Synthesis Of Coenzyme Research Articles

Can the join use of an enzyme inhibit or and an inhibit or of the synthesis of this enzymes coenzyme be a universal algorithm for creating anti-resistance herbicide compositions?

Can the join use of an enzyme inhibit or and an inhibit or of the synthesis of this enzymes coenzyme be a universal algorithm for creating anti-resistance herbicide compositions?

The influence of popular drugs inhibiting the synthesis of coenzyme Q, statins and bisphosphonates, on the oxygen metabolism of cells

The influence of popular drugs inhibiting the synthesis of coenzyme Q, statins and bisphosphonates, on the oxygen metabolism of cells

Exploring the anti-ovarian aging mechanism of He's Yangchao formula: Insights from multi-omics analysis in naturally aged mice

BackgroundThe rapid acceleration of female reproductive aging has become a major public health concern. He's Yangchao formula (HSYC), a compound comprising eight herbs, has demonstrated efficacy in enhancing ovarian function. Thus, an in-depth study of its anti-ovarian aging mechanism is required. PurposeTo evaluate the anti-ovarian aging effect of HSYC in naturally aged mice and investigate the underlying mechanism by analyzing the gut microbiota (GM), metabolome, and transcriptome. MethodsYoung and advanced maternal age (AMA) mice were selected for this study. Hematoxylin and eosin staining, fluorescence staining, western blotting, and qPCR analyses were used to detect the phenotypes associated with ovarian aging. Subsequently, analyses of the GM, transcriptome, and metabolome analyses were performed to explore the potential mechanisms of action of HSYC. Finally, in vivo and in vitro experiments were performed to verify potential therapeutic mechanisms. ResultsHSYC promoted follicular development in AMA mice and ameliorated age-related mitochondrial dysfunction, apoptosis, and defects in DNA damage repair. GM analysis revealed that HSYC treatment significantly increased the abundance of Akkermansia and Turicibacter. Transcriptome and metabolome analyses showed that HSYC might mitigate ovarian aging by regulating metabolic pathways, amino acid metabolism, glutathione metabolism, and the synthesis of pantothenic acid and coenzyme A. Combined transcriptomic and metabolomic analyses identified the glutathione metabolic pathway as the key pathway through which HSYC counteracts ovarian aging. Additional experimental verification confirmed that HSYC upregulated the glutathione metabolic genes GPX8, GSTA1, and GSTA4, increased glutathione-related products (GSH), and reduced ROS levels. ConclusionsHSYC exerts beneficial therapeutic effects on ovarian aging by regulating multiple endogenous metabolites, targets, and metabolic pathways, with an emphasis on its anti-ovarian aging effects through the glutathione metabolic pathway. These findings underscore the innovative potential of HSYC in addressing ovarian aging and offer a novel therapeutic approach that targets multiple biological pathways to improve the reproductive health of women with AMA..

Snapshot of the Probiotic Potential of Kluveromyces marxianus DMKU-1042 Using a Comparative Probiogenomics Approach.

Kluyveromyces marxianus is a rapidly growing thermotolerant yeast that secretes a variety of lytic enzymes, utilizes different sugars, and produces ethanol. The probiotic potential of this yeast has not been well explored. To evaluate its probiotic potential, the yeast strain Kluyveromyces marxianus DMKU3-1042 was analyzed using next-generation sequencing technology. Analysis of the genomes showed that the yeast isolates had a GC content of 40.10-40.59%. The isolates had many genes related to glycerol and mannose metabolism, as well as genes for acetoin and butanediol metabolism, acetolactate synthase subunits, and lactic acid fermentation. The strain isolates were also found to possess genes for the synthesis of different vitamins and Coenzyme A. Genes related to heat and hyperosmotic shock tolerance, as well as protection against reactive oxygen species were also found. Additionally, the isolates contained genes for the synthesis of lysine, threonine, methionine, and cysteine, as well as genes with anticoagulation and anti-inflammatory properties. Based on our analysis, we concluded that the strain DMKU3-1042 possesses probiotic properties that make it suitable for use in food and feed supplementation.

Starving the Beast: Limiting Coenzyme A Biosynthesis to Prevent Disease and Transmission in Malaria.

Malaria parasites must acquire all necessary nutrients from the vertebrate and mosquito hosts to successfully complete their life cycle. Failure to acquire these nutrients can limit or even block parasite development and presents a novel target for malaria control. One such essential nutrient is pantothenate, also known as vitamin B5, which the parasite cannot synthesize de novo and is required for the synthesis of coenzyme A (CoA) in the parasite. This review examines pantothenate and the CoA biosynthesis pathway in the human-mosquito-malaria parasite triad and explores possible approaches to leverage the CoA biosynthesis pathway to limit malaria parasite development in both human and mosquito hosts. This includes a discussion of sources for pantothenate for the mosquito, human, and parasite, examining the diverse strategies used by the parasite to acquire substrates for CoA synthesis across life stages and host resource pools and a discussion of drugs and alternative approaches being studied to disrupt CoA biosynthesis in the parasite. The latter includes antimalarial pantothenate analogs, known as pantothenamides, that have been developed to target this pathway during the human erythrocytic stages. In addition to these parasite-targeted drugs, we review studies of mosquito-targeted allosteric enzymatic regulators known as pantazines as an approach to limit pantothenate availability in the mosquito and subsequently deprive the parasite of this essential nutrient.

Patient and caregiver experiences with pantothenate kinase-associated neurodegeneration (PKAN): results from a patient community survey

BackgroundPantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive genetic disorder of PANK2, which enables mitochondrial synthesis of coenzyme A. Its loss causes neurodegeneration with iron accumulation primarily in motor-related brain areas. Symptoms include dystonia, parkinsonism, and other disabilities. PKAN has been categorized as classic PKAN, with an age of onset ≤ 10 years, rapid progression, and early disability or death; and atypical PKAN, with later onset, slower progression, generally milder, and more diverse symptom manifestations. Available treatments are mostly palliative. Information on the lived experience of patients with PKAN and their caregivers or on community-level disease burden is limited. It is necessary to engage patients as partners to expand our understanding and improve clinical outcomes. This patient-oriented research study used multiple-choice and free-form question surveys distributed by patient organizations to collect information on the manifestations and disease burden of PKAN. It also assessed respondents’ experiences and preferences with clinical research to inform future clinical trials.ResultsThe analysis included 166 surveys. Most respondents (87%) were parents of a patient with PKAN and 7% were patients, with 80% from Europe and North America. The study cohort included 85 patients with classic PKAN (mean ± SD age of onset 4.4 ± 2.79 years), 65 with atypical PKAN (13.8 ± 4.79 years), and 16 identified as “not sure”. Respondents reported gait disturbances and dystonia most often in both groups, with 44% unable to walk. The classic PKAN group reported more speech, swallowing, and visual difficulties and more severe motor problems than the atypical PKAN group. Dystonia and speech/swallowing difficulties were reported as the most challenging symptoms. Most respondents reported using multiple medications, primarily anticonvulsants and antiparkinsonian drugs, and about half had participated in a clinical research study. Study participants reported the most difficulties with the physical exertion associated with imaging assessments and travel to assessment sites.ConclusionsThe survey results support the dichotomy between classic and atypical PKAN that extends beyond the age of onset. Inclusion of patients as clinical research partners shows promise as a pathway to improving clinical trials and providing more efficacious PKAN therapies.

Metabolic programs of T cell tissue residency empower tumour immunity.

Tissue resident memoryCD8+ T (TRM) cells offer rapid and long-term protection at sites of reinfection1. Tumour-infiltrating lymphocytes with characteristics of TRM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting TRM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memoryCD8+ T cell populations. We found that memory CD8+T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate-cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where TRM cells interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memoryT cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of TRM cell metabolism, we reveal how these programs can be leveraged to fuel memoryCD8+ T cell formation in the context of acute infections and enhance antitumour immunity.

Synthesis and X-ray diffraction analysis of coenzyme Q derivatives obtained from natural polyalkoxyallylbenzenes

A general synthetic access to methoxy analogues of coenzymes Q bearing functional substituents with various chain lengths at the quinone ring was developed using available natural (polymethoxy)(methylenedioxy)allylbenzenes. The Baeyer–Villiger rearrangement of (methylenedioxy)benzaldehydes into phenols followed by facile oxidation to quinones with the methylenedioxy moiety opening was identified as the key step in the synthesis of the target 1,4- and 1,2-polyalkoxyquinones

Coenzyme biosynthesis in response to precursor availability reveals incorporation of β-alanine from pantothenate in prototrophic bacteria

Coenzymes are important for all classes of enzymatic reactions and essential for cellular metabolism. Most coenzymes are synthesized from dedicated precursors, also referred to as vitamins, which prototrophic bacteria can either produce themselves from simpler substrates or take up from the environment. The extent to which prototrophs use supplied vitamins and whether externally available vitamins affect the size of intracellular coenzyme pools and control endogenous vitamin synthesis is currently largely unknown. Here, we studied coenzyme pool sizes and vitamin incorporation into coenzymes during growth on different carbon sources and vitamin supplementation regimes using metabolomics approaches. We found that the model bacterium Escherichia coli incorporated pyridoxal, niacin, and pantothenate into pyridoxal 5'-phosphate, NAD, and coenzyme A (CoA), respectively. In contrast, riboflavin was not taken up and was produced exclusively endogenously. Coenzyme pools were mostly homeostatic and not affected by externally supplied precursors. Remarkably, we found that pantothenate is not incorporated into CoA as such but is first degraded to pantoate and β-alanine and then rebuilt. This pattern was conserved in various bacterial isolates, suggesting a preference for β-alanine over pantothenate utilization in CoA synthesis. Finally, we found that the endogenous synthesis of coenzyme precursors remains active when vitamins are supplied, which is consistent with described expression data of genes for enzymes involved in coenzyme biosynthesis under these conditions. Continued production of endogenous coenzymes may ensure rapid synthesis of the mature coenzyme under changing environmental conditions, protect against coenzyme limitation, and explain vitamin availability in naturally oligotrophic environments.

Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7

Coenzyme Q (or ubiquinone) is a redox-active lipid that serves as universal electron carrier in the mitochondrial respiratory chain and antioxidant in the plasma membrane limiting lipid peroxidation and ferroptosis. Mechanisms allowing cellular coenzyme Q distribution after synthesis within mitochondria are not understood. Here we identify the cytosolic lipid transfer protein STARD7 as a critical factor of intracellular coenzyme Q transport and suppressor of ferroptosis. Dual localization of STARD7 to the intermembrane space of mitochondria and the cytosol upon cleavage by the rhomboid protease PARL ensures the synthesis of coenzyme Q in mitochondria and its transport to the plasma membrane. While mitochondrial STARD7 preserves coenzyme Q synthesis, oxidative phosphorylation function and cristae morphogenesis, cytosolic STARD7 is required for the transport of coenzyme Q to the plasma membrane and protects against ferroptosis. A coenzyme Q variant competes with phosphatidylcholine for binding to purified STARD7 in vitro. Overexpression of cytosolic STARD7 increases ferroptotic resistance of the cells, but limits coenzyme Q abundance in mitochondria and respiratory cell growth. Our findings thus demonstrate the need to coordinate coenzyme Q synthesis and cellular distribution by PARL-mediated STARD7 processing and identify PARL and STARD7 as promising targets to interfere with ferroptosis.

PI3K-PANK4: a new target for de novo synthesis of coenzyme A

PI3K-PANK4: a new target for de novo synthesis of coenzyme A

PI3K–AKT Inhibits PANK4 to Promote De Novo Synthesis of Coenzyme A

AKT inhibits the metabolic enzyme PANK4 to promote the de novo synthesis of coenzyme A (CoA).

PI3K-AKT Inhibits PANK4 to Promote De Novo Synthesis of Coenzyme A.

AKT inhibits the metabolic enzyme PANK4 to promote the de novo synthesis of coenzyme A (CoA).

PI3K drives the de novo synthesis of coenzyme A from vitamin B5

In response to hormones and growth factors, the class I phosphoinositide-3-kinase (PI3K) signalling network functions as a major regulator of metabolism and growth, governing cellular nutrient uptake, energy generation, reducing cofactor production and macromolecule biosynthesis1. Many of the driver mutations in cancer with the highest recurrence, including in receptor tyrosine kinases, Ras, PTEN and PI3K, pathologically activate PI3K signalling2,3. However, our understanding of the core metabolic program controlled by PI3K is almost certainly incomplete. Here, using mass-spectrometry-based metabolomics and isotope tracing, we show that PI3K signalling stimulates the de novo synthesis of one of the most pivotal metabolic cofactors: coenzyme A (CoA). CoA is the major carrier of activated acyl groups in cells4,5 and is synthesized from cysteine, ATP and the essential nutrient vitamin B5 (also known as pantothenate)6,7. We identify pantothenate kinase 2 (PANK2) and PANK4 as substrates of the PI3K effector kinase AKT8. Although PANK2 is known to catalyse the rate-determining first step of CoA synthesis, we find that the minimally characterized but highly conserved PANK49 is a rate-limiting suppressor of CoA synthesis through its metabolite phosphatase activity. Phosphorylation of PANK4 by AKT relieves this suppression. Ultimately, the PI3K–PANK4 axis regulates the abundance of acetyl-CoA and other acyl-CoAs, CoA-dependent processes such as lipid metabolism and proliferation. We propose that these regulatory mechanisms coordinate cellular CoA supplies with the demands of hormone/growth-factor-driven or oncogene-driven metabolism and growth.

Inherited defects of cobalamin metabolism.

Cobalamin (vitamin B12) is required for activity of the enzymes methylmalonyl-CoA mutase and methionine synthase in human cells. Inborn errors affecting cobalamin uptake or metabolism are characterized by accumulation of the substrates for these enzymes, methylmalonic acid and homocysteine, in blood and urine. Inborn errors affecting synthesis of the adenosylcobalamin coenzyme required by methylmalonyl-CoA mutase (cblA and cblB) result in isolated methylmalonic aciduria; inborn errors affecting synthesis of the methylcobalamin coenzyme required by methionine synthase (cblE and cblG) result in isolated homocystinuria. Combined methylmalonic aciduria and homocystinuria is seen in patients with impaired intestinal cobalamin absorption (intrinsic factor deficiency, Imerslund-Gräsbeck syndrome) and with defects affecting synthesis of both cobalamin coenzymes (cblC, cblD, cblF and cblJ). A series of disorders caused by pathogenic variant mutations affecting gene regulators (transcription factors) of the MMACHC gene have recently been described (HCFC1 [cblX disorder] and deficiencies of THAP11, and ZNF143 [the cblK disorder]).

Substantively Lowered Levels of Pantothenic Acid (Vitamin B5) in Several Regions of the Human Brain in Parkinson's Disease Dementia.

Pantothenic acid (vitamin B5) is an essential trace nutrient required for the synthesis of coenzyme A (CoA). It has previously been shown that pantothenic acid is significantly decreased in multiple brain regions in both Alzheimer’s disease (ADD) and Huntington’s disease (HD). The current investigation aimed to determine whether similar changes are also present in cases of Parkinson’s disease dementia (PDD), another age-related neurodegenerative condition, and whether such perturbations might occur in similar regions in these apparently different diseases. Brain tissue was obtained from nine confirmed cases of PDD and nine controls with a post-mortem delay of 26 h or less. Tissues were acquired from nine regions that show high, moderate, or low levels of neurodegeneration in PDD: the cerebellum, motor cortex, primary visual cortex, hippocampus, substantia nigra, middle temporal gyrus, medulla oblongata, cingulate gyrus, and pons. A targeted ultra–high performance liquid chromatography—tandem mass spectrometry (UHPLC-MS/MS) approach was used to quantify pantothenic acid in these tissues. Pantothenic acid was significantly decreased in the cerebellum (p = 0.008), substantia nigra (p = 0.02), and medulla (p = 0.008) of PDD cases. These findings mirror the significant decreases in the cerebellum of both ADD and HD cases, as well as the substantia nigra, putamen, middle frontal gyrus, and entorhinal cortex of HD cases, and motor cortex, primary visual cortex, hippocampus, middle temporal gyrus, cingulate gyrus, and entorhinal cortex of ADD cases. Taken together, these observations indicate a common but regionally selective disruption of pantothenic acid levels across PDD, ADD, and HD.

3-[(2,4-dihydroxy-3,3-dimethylbutanoyl)amino]propanoic acid (Vitamin B5): Its Synthesis, Transformation into Coenzyme A and Role in Disease

This is a paper on Vitamin B5, it’s role in coenzyme A synthesis and how deficiency of B5 can have catastrophic consequences of human health. In this review, the process of pantothenate synthesis in bacteria and plants will be explored, followed by the role of B5 in the synthesis of coenzyme A (CoA). Understanding these mechanisms is of critical importance to nutritional and clinical authorities to aid the formation of guidelines that promote good health and clinical treatment. The biosynthesis pathway of pantothenate in pathogenic bacteria is of particular interest in the future design of antibiotic drugs as it contains many potential enzyme targets that are absent and unnecessary in humans. The importance of B5 and the CoA synthesis pathway is highlighted via a discussion of diseases that result or are linked with improper functioning of these systems. Subsequently, the paper explores the benefits of B5 supplementation for cholesterol and inflammation reduction and immune response during tuberculosis infection. The paper then explores the prevalence of poor vitamin B5 intake in certain populations to highlight where B5 consumption increases or supplementation should be promoted.

Biotin, a universal and essential cofactor: synthesis, ligation and regulation.

Biotin is a covalently attached enzyme cofactor required for intermediary metabolism in all three domains of life. Several important human pathogens (e.g. Mycobacterium tuberculosis) require biotin synthesis for pathogenesis. Humans lack a biotin synthetic pathway hence bacterial biotin synthesis is a prime target for new therapeutic agents. The biotin synthetic pathway is readily divided into early and late segments. Although pimelate, a 7-carbon α,ω-dicarboxylic acid that contributes 7 of the 10 biotin carbons atoms, was long known to be a biotin precursor, its biosynthetic pathway was a mystery until the Escherichia colipathway was discovered in 2010. Since then, diverse bacteria encode evolutionarily distinct enzymes that replace enzymes in the E. coli pathway. Two new bacterial pimelate synthesis pathways have been elucidated. In contrast to the early pathway, the late pathway, assembly of the fused rings of the cofactor, was long thought settled. However, a new enzyme that bypasses a canonical enzyme was recently discovered as well as homologs of another canonical enzyme that functions in synthesis of another protein-bound coenzyme, lipoic acid. Most bacteria tightly regulate transcription of the biotin synthetic genes in a biotin-responsive manner. The bifunctional biotin ligases which catalyze attachment of biotin to its cognate enzymes and repress biotin gene transcription are best understood regulatory system.

Synthesis and Biological Activities of Coenzyme Q Derivatives Containing (4-Aryloxylaryl)amino Moiety

Synthesis and Biological Activities of Coenzyme Q Derivatives Containing (4-Aryloxylaryl)amino Moiety

A strategic Ser/Cys exchange in the catalytic triad unlocks an acyltransferase-mediated synthesis of thioesters and tertiary amides

Expanding the toolbox of enzymatic reactions accessible to organic chemists is one of the major goals in biocatalysis. Here we describe the development of an acyltransferase variant from Mycobacterium smegmatis in which a strategic Ser/Cys exchange in the catalytic triad dramatically expanded its synthetic capability to yield a biocatalyst able to efficiently catalyse the formation of thioesters and tertiary amides in water. Preparative scale (250 mM) biotransformations were performed starting from different thiols and secondary amines with excellent yields and reactions times, using vinyl esters as acylating agents. The high substrate-to-catalyst ratio and the cofactor independence make this process a sustainable and cost-effective procedure that was successfully applied to the synthesis of acetyl coenzyme A as well as structurally simpler analogues. Computational studies provided insights into the enzymatic selectivity and substrate recognition. Preparative methods for thioester and tertiary amide formation are currently missing in the biocatalysis repertoire. Now, a mutation of serine to cysteine in the catalytic triad of an acyltransferase expands its synthetic capability to generate these compounds while retaining its natural activity towards alcohols.