Mitochondrial targeting signals and mature peptides of 3-methylcrotonyl-CoA carboxylase

Stadler, Sonja; Polanetz, Roman; Meier, Stephan; Mayerhofer, Peter; Herrmann, Johannes M.; Anslinger, Katja; Roscher, Adelbert A.; Röschinger, Wulf; Holzinger, Andreas

doi:10.1016/j.bbrc.2005.06.190

Cited by 9 publications

(4 citation statements)

References 24 publications

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“…1B). MCC is located in the mitochondrial matrix in eukaryotes, and mutations in the N-terminal mitochondrial targeting sequence of both subunits can affect their localization [215]. Human MCC has been expressed and purified from the baculovirus system in the active form [216].…”

Section: -Methylcrotonyl-coa Carboxylase (Mcc)mentioning

confidence: 99%

Structure and function of biotin-dependent carboxylases

Tong

2012

Cell. Mol. Life Sci.

373

338

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Biotin-dependent carboxylases include acetyl-CoA carboxylase (ACC), propionyl-CoA carboxylase (PCC), 3-methylcrotonyl-CoA carboxylase (MCC), geranyl-CoA carboxylase (GCC), pyruvate carboxylase (PC), and urea carboxylase (UC). They contain biotin carboxylase (BC), carboxyltransferase (CT) and biotin-carboxyl carrier protein (BCCP) components. These enzymes are widely distributed in nature and have important functions in fatty acid metabolism, amino acid metabolism, carbohydrate metabolism, polyketide biosynthesis, urea utilization, and other cellular processes. ACCs are also attractive targets for drug discovery against type 2 diabetes, obesity, cancer, microbial infections, and other diseases, and the plastid ACC of grasses is the target of action of three classes of commercial herbicides. Deficiencies in the activities of PCC, MCC or PC are linked to serious diseases in humans. Our understanding of these enzymes has been greatly enhanced over the past few years by the crystal structures of the holoenzymes of PCC, MCC, PC, and UC. The structures reveal unanticipated features in the architectures of the holoenzymes, including the presence of previously unrecognized domains, and provide a molecular basis for understanding their catalytic mechanism as well as the large collection of disease-causing mutations in PCC, MCC and PC. This review will summarize the recent advances in our knowledge on the structure and function of these important metabolic enzymes.

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Section: -Methylcrotonyl-coa Carboxylase (Mcc)mentioning

confidence: 99%

Structure and function of biotin-dependent carboxylases

Tong

2012

Cell. Mol. Life Sci.

373

338

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“…Both subunits possess amino terminal cleavable targeting signals, which direct them to the mitochondrial matrix in a membrane potential-dependent manner. The MCCa signal peptide is cleaved between amino acid residue 41 and 42, while the processed mature MCCb peptide starts with amino acid residue 22 [Stadler et al, 2005]. To date, 18 different mutant alleles have been identified in MCCA and 29 in MCCB without evidence for a prevalent mutation [Baumgartner et al, 2001;Gallardo et al, 2001;Holzinger et al, 2001;Baykal et al, 2005;Dantas et al, 2005].…”

Section: Introductionmentioning

confidence: 98%

Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity ofMCCA andMCCB mutations and impact on risk assessment

et al. 2006

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New technology enables expansion of newborn screening (NBS) of inborn errors aimed to prevent adverse outcome. In conditions with a large share of asymptomatic phenotypes, the potential harm created by NBS must carefully be weighed against benefit. Policies vary throughout the United States, Australia, and Europe due to limited data on outcome and treatability of candidate screening conditions. We elaborated the rationale for decision making in 3-methylcrotonyl-coenzyme A (CoA) carboxylase deficiency (MCCD), which afflicts leucine catabolism, with reported outcomes ranging from asymptomatic to death. In Bavaria, we screened 677,852 neonates for 25 conditions, including MCCD, based on elevated concentrations of 3-hydroxyisovalerylcarnitine (3-HIVA-C). Genotypes of MCCA (MCCC1) and MCCB (MCCC2) were assessed in identified newborns, their relatives, and in individuals (n = 17) from other regions, and correlated to biochemical and clinical phenotypes. NBS revealed eight newborns and six relatives with MCCD, suggesting a higher frequency than previously assumed (1:84,700). We found a strikingly heterogeneous spectrum of 22 novel and eight reported mutations. Allelic variants were neither related to biochemical nor anamnestic data of our probands showing all asymptomatic or benign phenotypes. Comparative analysis of case reports with NBS data implied that only few individuals (< 10%) develop symptoms. In addition, none of the symptoms reported so far can clearly be attributed to MCCD. MCCD is a genetic condition with low clinical expressivity and penetrance. It largely represents as nondisease. So far, there are no genetic or biochemical markers that would identify the few individuals potentially at risk for harmful clinical expression. The low ratio of benefit to harm was pivotal to the decision to exclude MCCD from NBS in Germany. MCCD may be regarded as exemplary of the ongoing controversy arising from the inclusion of potentially asymptomatic conditions, which generates a psychological burden for afflicted families and a financial burden for health care systems.

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“…The most significant trans -eQTL in the UE cohort was UKUL2765 and expression of the methylcrotonoyl-CoA carboxylase 2 gene ( MCCC2 ) ( Table 4 ). MCCC2 encodes a subunit of 3-methylcrotonyl-CoA carboxylase (MCC), an enzyme which catabolises leucine (Stadler et al, 2005). Mutations within MCCC2 have been found to result in MCC deficiency, which has varying implications for patients from no symptoms at all to death in early infancy (Fonseca et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Expression Quantitative Trait Loci in Equine Skeletal Muscle Reveals Heritable Variation in Metabolism and the Training Responsive Transcriptome

et al. 2019

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While over ten thousand genetic loci have been associated with phenotypic traits and inherited diseases in genome-wide association studies, in most cases only a relatively small proportion of the trait heritability is explained and biological mechanisms underpinning these traits have not been clearly identified. Expression quantitative trait loci (eQTL) are subsets of genomic loci shown experimentally to influence gene expression. Since gene expression is one of the primary determinants of phenotype, the identification of eQTL may reveal biologically relevant loci and provide functional links between genomic variants, gene expression and ultimately phenotype. Skeletal muscle (gluteus medius) gene expression was quantified by RNA-seq for 111 Thoroughbreds (47 male, 64 female) in race training at a single training establishment sampled at two time-points: at rest (n = 92) and four hours after high-intensity exercise (n = 77); n = 60 were sampled at both time points. Genotypes were generated from the Illumina Equine SNP70 BeadChip. Applying a False Discovery Rate (FDR) corrected P-value threshold (P FDR < 0.05), association tests identified 3,583 cis-eQTL associated with expression of 1,456 genes at rest; 4,992 cis-eQTL associated with the expression of 1,922 genes post-exercise; 1,703 trans-eQTL associated with 563 genes at rest; and 1,219 trans-eQTL associated with 425 genes post-exercise. The gene with the highest cis-eQTL association at both time-points was the endosome-associated-trafficking regulator 1 gene (ENTR1; Rest: P FDR = 3.81 × 10-27, Post-exercise: P FDR = 1.66 × 10-24), which has a potential role in the transcriptional regulation of the solute carrier family 2 member 1 glucose transporter protein (SLC2A1). Functional analysis of genes with significant eQTL revealed significant enrichment for cofactor metabolic processes. These results suggest heritable variation in genomic elements such as regulatory sequences (e.g. gene promoters, enhancers, silencers), microRNA and transcription factor genes, which are associated with metabolic function and may have roles in determining end-point muscle and athletic performance phenotypes in Thoroughbred horses. The incorporation of the eQTL identified with genome and transcriptome-wide association may reveal useful biological links between genetic variants and their impact on traits of interest, such as elite racing performance and adaptation to training.

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Mitochondrial targeting signals and mature peptides of 3-methylcrotonyl-CoA carboxylase

Cited by 9 publications

References 24 publications

Structure and function of biotin-dependent carboxylases

Structure and function of biotin-dependent carboxylases

Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity ofMCCA andMCCB mutations and impact on risk assessment

Expression Quantitative Trait Loci in Equine Skeletal Muscle Reveals Heritable Variation in Metabolism and the Training Responsive Transcriptome

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