Relief of <scp>CoA</scp> sequestration and restoration of mitochondrial function in a mouse model of propionic acidemia

Subramanian, Chitra; Frank, Matthew W.; Tangallapally, Rajendra; Yun, Mi‐Kyung; White, Stephen W.; Lee, Richard; Rock, Charles O.; Jackowski, Suzanne

doi:10.1002/jimd.12570

Cited by 11 publications

(23 citation statements)

References 103 publications

(252 reference statements)

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“…A first-in-human trial to assess the safety and tolerability of an improved pantazine (BP-671) in healthy volunteers has recently begun (NCT04836494). The molecule was also proposed as a therapeutic option for patients with Propionic Acidemia and Methylmalonic Acidemia [ 132 ].…”

Section: Proposed Therapeutic Optionsmentioning

confidence: 99%

Inherited Disorders of Coenzyme A Biosynthesis: Models, Mechanisms, and Treatments

Cavestro

Diodato

Tiranti

et al. 2023

IJMS

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Coenzyme A (CoA) is a vital and ubiquitous cofactor required in a vast number of enzymatic reactions and cellular processes. To date, four rare human inborn errors of CoA biosynthesis have been described. These disorders have distinct symptoms, although all stem from variants in genes that encode enzymes involved in the same metabolic process. The first and last enzymes catalyzing the CoA biosynthetic pathway are associated with two neurological conditions, namely pantothenate kinase-associated neurodegeneration (PKAN) and COASY protein-associated neurodegeneration (CoPAN), which belong to the heterogeneous group of neurodegenerations with brain iron accumulation (NBIA), while the second and third enzymes are linked to a rapidly fatal dilated cardiomyopathy. There is still limited information about the pathogenesis of these diseases, and the knowledge gaps need to be resolved in order to develop potential therapeutic approaches. This review aims to provide a summary of CoA metabolism and functions, and a comprehensive overview of what is currently known about disorders associated with its biosynthesis, including available preclinical models, proposed pathomechanisms, and potential therapeutic approaches.

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Section: Proposed Therapeutic Optionsmentioning

confidence: 99%

Inherited Disorders of Coenzyme A Biosynthesis: Models, Mechanisms, and Treatments

Cavestro

Diodato

Tiranti

et al. 2023

IJMS

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Section: Figurementioning

confidence: 99%

“…Earlier studies have demonstrated the mitochondrial protective function of pantothenic acid (Tahiliani & Beinlich 1991, Williams et al 2013, Sm et al 2018, Subramanian et al 2021, Subramanian et al 2023. Pantothenic acid is a major precursor for CoA synthesis (Tahiliani & Beinlich 1991, Williams et al 2013, Sm et al 2018, Subramanian et al 2021, Subramanian et al 2023. Pantothenic acid-mediated CoA biosynthesis is required for the effective metabolism of all substrates by converting them to Acetyl CoA which is the preferred form for https://doi.org/10.1530/REM-23-0005…”

Section: Figurementioning

confidence: 99%

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Untargeted metabolomics reveal sex-specific and non-specific redox-modulating metabolites in kidneys following binge drinking

Rafferty,

Martins de Carvalho,

Sutter

et al. 2023

Redox Experimental Medicine

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Binge drinking is a growing health concern among all age groups. The ability of individuals to handle ethanol in their systems differs not due to differences in enzyme expression but also due to other factors. Vital organs including brain, liver, heart and kidneys are at high risk following repeated exposure to high concentrations of ethanol from binge drinking. The impact of chronic binge drinking on kidneys is not well studied. Using a mouse model of chronic binge drinking, we have identified major metabolic alterations that could set the stage for detrimental effects in the kidneys of male and female mice. We have deciphered that even though there are pathway overlaps, the different sexes exhibited unique and divergent metabolic pathway dysregulations as per the metabolite panels following binge drinking. We have reported that binge drinking could negatively influence renal redox homeostasis in both sexes through regulation of different metabolite clusters. In male mice by downregulation of pantothenic acid and riboflavin synthesis, and female mice by upregulation of α-aminoadipic acid and formyl kynurenine level. Interestingly, uric acid biosynthesis pathway has been upregulated independent of the sex specific effects, portraying the significance of uric acid as a potential marker for binge drinking induced injury in both the sexes. Thus, by altering renal metabolome binge drinking sets the stage for renal damage by disturbing renal redox balance. Our data has high translational potential and will aid in finding ideal therapeutics in a sex-specific manner for subjects exposed to binge drinking induced renal injury.

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“…Pantazines induce a conformational change in homodimeric PanK, which obscures the CoA binding pocket and prevents CoA inhibition. The effects of pantazines are concentration-dependent [ 100 ]. At low concentrations, the majority of PanK protomers are not bound to pantazines, and thus PanK dimerization typically occurs between one bound protomer and one unbound protomer.…”

Section: Development Of Drugs Targeting the Coa Biosynthesis Pathwaymentioning

confidence: 99%

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

Riske,

Luckhart,

Riehle

2023

IJMS

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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.

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Relief of CoA sequestration and restoration of mitochondrial function in a mouse model of propionic acidemia

Cited by 11 publications

References 103 publications

Inherited Disorders of Coenzyme A Biosynthesis: Models, Mechanisms, and Treatments

Inherited Disorders of Coenzyme A Biosynthesis: Models, Mechanisms, and Treatments

Untargeted metabolomics reveal sex-specific and non-specific redox-modulating metabolites in kidneys following binge drinking

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

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