Coenzyme A biosynthesis in Bacillus subtilis: Discovery of a novel precursor metabolite for salvage and its uptake system
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB77606 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR13363262_1.fastq.gz | Fastqsanger.gz | |||
| ERR13363262_2.fastq.gz | Fastqsanger.gz | |||
| ERR13363263_1.fastq.gz | Fastqsanger.gz | |||
| ERR13363263_2.fastq.gz | Fastqsanger.gz | |||
| ERR13363264_1.fastq.gz | Fastqsanger.gz |
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Project description:The Gram-positive model bacterium Bacillus subtilis is used for many biotechnological applications, including the large-scale production of vitamins. For vitamin B5, a precursor for coenzyme A synthesis, there is so far no established fermentation process available, and the metabolic pathways that involve this vitamin are only partially understood. In this study, we have elucidated the complete pathways for the biosynthesis of pantothenate and coenzyme A in B. subtilis. Pantothenate can not only be synthesized but also be taken up from the medium. We have identified the enzymes and the transporter involved in the pantothenate biosynthesis and uptake. High-affinity vitamin B5 uptake in B. subtilis requires an ATP-driven energy coupling factor transporter with PanU (previously YhfU) as the substrate-specific subunit. Moreover, we have identified a salvage pathway for coenzyme A acquisition that acts on complex medium even in the absence of pantothenate synthesis. This pathway requires rewiring of sulfur metabolism resulting in the increased expression of a cysteine transporter. In the salvage pathway, the bacteria import cysteinopantetheine, a novel naturally occurring metabolite, using the cystine transport system TcyJKLMN. This work lays the foundation for the development of effective processes for vitamin B5 and coenzyme A production using B. subtilis.ImportanceVitamins are essential components of the diet of animals and humans. Vitamins are thus important targets for biotechnological production. While efficient fermentation processes have been developed for several vitamins, this is not the case for vitamin B5 (pantothenate), the precursor of coenzyme A. We have elucidated the complete pathway for coenzyme A biosynthesis in the biotechnological workhorse Bacillus subtilis. Moreover, a salvage pathway for coenzyme A synthesis was found in this study. Normally, this pathway depends on pantetheine; however, we observed activity of the salvage pathway on complex medium in mutants lacking the pantothenate biosynthesis pathway even in the absence of supplemented pantetheine. This required rewiring of metabolism by expressing a cystine transporter due to acquisition of mutations affecting the regulation of cysteine metabolism. This shows how the hidden "underground metabolism" can give rise to the rapid formation of novel metabolic pathways.
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Project description:Coenzyme Q (CoQ), a redox-active lipid essential for oxidative phosphorylation, is synthesized by virtually all cells, but how eukaryotes make the universal CoQ head group precursor 4-hydroxybenzoate (4-HB) from tyrosine is unknown. The first and last steps of this pathway have been defined in Saccharomyces cerevisiae, but the intermediates and enzymes involved in converting 4-hydroxyphenylpyruvate (4-HPP) to 4-hydroxybenzaldehyde (4-HBz) have not been described. Here, we interrogate this pathway with genetic screens, targeted LC-MS, and chemical genetics. We identify three redundant aminotransferases (Bna3, Bat2, and Aat2) that support CoQ biosynthesis in the absence of the established pathway tyrosine aminotransferases, Aro8 and Aro9. We use isotope labeling to identify bona fide tyrosine catabolites, including 4-hydroxyphenylacetate (4-HPA) and 4-hydroxyphenyllactate (4-HPL). Additionally, we find multiple compounds that rescue this pathway when exogenously supplemented, most notably 4-hydroxyphenylacetaldehyde (4-HPAA) and 4-hydroxymandelate (4-HMA). Finally, we show that the Ehrlich pathway decarboxylase Aro10 is dispensable for 4-HB production. These results define new features of 4-HB synthesis in yeast, demonstrate the redundant nature of this pathway, and provide a foundation for further study.
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Project description:The tumor microenvironment is a dynamic network of stromal, cancer and immune cells that interact and compete for resources. Mitochondria play an essential role in the control of metabolic plasticity and contribute to tumor progression and immune cell functionality. We previously identified the Vanin1 pathway as a tumor suppressor of sarcoma development via vitamin B5 and coenzyme A regeneration. Using an aggressive sarcoma cell line that lacks Vnn1 expression, we showed that administration of pantethine, a vitamin B5 precursor, impairs tumor growth in immunocompetent mice. Pantethine boosts anti-tumor type 1 immunity including polarization of myeloid and dendritic cells towards enhanced IFNγ-driven antigen presentation pathways and improved development of hypermetabolic effector CD8+ T cells endowed with potential anti-tumor activity. At later stages of treatment, the effect of pantethine is limited by the development of immune cell exhaustion. Nevertheless, its activity is comparable to that of anti-PD1 treatment in sensitive tumors. In humans, VNN1 expression correlates with improved survival and immune cell infiltration in soft tissue sarcomas but not osteosarcomas. Pantethine could be a potential therapeutic immunoadjuvant for the development of anti-tumor immunity.
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Project description:Coenzyme Q10 deficiency syndrome includes a clinically heterogeneous group of mitochondrial diseases characterized by low content of CoQ10 in tissues. The only currently available treatment is supplementation with CoQ10, which improves the clinical phenotype in some patients but does not reverse established damage. We analyzed the transcriptome profiles of fibroblasts from different patients irrespective of the genetic origin of the disease. These cells showed a survival genetic profile apt at maintaining growth and undifferentiated phenotype, promoting anti-apoptotic pathways, and favoring bioenergetics supported by glycolysis and low lipid metabolism. WE conclude that the mitochondrial dysfunction caused byCoQ10 deficiency induces a stable survival adaptation of somatic cells from patients. All samples in triplicate. We compare the gene expresion of human derman fibroblast to fibroblast from 4 different patient diagnosed with the human syndrome of coenzyme Q10 deficiency.
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