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Maple syrup urine disease (branched-chain oxoaciduria)
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
In the reaction, as in the case of pyruvate or α-ketoglutarate, there is first a thiamine pyrophosphate (TPP)-mediated conversion of the carboxyl group to CO2 and the formation of a covalently bound enzyme, TPP, substrate complex (Figure 19.2). Next, there is an oxidative transfer to the second, lipoic acid-bearing enzyme, liberating TPP after which there is transfer to coenzyme A, and lipoic acid is regenerated. Regulation of enzyme involves acylCoA compounds, and activity is stimulated by carnitine [58], presumably by the formation of acylcarnitine esters of acylCoA compounds and prevention of product inhibition. The enzyme is inhibited by adenosinediphosphate (ADP), a condition under which pyruvate decarboxylation is stimulated. Additional regulation has been demonstrated in a phosphorylation/dephosphorylation cycle in which the dehydrogenase complex is inactivated by the kinase BCKDK catalyzed phosphorylation and activated through action of the phosphatase. Recently, mutations in BCKDK were identified in patients with very low branched-chain amino acids and clinical symptoms of autism, epilepsy, and intellectual disability that may respond to dietary treatment [59].
Effects of PPM1K rs1440581 and rs7678928 on serum branched-chain amino acid levels and risk of cardiovascular disease
Published in Annals of Medicine, 2021
Wen Hu, Ziyu Liu, Weinan Yu, Surong Wen, Xiaoqing Wang, Xing Qi, Hairong Hao, Yanwen Lu, Jing Li, Shayan Li, Hongwen Zhou
Branched chain α-ketoacid dehydrogenase complex (BCKDC) is the key enzyme that catalyses the first irreversible step in the BCAA metabolism, and the phosphorylation of branched chain α-ketoacid dehydrogenase kinase (BCKDK) can inhibit the activity of BCKDC. Conversely, BCKDC is activated by the mitochondrial isoform of PP2C domain-containing protein phosphatase 1K (PPM1K, also known as PP2CM) [5]. A genome-wide association study (GWAS) in Caucasians found that a marker (rs1440581) at 4q22 of PPM1K was associated with both Fischer’s ratio (ratio of BCAA levels to the concentrations of phenylalanine (Phe) plus tyrosine (Tyr)) and Val [6]. In addition, Mendelian randomization analysis in 16,596 Caucasians showed that the PPM1K rs1440581 and rs7678928 single nucleotide polymorphisms (SNPs) were associated with serum Leu and Val levels, and rs7678928 SNP was associated with serum Ile level. Both SNPs were found to reach the genome-wide level of significance [7]. However, no study has been conducted to investigate the correlations between PPM1K SNPs and serum BCAA levels in Chinese population. It is also unclear whether the rs1440581 and rs7678928 SNPs affect the CVD risk in the Chinese population.