Dataset reporting BCKDK interference in a BCAA-catabolism restricted environment

Bravo-Alonso, Irene; Oyarzábal, Alfonso; Sánchez‐Aragó, María; Rejas, María Teresa; Merinero, Begoña; García‐Cazorla, Àngels; Artuch, Rafael; Ugarte, Magdalena; Rodríguez‐Pombo, Pilar

doi:10.1016/j.dib.2016.03.038

Cited by 5 publications

(5 citation statements)

References 6 publications

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“…For the expression of PPCDC ‐interfering shRNA (PPCDC MISSION shRNA Bacterial Glycerol Stock—SHCLNG‐NM_021823: TRCN0000155649, TRCN0000152453, TRCN0000154478, TRCN0000155901, and TRCN0000155902; Sigma‐Aldrich), the plasmids were packaged in lentiviral particles for subsequent infection of the fibroblasts as previously described 20 …”

Section: Methodsmentioning

confidence: 99%

Pathogenic variants of the coenzyme A biosynthesis‐associated enzyme phosphopantothenoylcysteine decarboxylase cause autosomal‐recessive dilated cardiomyopathy

Bravo-Alonso

Morín

Arribas-Carreira

et al. 2023

J of Inher Metab Disea

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Coenzyme A (CoA) is an essential cofactor involved in a range of metabolic pathways including the activation of long-chain fatty acids for catabolism.Cells synthesize CoA de novo from vitamin B5 (pantothenate) via a pathway strongly conserved across prokaryotes and eukaryotes. In humans, it involves five enzymatic steps catalyzed by four enzymes: pantothenate kinase (PANK [isoforms 1-4]), 4 0 -phosphopantothenoylcysteine synthetase (PPCS), phosphopantothenoylcysteine decarboxylase (PPCDC), and CoA synthase (COASY). To date, inborn errors of metabolism associated with all of these genes, except PPCDC, have been described, two related to neurodegeneration with brain iron accumulation (NBIA), and one associated with a cardiac phenotype. This paper reports another defect in this pathway (detected in two sisters), associated with a fatal cardiac phenotype, caused by biallelic variants (p.Thr53Pro and p.Ala95Val) of PPCDC. PPCDC enzyme (EC 4.1.1.36) catalyzes the decarboxylation of 4 0 -phosphopantothenoylcysteine to 4 0 -phosphopantetheine in CoA biosynthesis. The variants p.Thr53Pro and p.Ala95Val affect residues highly conserved across different species; p.Thr53Pro is involved in the binding of flavin mononucleotide, and p.Ala95Val is likely a destabilizing mutation. Patient-derived fibroblasts showed an absence of PPCDC protein, and nearly 50% reductions in CoA levels. The cells showed clear energy deficiency problems, with defects in mitochondrial respiration, and mostly glycolytic ATP synthesis. Functional studies performed in yeast suggest these mutations to be

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Section: Methodsmentioning

confidence: 99%

Pathogenic variants of the coenzyme A biosynthesis‐associated enzyme phosphopantothenoylcysteine decarboxylase cause autosomal‐recessive dilated cardiomyopathy

Bravo-Alonso

Morín

Arribas-Carreira

et al. 2023

J of Inher Metab Disea

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“…The cellular oxygen consumption rate (OCR) was measured using an XF24 Extracellular Flux Analyzer (Seahorse Bioscience, Izasa Scientific) as previously described [26], except that 60,000 fibroblasts per well were seeded in XF 24-well cell culture microplates and 1 h before the assay the growth medium was replaced with 700 μL of un-buffered fresh MEM medium with 0.5% FBS. After taking an OCR baseline measurement, 50 μL of oligomycin, carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP), rotenone and antimycin A solutions were sequentially added to each well to reach final working concentrations 6 μM, 20 μM, 1 μM and 1 μM respectively.…”

Section: Methodsmentioning

confidence: 99%

Genes and Variants Underlying Human Congenital Lactic Acidosis—From Genetics to Personalized Treatment

Bravo-Alonso

Navarrete

Vega

et al. 2019

JCM

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Congenital lactic acidosis (CLA) is a rare condition in most instances due to a range of inborn errors of metabolism that result in defective mitochondrial function. Even though the implementation of next generation sequencing has been rapid, the diagnosis rate for this highly heterogeneous allelic condition remains low. The present work reports our group’s experience of using a clinical/biochemical analysis system in conjunction with genetic findings that facilitates the taking of timely clinical decisions with minimum need for invasive procedures. The system’s workflow combines different metabolomics datasets and phenotypic information with the results of clinical exome sequencing and/or RNA analysis. The system’s use detected genetic variants in 64% of a cohort of 39 CLA-patients; these variants, 14 of which were novel, were found in 19 different nuclear and two mitochondrial genes. For patients with variants of unknown significance, the genetic analysis was combined with functional genetic and/or bioenergetics analyses in an attempt to detect pathogenicity. Our results warranted subsequent testing of antisense therapy to rescue the abnormal splicing in cultures of fibroblasts from a patient with a defective GFM1 gene. The discussed system facilitates the diagnosis of CLA by avoiding the need to use invasive techniques and increase our knowledge of the causes of this condition.

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“…Dysfunction of BCKDK is closely related to various human diseases, especially maple syrup urine disease. McConnell et al found that excessive activity of BCKDK resulted in maple syrup urine disease [18][19][20]. People with diabetes have increased susceptibility to OC, and they are always initially diagnosed in the late stages and have a poor prognosis [21].…”

Section: Introductionmentioning

confidence: 99%

BCKDK Promotes Ovarian Cancer Proliferation and Migration by Activating the MEK/ERK Signaling Pathway

et al. 2022

Journal of Oncology

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Background. Ovarian cancer (OC) is the most fatal gynecologic cancer. The branched-chain α-keto acid dehydrogenase kinase (BCKDK) plays an important role in many serious human diseases, including cancers. Its function in promoting cell proliferation and migration has been reported in various cancers. However, the biological role of BCKDK and its molecular mechanisms underlying OC initiation and progression are unclear. Methods. First, the expression level of BCKDK in OC cell lines or tissues was determined using tissue microarray- (TMA-) based immunohistochemistry or western blotting. Then, growth curve analysis, anchorage-independent cell transformation assays, wound healing assays, cell migration assays, and tumor xenografts were used to test whether BCKDK could promote cell transformation or metastasis. Finally, the signaling pathways involved in this process were investigated by western blotting or immunoprecipitation. Results. We found that the expression of BCKDK was upregulated in OC tissues and the high expression of BCKDK was correlated with an advanced pathological grade in patients. The ectopic overexpression of BCKDK promoted the proliferation and migration of OC cells, and the knockdown of BCKDK with shRNAs inhibited the proliferation and migration of OC ex vivo and in vivo. Moreover, BCKDK promoted OC proliferation and migration by activating MEK. Conclusions. Our results demonstrate that BCKDK promotes OC proliferation and migration by activating the MEK/ERK signaling pathway. Targeting the BCKDK-MEK axis may provide a new therapeutic strategy for treating patients with OC.

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Dataset reporting BCKDK interference in a BCAA-catabolism restricted environment

Cited by 5 publications

References 6 publications

Pathogenic variants of the coenzyme A biosynthesis‐associated enzyme phosphopantothenoylcysteine decarboxylase cause autosomal‐recessive dilated cardiomyopathy

Pathogenic variants of the coenzyme A biosynthesis‐associated enzyme phosphopantothenoylcysteine decarboxylase cause autosomal‐recessive dilated cardiomyopathy

Genes and Variants Underlying Human Congenital Lactic Acidosis—From Genetics to Personalized Treatment

BCKDK Promotes Ovarian Cancer Proliferation and Migration by Activating the MEK/ERK Signaling Pathway

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