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Nonketotic hyperglycinemia
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
The glycine cleavage system (see Figure 23.1) is a mitochondrial complex with four individual protein components [4, 26, 45]. The P-protein is a pyridoxal phosphate-dependent glycine decarboxylase. The P- and H-proteins, lipoic acid-containing proteins, are required for the formation of CO2 from glycine. All four are required for the conversion of glycine to CO2, NH3 and a one-carbon tetrahydrofolate (FH4) derivative, which can then function in one carbon transfer, as in the formation of serine from glycine. The T-protein contains FH4 and the L-protein is a lipoamide dehydrogenase.
Pharmacotherapy of Neurochemical Imbalances
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Rupali Patil, Aman Upaganlawar, Suvarna Ingale
Glycine is inactivated from the synaptic cleft by reuptake transporters located on the plasma membranes of glial cells and of presynaptic nerve terminals. The degradation of glycine occurs mainly by means of the glycine cleavage system (GCS) in the inner mitochondrial membrane (Rang et al., 2011; Nestler et al., 2009; Smith, 2002; Barrett et al., 2009).
Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
Enzyme activity can be measured on liver biopsy; however, the interpretation of results can be challenging. Glycine is degradated by the glycine cleavage system that is encoded by three different large genes (P, T and H protein). Hence mutation analysis can be laborious.
Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects
Published in Drug Metabolism Reviews, 2020
Ana Rita Silva, Ricardo Jorge Dinis-Oliveira
DXM has been proposed for the treatment of nonketotic hyperglycinemia. Nonketotic hyperglycinemia is a genetic defect of glycine metabolism, in which deficiency of glycine cleavage system leads to increased levels of glycine in all tissues, including the brain (Bjoraker et al. 2016). Among other effects, and because glycine is an allosteric co-activator of the NMDA receptor, the high levels of glycine over-stimulate these NMDA receptors, causing an excitotoxic response (Bjoraker et al. 2016; McQueen 2017). Progressive neurodegeneration and recurrent uncontrollable seizures are usually present in this syndrome (McQueen 2017). DXO has a higher affinity for the noncompetitive binding domain of the NMDA receptor (Franklin and Murray 1992), and electrophysiological data show that DXO is a more potent NMDA receptor antagonist than DXM both in vitro and in vivo (Church et al. 1985, 1989; Ishmael et al. 1998; Pechnick and Poland 2004). DXM as a weak inhibitor of NMDA receptors, blocks the effect of excess glycine, and can decrease the associated seizures, combined with benzoate to reduce the glycine levels (Bjoraker et al. 2016).
Nonketotic Hyperglycinemia: Two Case Reports and Review
Published in The Neurodiagnostic Journal, 2019
Rajesh P. Poothrikovil, Khalid Al Thihli, Amna Al Futaisi, Fathiya Al Murshidi
Nonketotic hyperglycinemia (NKH) or glycine encephalopathy is an autosomal recessive disorder of glycine metabolism resulting in an excessive accumulation of glycine in all body tissues, including the central nervous system. The primary biochemical defect in glycine encephalopathy is in the glycine cleavage system, which consists of a mitochondrial enzyme complex. It is considered a rare disorder with an estimated prevalence of 1:60,000 (Applegarth et al. 2000; Hamosh and Johnston 2001). Four forms of glycine encephalopathy have been identified: neonatal, infantile, transient and late (Rezvani 2004). The neonatal form presents in the first few days of life with progressive encephalopathy, hypotonia, myoclonic jerks, hiccups, and seizures. Death due to central apnea occurs early in the disease course. Surviving infants often have severe developmental delay and refractory seizures.
A comprehensive proteomics analysis of the response of Pseudomonas aeruginosa to nanoceria cytotoxicity
Published in Nanotoxicology, 2023
Lidija Izrael Živković, Nico Hüttmann, Vanessa Susevski, Ana Medić, Vladimir Beškoski, Maxim V. Berezovski, Zoran Minić, Ljiljana Živković, Ivanka Karadžić
The presence of NC caused significant changes in amino acid metabolism, in particular in their anabolism. Biosynthesis of the glucogenic amino acids was intensified, according to the upregulation of their biosynthesis enzymes. Furthermore, the biosynthesis of aromatic amino acids and isoleucine, both considered as glucogenic and ketogenic, was enhanced (Table 1). In particular, proteins involved in the synthesis of the ketogenic amino acid lysine were significantly upregulated. Enzymes involved in lysine degradation were also upregulated, along with glutarate-semialdehyde dehydrogenase that catalyzes the conversion of glutarate-semialdehyde to glutarate and NADPH, where the latter protects cells from redox stress. Upregulation of enzymes involved in arginine and histidine degradation was also noticed. Arginine deiminase, which regulates L-arginine degradation, is involved in the first step of the sub-pathway (ADI) that synthesizes carbamoyl phosphate from L-arginine and can serve as a non-redox, ATP producing process that can be induced under various stress conditions (White 2000; Eschbach 2004). Histidine ammonia-lyase catalyzes the synthesis of N-formimidoyl-L-glutamate from L-histidine, as a part of the pathway degrading L-histidine into L-glutamate, which after transformation, can replenish the TCA cycle through α-ketoglutarate. In addition, upregulation of glycine dehydrogenase, as a part the glycine cleavage system that is highly sensitive to alterations in the oxidation–reduction state of the respiratory chain, was observed. Upregulated aromatic-amino-acid aminotransferase is related to chorismate, which is a branch-point metabolite used for the synthesis of aromatic amino acids and phenazine metabolites such as pyocyanin.