Turnover rate of coenzyme A in mouse brain and liver

Orsatti, Laura; Orsale, Maria Vittoria; Pasquale, Pamela di; Vecchi, Andrea; Colaceci, Fabrizio; Ciammaichella, A; Rossetti, Ilaria; Bonelli, Fabio; Baumgaertel, Karsten; Li, Kai; Elbaum, Daniel; Monteagudo, Edith

doi:10.1371/journal.pone.0251981

Cited by 9 publications

(6 citation statements)

References 39 publications

(53 reference statements)

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“…In both tissues, total CoA was elevated at 8 hours although the plasma levels of BBP-671 were rapidly falling. This observation was in agreement with the slow dissociation of BBP-671 from the intracellular PANKs (Subramanian et al, 2023) and the respective tissue CoA degradation rates (Orsatti et al, 2021).…”

Section: Resultssupporting

confidence: 87%

Pantothenate Kinase Activation Restores Brain Coenzyme A in a Mouse Model of Pantothenate Kinase-Associated Neurodegeneration

Subramanian,

Frank,

Sukhun

et al. 2023

J Pharmacol Exp Ther

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Pantothenate kinase associated neurodegeneration (PKAN) is characterized by a motor disorder with combinations of dystonia, parkinsonism and spasticity, leading to premature death. PKAN is caused by mutations in the PANK2 gene that result in loss or reduction of PANK2 protein function.PANK2 is one of three kinases that initiate and regulate coenzyme A biosynthesis from vitamin B5 and the ability of BBP-671, an allosteric activator of pantothenate kinases, to enter the brain and elevate coenzyme A was investigated. The metabolic stability, protein binding and membrane permeability of BBP-671 all suggest it has the physical properties required to cross the blood brain barrier. BBP-671 was detected in plasma, liver, cerebrospinal fluid and brain following oral administration in rodents demonstrating the ability of BBP-671 to penetrate the brain. The pharmacokinetic and pharmacodynamic properties of orally administered BBP-671 evaluated in cannulated rats showed that CoA concentrations were elevated in blood, liver and brain. BBP-671 elevation of whole blood acetyl-CoA served as a peripheral pharmacodynamic marker and provided a suitable method to assess target engagement. BBP-671 treatment elevated brain coenzyme A concentrations, and improved movement and body weight in a PKAN mouse model. Thus, BBP-671 crosses the blood brain barrier to correct the brain CoA deficiency in a PKAN mouse model resulting in improved locomotion and survival, providing a preclinical foundation for the development of BBP-671 as a potential treatment for PKAN. SIGNIFICANCE STATEMENTThe blood brain barrier represents a major hurdle for drugs targeting brain metabolism. This work describes the pharmacokinetic/pharmacodynamic properties of BBP-671, a pantothenate kinase activator. BBP-671 crosses the blood brain barrier to correct the neuron-specific CoA deficiency and improve motor function in a mouse model of pantothenate kinase associated neurodegeneration. The central role of CoA and acetyl-CoA in intermediary metabolism suggests that pantothenate kinase activators may be useful in modifying neurological metabolic disorders.

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Section: Resultssupporting

confidence: 87%

Pantothenate Kinase Activation Restores Brain Coenzyme A in a Mouse Model of Pantothenate Kinase-Associated Neurodegeneration

Subramanian,

Frank,

Sukhun

et al. 2023

J Pharmacol Exp Ther

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“…Hypotaurine can also be generated by CoA turnover and ADO, which mediates cysteamine metabolism to hypotaurine, was also increased (Figure 7D). Unfortunately, we did not detect pathway specific metabolites that can distinguish the CSAD vs ADO pathways, but CoA turnover is known to be very slow (Orsatti et al, 2021), suggesting label may be coming via the CDO1 pathway. Despite a reduction in CDO1, cysteine levels were significantly higher in HCC (Figure 7B), which may mediate increased entry of cysteine into the CDO1 pathway regardless of CDO1 expression level.…”

Section: Resultsmentioning

confidence: 82%

The Origin of Cysteine and its Catabolism in Mammalian Tissues and Tumors

Yoon

Combs

Falzone

et al. 2022

Preprint

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Cysteine plays critical roles in cellular biosynthesis, enzyme catalysis, and is an essential contributor to redox metabolism. While cultured cells are highly dependent on exogenous cystine for proliferation and survival, how diverse tissues obtain and use cysteine in vivo has not been characterized. We comprehensively interrogated cysteine metabolism in normal murine tissues and the cancer that arise from them using stable isotope 13C-serine and 13C-cystine tracing. We found that de novo cysteine synthesis was highest in normal liver and pancreas and absent in lung tissue. In tumors, cysteine synthesis was either inactive or downregulated during tumorigenesis. By contrast, cystine uptake and metabolism to downstream metabolites was a universal feature of normal tissues and tumors. Differences in cysteine catabolism were evident across tumor types, including glutathione synthesis. Thus, cystine is a major contributor to the cysteine pool in tumors and cysteine catabolic pathways are differentially active across tumor types.

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“…Perhaps mitochondrial COASY activity is needed for PANK2dependent CoA synthesis necessary for carrier protein activation and essential for normal GP function. In contrast, cytosolic COASY activity may be needed to replenish recycled CoA from a much smaller pool given the low turnover rate for CoA [56]. Cytosolic COASY activity may be essential for normal function of cells in all brain regions.…”

Section: Other Genetic Diseases Linked To Coa Biosynthesis Enzymesmentioning

confidence: 99%