Valine metabolites analysis in ECHS1 deficiency

Kuwajima, Mari; Kojima, Karin; Osaka, Hitoshi; Hamada, Yusuke; Jimbo, Eriko F.; Watanabe, Miyuki; Aoki, Shigenobu; Sato-Shirai, Ikuko; Ichimoto, Keiko; Fushimi, Takuya; Murayama, Kei; Ohtake, Akira; Kohda, Masakazu; Kishita, Yoshihito; Yatsuka, Yukiko; Uchino, Shumpei; Mimaki, Masakazu; Miyake, Noriko; Matsumoto, Naomichi; Okazaki, Yasushi; Ogata, Tomomi; Yamagata, Takanori; Muramatsu, Kazuhiro

doi:10.1016/j.ymgmr.2021.100809

Cited by 12 publications

(21 citation statements)

References 18 publications

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“…Targeted analysis was unsuccessful in confirming the identity of acrylyl-CoA due its high reactivity. Alternatively, the presence of acrylyl-CoA was confirmed following the detection of S-(2-carboxyethyl) cysteine (SCEC), a conjugate formed following the spontaneous reaction between acrylyl-CoA and the sulfhydryl group of cysteine (52). Hepatic SCEC levels increased 15.6-fold following oral gavage of male mice with 30 μg/kg TCDD every 4 days for 28 days ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Hepatic SCEC levels increased 15.6-fold following oral gavage of male mice with 30 μg/kg TCDD every 4 days for 28 days ( Table 1 ). Urine cysteine/cysteamine conjugates with acrylyl-CoA are routinely used to diagnose Leigh syndrome where the conversion of acrylyl-CoA to 3-hydroxypropionyl-CoA is inhibited due to a deficiency in the short chain enoyl-CoA hydratase (ECHS1) activity (52). The increased levels of SCEC not only confirmed acrylyl-CoA accumulation but also ECHS1 inhibition, and that propionyl-CoA was metabolized via the alternate Cbl-independent β–oxidation-like pathway as opposed to the preferred Cbl-dependent carboxylation pathway (53).…”

Section: Resultsmentioning

confidence: 99%

“…In this study, metabolomics and gene expression datasets were integrated to examine the increase in the levels of SCEC, an acrylyl-CoA conjugate detected in hepatic extracts from mice orally gavaged with TCDD every 4 days for 28 days. Acrylyl-CoA is a highly reactive intermediate that spontaneously reacts with free sulfhydryl groups, including the sulfhydryl group of cysteine to form the SCEC conjugate, an indicator of acrylyl-CoA, a metabolite normally not detected in healthy individuals at appreciable levels (52, 68). Acrylyl-CoA and 3-HP are intermediates in the catabolism of propionyl-CoA to acetyl-CoA and pyruvate via the Cbl-independent β–oxidation-like pathway, and used as biomarkers of inborn metabolic disorders associated with propionic- and methylmalonic acidemia (69) (70).…”

Section: Discussionmentioning

confidence: 99%

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Dioxin-elicited decrease in cobalamin redirects hepatic propionyl-CoA metabolism to the β–oxidation-like pathway resulting in acrylyl-CoA conjugate accumulation

Orlowska

Fling

Nault

et al. 2021

Preprint

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2,3,7,8 –Tetrachlorodibenzo –p –dioxin (TCDD) is a persistent environmental contaminant and the prototypical ligand for the aryl hydrocarbon receptor (AhR). AhR mediates the effects of TCDD and related compounds, including the reprograming of intermediate metabolism. Untargeted metabolomics analysis of hepatic extracts prepared from mice orally gavaged with TCDD every 4 days for 28 days identified the dose –dependent induction of acrylyl –CoA, a highly reactive toxic intermediate produced during the metabolism of propionyl –CoA in the cobalamin (Cbl) –independent β –oxidation –like pathway. Acrylyl –CoA is a biomarker of inborn errors of metabolism associated with propionic and methylmalonic acidemia associated with Cbl deficiency, transport and/or defects in Cbl –dependent methylmalonyl –CoA mutase (MUT). Although TCDD repressed gene expression for both the canonical Cbl –dependent carboxylase and the alternate Cbl –independent β –oxidation –like pathways, inhibition occurred only at 30 μg/kg TCDD while acrylyl –CoA levels increased at ~3 μg/kg. In contrast, TCDD decreased serum Cbl and hepatic cobalt levels at ~3 μg/kg TCDD consistent with the dose –dependent increase in acrylyl –CoA levels. TCDD elicited negligible effects on the expression of genes associated with Cbl absorption, transport, trafficking and derivatization to 5 –deoxy –adenosylcobalamin (AdoCbl), the required MUT cofactor. In addition, TCDD induced the decarboxylation of cis –aconitate to itaconate by Acod1. Itaconate can then be activated to itaconyl –CoA, a MUT suicide inactivator that forms an adduct with AdoCbl, blocking MUT activity and reducing Cbl levels. Collectively, these results suggest MUT activity was impaired due to Cbl depletion by TCDD causing propionyl –CoA metabolism to be redirected to the alternate Cbl –independent β –oxidation –like pathway resulting in hepatic acrylyl –CoA accumulation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Dioxin-elicited decrease in cobalamin redirects hepatic propionyl-CoA metabolism to the β–oxidation-like pathway resulting in acrylyl-CoA conjugate accumulation

Orlowska

Fling

Nault

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…At the time, no isoleucine supplementation was necessary, as isoleucine and leucine levels were within the normal range, showing results similar to those described by Abdenur et al [ 3 ]. Recently, Kuwajima et al reported that protein restriction therapy may alleviate the symptoms of ECHS1 deficiency [ 37 ]. A low-protein diet may prevent disease progression, while a valine-restricted diet may lead to a clinical and neuroradiological improvement in ECHS1 deficiency [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Pathogenic Biallelic Mutations in ECHS1 in a Case with Short-Chain Enoyl-CoA Hydratase (SCEH) Deficiency-Case Report and Literature Review

Muntean

Tripon

Bogliș

et al. 2022

IJERPH

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ECHS1 gene mutations are known to cause mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, a neurodegenerative disorder characterized by psychomotor development delay, lactic acidosis, and basal ganglia lesions resembling Leigh syndrome. Short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency is a very rare and new disorder, with a wide phenotypic spectrum and different outcomes ranging from neonatal death to survival into adulthood. Since the identification of ECHS1 deficiency in 2014, almost 63 patients with pathogenic mutations in the ECHS1 gene have been described to date. This paper focuses on the clinical and molecular findings as well as the evolution of a Caucasian girl diagnosed with ECHS1 deficiency who carries a new compound heterozygous mutation in the ECHS1 gene. Polymorphic symptoms, namely failure to thrive, significant global developmental delay/regression, movement disorders, ocular abnormalities, hearing loss, seizure, and cardiac myopathy, may be a challenge in mitochondrial disorder suspicion. Early diagnosis, an appropriate diet with valine restriction, and trigger avoidance are essential, as there is no effective therapy for the disease. This disorder influences life quality in these patients and their caregivers, and it has the potential to be fatal.

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“…Ectonucleotide pyrophosphatase/phosphodiesterase3 (ENPP3), as a regulator of N-acetylglucosaminyltransferase GnT-IX (GnT-Vb), would have widespread and significant impacts on glycosyltransferase activities [26]. Short-chain enoyl-CoA hydratase (ECHS1) is involved in amino and fatty acid catabolism in mitochondria and its deficiency results in Leigh syndrome or exercise-induced dystonia [27]. Niemann-Pick C1-Like 1 (NPC1L1) was widely verified to be a cholesterol import protein and mediated intestinal cholesterol absorption [28].…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Selective Analysis of Boer Goat to Investigate the Dynamic Heredity Evolution under Different Stages

Yuan

Zhang

Liu

et al. 2022

Animals

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Boer goats, as kemp in meat-type goats, are selected and bred from African indigenous goats under a long period of artificial selection. Their advantages in multiple economic traits, particularly their plump growth, have attracted worldwide attention. The current study displayed the genome-wide selection signature analyses of South African indigenous goat (AF), African Boer (BH), and Australian Boer (AS) to investigate the hereditary basis of artificial selection in different stages. Four methods (principal component analysis, nucleotide diversity, linkage disequilibrium decay, and neighbor-joining tree) implied the genomic diversity changes with different artificial selection intensities in Boer goats. In addition, the θπ, FST, and XP-CLR methods were used to search for the candidate signatures of positive selection in Boer goats. Consequently, 339 (BH vs. AF) and 295 (AS vs. BH) candidate genes were obtained from SNP data. Especially, 10 genes (e.g., BMPR1B, DNER, ITGAL, and KIT) under selection in both groups were identified. Functional annotation analysis revealed that these genes are potentially responsible for reproduction, metabolism, growth, and development. This study used genome-wide sequencing data to identify inheritance by artificial selection. The results of the current study are valuable for future molecular-assisted breeding and genetic improvement of goats.

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Valine metabolites analysis in ECHS1 deficiency

Cited by 12 publications

References 18 publications

Dioxin-elicited decrease in cobalamin redirects hepatic propionyl-CoA metabolism to the β–oxidation-like pathway resulting in acrylyl-CoA conjugate accumulation

Dioxin-elicited decrease in cobalamin redirects hepatic propionyl-CoA metabolism to the β–oxidation-like pathway resulting in acrylyl-CoA conjugate accumulation

Pathogenic Biallelic Mutations in ECHS1 in a Case with Short-Chain Enoyl-CoA Hydratase (SCEH) Deficiency-Case Report and Literature Review

Genome-Wide Selective Analysis of Boer Goat to Investigate the Dynamic Heredity Evolution under Different Stages

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