Pantothenate kinase activation relieves coenzyme A sequestration and improves mitochondrial function in mice with propionic acidemia

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

doi:10.1126/scitranslmed.abf5965

Cited by 20 publications

(63 citation statements)

References 100 publications

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“…These results support a model whereby the hypermorphic PANK3 G193A mutation drives the accumulation of supraphysiological acetyl-CoA concentrations that effectively compete with the drug at the HAT active site. To validate this orthogonally, we used a smallmolecule PANK agonist, PZ-3022, that increases cellular levels of acetyl-CoA 44 . As expected, treatment with this compound reduced sensitivity to CBP/p300 HAT inhibitors but did not affect sensitivity to CBP/p300 bromodomain inhibitors (Fig.…”

Section: Resultsmentioning

confidence: 99%

Metabolic adaptations underpin resistance to histone acetyltransferase inhibition

Bishop

Subramanian

Bilotta

et al. 2022

Preprint

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Histone acetyltransferases (HAT) catalyze the acylation of lysine side chains and are implicated in diverse human cancers as both oncogenes and non-oncogene dependencies1. Acetyl-CoA-competitive HAT inhibitors have garnered attention as potential cancer therapeutics and the first clinical trial for this class is ongoing (NCT04606446). Despite broad enthusiasm for these targets, notably including CBP/p300 and KAT6A/B2-5, the potential mechanisms of therapeutic response and evolved drug resistance remain poorly understood. Using comparative transcriptional genomics, we found that the direct gene regulatory consequences of CBP/p300 HAT inhibition are indistinguishable in models of intrinsically hypersensitive and insensitive acute myeloid leukemia (AML). We therefore modelled acquired drug resistance using a forward genetic selection and identified dysregulation of coenzyme A (CoA) metabolism as a facile driver of resistance to HAT inhibitors. Specifically, drug resistance selected for mutations in PANK3, a pantothenate kinase that controls the rate limiting step in CoA biosynthesis6. These mutations prevent negative feedback inhibition, resulting in drastically elevated concentrations of intracellular acetyl-CoA, which directly outcompetes drug-target engagement. This not only impacts the activity of structurally diverse CBP/p300 HAT inhibitors, but also agents related to an investigational KAT6A/B inhibitor that is currently in Phase-1 clinical trials. We further validated these results using a genome-scale CRISPR/Cas9 loss-of-function genetic modifier screen, which identified additional gene-drug interactions between HAT inhibitors and the CoA biosynthetic pathway. Top hits from the screen included the phosphatase, PANK4, which negatively regulates CoA production and therefore suppresses sensitivity to HAT inhibition upon knockout7, as well as the pantothenate transporter, SLC5A68, which enhances sensitivity. Altogether, this work uncovers CoA plasticity as an unexpected but potentially class-wide liability of anti-cancer HAT inhibitors and will therefore buoy future efforts to optimize the efficacy of this new form of targeted therapy.

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Section: Resultsmentioning

confidence: 99%

Metabolic adaptations underpin resistance to histone acetyltransferase inhibition

Bishop

Subramanian

Bilotta

et al. 2022

Preprint

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“…BBP-671 treatment activates the PANK3 isoform to increase CoA production that, in turn, has a direct role on TCA cycle metabolism (Fig. 1) [5] and hence Glx production. In contrast to our findings, a study performed on 3 human PKAN patients reported an increase of Glx in the white matter [25].…”

Section: Discussionmentioning

confidence: 99%

“…Figure 1a depicts the effects of loss of CoA synthesis due to disruption of murine Pank1 and Pank2 genes in neurons. Pyruvate produced from glycolysis requires CoA to form acetyl-CoA, a substrate for the mitochondrial TCA cycle, and CoA limitation can disrupt TCA cycling [5] which, in turn, affects glutamate metabolism thereby causing cell death [6,7] (Fig. 1a).…”

Section: Open Accessmentioning

confidence: 99%

Proton magnetic resonance spectroscopy detects cerebral metabolic derangement in a mouse model of brain coenzyme a deficiency

Li¹,

Steinberg²,

Coleman³

et al. 2022

J Transl Med

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Background Pantothenate kinase (PANK) is the first and rate-controlling enzymatic step in the only pathway for cellular coenzyme A (CoA) biosynthesis. PANK-associated neurodegeneration (PKAN), formerly known as Hallervorden–Spatz disease, is a rare, life-threatening neurologic disorder that affects the CNS and arises from mutations in the human PANK2 gene. Pantazines, a class of small molecules containing the pantazine moiety, yield promising therapeutic effects in an animal model of brain CoA deficiency. A reliable technique to identify the neurometabolic effects of PANK dysfunction and to monitor therapeutic responses is needed. Methods We applied 1H magnetic resonance spectroscopy as a noninvasive technique to evaluate the therapeutic effects of the newly developed Pantazine BBP-671. Results 1H MRS reliably quantified changes in cerebral metabolites, including glutamate/glutamine, lactate, and N-acetyl aspartate in a neuronal Pank1 and Pank2 double-knockout (SynCre+Pank1,2 dKO) mouse model of brain CoA deficiency. The neuronal SynCre+Pank1,2 dKO mice had distinct decreases in Glx/tCr, NAA/tCr, and lactate/tCr ratios compared to the wildtype matched control mice that increased in response to BBP-671 treatment. Conclusions BBP-671 treatment completely restored glutamate/glutamine levels in the brains of the mouse model, suggesting that these metabolites are promising clinically translatable biomarkers for future therapeutic trials.

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“…A recent analysis of a hypomorphic mouse model of PA suggests that reduced cellular CoASH triggers mitochondrial dysfunction and represents an underlying metabolic crisis in PA 7 . CoASH functions as a cofactor in numerous reactions in intermediary metabolism and is a critical substrate for two key steps in mitochondrial energy metabolism: pyruvate and α‐ketoglutarate dehydrogenases.…”

Section: Introductionmentioning

confidence: 99%

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

Subramanian

Frank

Tangallapally

et al. 2022

J of Inher Metab Disea

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Propionic acidemia (PA, OMIM 606054) is a devastating inborn error of metabolism arising from mutations that reduce the activity of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). The defects in PCC reduce the concentrations of nonesterified coenzyme A (CoASH), thus compromising mitochondrial function and disrupting intermediary metabolism. Here, we use a hypomorphic PA mouse model to test the effectiveness of BBP-671 in correcting the metabolic imbalances in PA. BBP-671 is a high-affinity allosteric pantothenate kinase activator that counteracts feedback inhibition of the enzyme to increase the intracellular concentration of CoA. Liver CoASH and acetyl-CoA are depressed in PA mice and BBP-671 treatment normalizes the cellular concentrations of these two key cofactors. Hepatic propionyl-CoA is also reduced by BBP-671 leading to an improved intracellular C3:C2-CoA ratio. Elevated plasma C3:C2-carnitine ratio and methylcitrate, hallmark biomarkers of PA, are significantly reduced by BBP-671. The large elevations of malate and α-ketoglutarate in the urine of PA mice are biomarkers for compromised tricarboxylic acid cycle activity and BBP-671 therapy reduces the amounts of both metabolites. Furthermore, the low survival of PA mice is restored to normal by BBP-671. These data show that BBP-671 relieves CoA sequestration, improves mitochondrial function, reduces plasma PA biomarkers, and extends the lifespan of PA mice, providing the preclinical foundation for the therapeutic potential of BBP-671.

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Pantothenate kinase activation relieves coenzyme A sequestration and improves mitochondrial function in mice with propionic acidemia

Abstract: Therapeutic relief of CoA sequestration improves mitochondrial dysfunction in a propionic acidemia mouse model.

Cited by 20 publications

References 100 publications

Metabolic adaptations underpin resistance to histone acetyltransferase inhibition

Metabolic adaptations underpin resistance to histone acetyltransferase inhibition

Proton magnetic resonance spectroscopy detects cerebral metabolic derangement in a mouse model of brain coenzyme a deficiency

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

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