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Propionic acidemia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Propionic acidemia is inherited as an autosomal recessive trait. The enzymatic site of the defect is propionyl CoA carboxylase [36, 37]. Activity in extracts of leukocytes and fibroblasts is very low, usually less than 5 percent of control (Table 2.1). Studies with somatic cell hybrids have provided evidence of two complementation groups, PccA and PccBC, which correspond to abnormalities in the α and β subunits, respectively [38–43]. The BC group contains two subgroups, B and C, in which intragroup complementation is thought to be interallelic. Patients in the A subgroup have mutations in the A gene for the α chain, and those in the BC groups have mutations in the B gene for the β chain. Residual activity of propionyl CoA carboxylase correlates poorly with severity of disease or outcome [14].
Organic acid disorders and disorders of fatty acid oxidation
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
Propionic acidaemia is usually diagnosed on the basis of a clinical evaluation, routine laboratory tests and specialised tests to demonstrate the deicient activity of the propionyl CoA carboxylase enzyme. Prenatal diagnosis is possible by testing the amniotic fluid for abnormal enzyme activity or by analysing a portion of the placenta by chorionic villus sampling (CVS). In some instances this disorder can be diagnosed at birth through newborn screening programmes.
The Reaction Mechanism
Published in D. B. Keech, J. C. Wallace, Pyruvate Carboxylase, 2018
The first report suggesting that the first partial reaction proceeded via a concerted mechanism came from Kaziro et al.,436 who were investigating the carboxylation of propionyl-CoA by propionyl-CoA-carboxylase. In their experiments using18O-labeled bicarbonate, they found that the equivalent of one 18O atom was incorporated into orthophosphate for every two18O atoms incorporated into the carboxyl group of methyl-malonyl-CoA. This finding showed two points about the mechanism. First of all, it showed that bicarbonate rather than free CO2 was the reactant — if CO2 were the reactant only two atoms of 18O would be expected to be utilized. Secondly, it implied the direct participation of HCO3- in the phosphoryl bond cleavage during the activation process. Consequently, a concerted reaction between the enzyme-bound biotin, HCO3-, and the γ-phosphoryl group of ATP was proposed.
Inherited causes of exocrine pancreatic insufficiency in pediatric patients: clinical presentation and laboratory testing
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Tatiana N. Yuzyuk, Heather A. Nelson, Lisa M. Johnson
Pancreatic dysfunction is not commonly seen in inborn errors of metabolism. Nevertheless, in addition to Pearson syndrome, methylmalonic acidemia (MMA; isolated) and propionic acidemia (PA) are two other inborn errors of metabolism characterized by pancreatic complications. MMA and PA are autosomal recessive disorders of propionate catabolism caused by the impaired function of mitochondrial enzymes, methylmalonyl-CoA mutase or propionyl-CoA carboxylase, respectively [75,76]. The enzymatic defects lead to a metabolic block in the final steps of the catabolic pathways of valine, isoleucine, methionine, threonine, cholesterol, and odd-chain fatty acids, resulting in the accumulation of specific metabolites (propionylcarnitine, methylcitric and 3-hydroxypropionic acids; methylmalonic acid specific to MMA). Most patients are identified by NBS and present in the neonatal period with vomiting, dehydration, weight loss, temperature instability, neurological involvement, irritability, and lethargy progressing to coma and seizures if left untreated. Mild and late-onset cases are also well documented [77,78].
Sericin-mediated improvement of dysmorphic cardiac mitochondria from hypercholesterolaemia is associated with maintaining mitochondrial dynamics, energy production, and mitochondrial structure
Published in Pharmaceutical Biology, 2022
Kitiya Rujimongkon, Sumate Ampawong, Duangnate Isarangkul, Onrapak Reamtong, Pornanong Aramwit
Regarding mitochondrial metabolism, the function of the amino acid metabolism pathway revealed that sericin led to upregulated GOT2 levels in cardiac mitochondria. GOT2 catalyses the transamination of L-aspartate and 2-oxoglutarate to oxaloacetate and glutamate in cardiac mitochondria (Hoffmann & Solter 2008). An increased level of GOT2 is associated with oxidative stress, leading to cardiovascular mortality (Zoppini et al. 2016). Sericin-induced GOT2 expression may be related to heart dysfunction. In contrast, in liver mitochondria, reduced GOT2 has been observed after sericin treatment, which is related to decreased liver injury from hypercholesterolaemia (Ampawong et al. 2018). Therefore, amino acid metabolism may reflect different activities depending on the organ affected by hypercholesterolaemia. In contrast, this study revealed reduced PCCB, which functions in mitochondrial metabolism and is a subunit of propionyl-CoA carboxylase (PCC). PCC is an active enzyme in the mitochondrial matrix that catalyses the conversion of propionyl-CoA to d-methylmalonyl-CoA (Jiang et al. 2005). Dysfunction of PCC is related to metabolic disorders that cause morbidity and mortality (Wongkittichote et al. 2017). A pathogenic PCCB gene (mutation) is related to cardiomyopathy in clinical reports (Bernheim et al. 2017). The relationship between the PCCB expression level and cardiovascular defects remains unclear. Therefore, reduced PCCB after sericin treatment may result from mitochondrial compensation by the cell. From the information regarding mitochondrial metabolism proteins in relation to mitochondrial function, it cannot be concluded that this group of proteins is related to the improved effects of sericin on the mitochondrial structure.
The potential role of gut microbiota and its modulators in the management of propionic and methylmalonic acidemia
Published in Expert Opinion on Orphan Drugs, 2018
Alberto Burlina, Sebastian Tims, Francjan van Spronsen, Wolfgang Sperl, Alessandro P. Burlina, Mirjam Kuhn, Jan Knol, Maryam Rakhshandehroo, Turgay Coşkun, Rani H Singh, Anita MacDonald
Propionic and methylmalonic acidemia (PA/MMA) are rare inborn errors of metabolism characterized by accumulation of propionyl CoA and/or methylmalonyl CoA caused by a deficiency of propionyl-CoA carboxylase or methylmalonyl-CoA mutase, respectively [1]. Figure 1 shows the biochemical pathway associated with PA/MMA [2]. Defects in propionyl-CoA carboxylase or methylmalonyl-CoA mutase disrupt this pathway resulting in acidosis [3].