthetic genes involved in CoA biosynthesis from pantothenate are essential (44), but the pantothenate biosynthetic genes can be dispensable in some organisms due to the expression of a pantothenate permease which transports the vitamin into the cell.…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of Pantothenic Acid and Coenzyme A

2007

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Pantothenate is vitamin B5 and is the key precursor for the biosynthesis of coenzyme A (CoA), a universal and essential cofactor involved in a myriad of metabolic reactions, including the synthesis of phospholipids, the synthesis and degradation of fatty acids, and the operation of the tricarboxylic acid cycle. CoA is also the only source of the phosphopantetheine prosthetic group for enzymes that shuttle intermediates between the active sites of enzymes involved in fatty acid, nonribosomal peptide, and polyketide synthesis. Pantothenate can be synthesized de novo and/or transported into the cell through a pantothenatepermease. Pantothenate uptake is essential for those organisms that lack the genes to synthesize this vitamin. The intracellular levels of CoA are controlled by the balance between synthesis and degradation. In particular, CoA is assembled in five enzymatic steps, starting from the phosphorylation of pantothenate to phosphopantothenatecatalyzed by pantothenate kinase, the product of the coaA gene. In some bacteria, the production of phosphopantothenate by pantothenate kinase is the rate limiting and most regulated step in the biosynthetic pathway. CoA synthesis additionally networks with other vitamin-associated pathways, such as thiamine and folic acid.

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“…It has important roles in the synthesis and oxidation of fatty acids, ketogenesis, biosynthesis of cholesterol and acetylcholine, regulation of gene expression, and cellular metabolism 28‐30 . In addition, CoA functions are critical for early metabolic pathways 31,32 and for the development of the nervous system 33 . Defects in the transportation of acetyl‐CoA to the mitochondria would result in the accumulation of the enzyme in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

SLC25A42‐associated mitochondrial encephalomyopathy: Report of additional founder cases and functional characterization of a novel deletion

et al. 2021

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SLC25A42 is the main transporter of coenzyme A (CoA) into mitochondria. To date, 15 individuals have been reported to have one of two bi‐allelic homozygous missense variants in the SLC25A42 as the cause of mitochondrial encephalomyopathy, of which 14 of them were of Saudi origin and share the same founder variant, c.871A > G:p.Asn291Asp. The other subject was of German origin with a variant at canonical splice site, c.380 + 2 T > A. Here, we describe the clinical manifestations and the disease course in additional six Saudi patients from four unrelated consanguineous families. While five patients have the Saudi founder p.Asn291Asp variant, one subject has a novel deletion. Functional analyses on fibroblasts obtained from this patient revealed that the deletion causes significant decrease in mitochondrial oxygen consumption and ATP production compared to healthy individuals. Moreover, extracellular acidification rate revealed significantly reduced glycolysis, glycolytic capacity, and glycolytic reserve as compared to control individuals. There were no changes in the mitochondrial DNA (mtDNA) content of patient fibroblasts. Immunoblotting experiments revealed significantly diminished protein expression due to the deletion. In conclusion, we report additional patients with SLC25A42‐associated mitochondrial encephalomyopathy. Our study expands the molecular spectrum of this condition and provides further evidence of mitochondrial dysfunction as a central cause of pathology. We therefore propose that this disorder should be included in the differential diagnosis of any patient with an unexplained motor and speech delay, recurrent encephalopathy with metabolic acidosis, intermittent or persistent dystonia, lactic acidosis, basal ganglia lesions and, especially, of Arab ethnicity. Finally, deep brain stimulation should be considered in the management of patients with life altering dystonia.

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Prebiotic syntheses of vitamin coenzymes: II. Pantoic acid, pantothenic acid, and the composition of coenzyme A

Cited by 22 publications

References 37 publications

Metabolic Reprogramming of Clostridioides difficile During the Stationary Phase With the Induction of Toxin Production

Metabolic Reprogramming of Clostridioides difficile During the Stationary Phase With the Induction of Toxin Production

Biosynthesis of Pantothenic Acid and Coenzyme A

SLC25A42‐associated mitochondrial encephalomyopathy: Report of additional founder cases and functional characterization of a novel deletion

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