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Argininemia
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
Phenylbutyrate increases expression of some genes, and it has been reported [55] to increase the activity of arginase in mice and in cultured cells. It was not tested in cells of patients with argininemia, but might be useful in patients with residual activity. Another new therapeutic approach is to reduce guanidinoacetate similarly to the treatment in guanidinoacetate methyltransferase deficiency (Chapter 101). A 9-year-old boy with argininemia and elevated concentration of guanidinoacetate received creatine, L-ornithine, and sodium benzoate along with an arginine-restricted diet. This resulted in a reduction of guanidinoacetate and clinical improvement with reduced seizure frequency and improved alertness [45].
Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
These conditions present with intellectual disability and speech delay, autistic features and epilepsy. The conditions are variable and can cause mild or severe neurological disease. The more severe end of the clinical spectrum tends to present in the first few years of life. Severely affected patients may have microcephaly. Patients with guanidinoacetate methyltransferase (GAMT) deficiency in addition may have muscular hypotonia, weakness, progressive extrapyramidal signs and autistic and/or self-aggressive behaviour.
Creatine supplementation in sport, exercise and health
Published in Jay R Hoffman, Dietary Supplementation in Sport and Exercise, 2019
Eric S Rawson, Eimear Dolan, Bryan Saunders, Meghan E Williams, Bruno Gualano
Ultimately, the ability of creatine to contribute to high-intensity exercise performance is dependent on its concentration within the cell. Although dietary or supplementary intake of creatine is an important determinant of creatine content (as described later), it is not an essential nutrient and can be endogenously synthesized within the liver, kidneys and pancreas. This occurs in a two-step reaction. The first step in this reaction is catalyzed by the AGAT enzyme (L-arginine:glycine amidinotransferase), whereby an amine group is transferred from arginine to the amino group of glycine, forming guanidinoacetate and ornithine. The second reaction, catalyzed by the GAMT enzyme (guanidinoacetate methyltransferase), joins S-adenosylmethionine with guanidinoacetate methylate, forming creatine and S-adenosyl homocysteine (12). Following synthesis, creatine is transported to the muscle, where it is taken up against a concentration gradient by a specific sodium dependent transporter (Creat-T). Creatinine is the degradation product of creatine and phosphorylcreatine and is excreted via the kidneys at a rate of about 2 g per day (140), necessitating a similar intake to maintain equilibrium. The body has the capacity to synthesize approximately 1 g.day-1 with the rest coming from dietary intake.
CARD9 deficiency promotes pancreatic cancer growth by blocking dendritic cell maturation via SLC6A8-mediated creatine transport
Published in OncoImmunology, 2023
Cheng Tian, Huimin Yuan, Yi Lu, Henghui He, Qing Li, Senlin Li, Jian Yang, Mengheng Wang, Ruochen Xu, Qian Liu, Ming Xiang
Creatine, an organic acid containing nitrogen, is associated with the progression and metastasis of PC20. It is also implicated in the activation of CD8+ T cells and polarization of macrophages21,22. Creatine is mainly synthesized by glycine amidinotransferase (GATM) and N-guanidinoacetate methyltransferase (GAMT) in the liver and kidney. GATM acts on glycine and L-arginine to produce guanidinoacetate, which is subsequently transformed into creatine by GAMT. Creatine is also transported into cells from circulation through solute carrier family 6 member 8 (SLC6A8), a specific transporter of creatine22, and is subsequently phosphorylated to phosphocreatine. Phosphocreatine is an energy storage metabolite that participates in ATP metabolism and provides energy for energy-consuming cells through the action of creatine kinase23. Cyclocreatine, a creatine analog, exerted the similar effect as creatine without the transporter SLC6A822. Cyclocreatine is phosphorylated to cyclocreatine phosphate, which provides energy for cells with high energy demands24.
Preclinical and clinical developments in enzyme-loaded red blood cells: an update
Published in Expert Opinion on Drug Delivery, 2023
Marzia Bianchi, Luigia Rossi, Francesca Pierigè, Sara Biagiotti, Alessandro Bregalda, Filippo Tasini, Mauro Magnani
Creatine deficiency disorders (CDDs) are inborn errors of creatine metabolism and transport, which can be caused by three different gene defects: guanidinoacetate methyltransferase (GAMT) deficiency, L-arginine:glycine amidinotransferase (AGAT) deficiency and creatine transporter (CRTR) deficiency [98]. Although they share common traits (developmental delay and cognitive dysfunction or intellectual disability and speech-language disorder), GAMT deficiency can present the most severe phenotype, and is characterized by neurocognitive dysfunction due to creatine (Cr) deficiency and accumulation of guanidinoacetate (GAA) in the brain. GAMT catalyzes the second and final step of creatine biosynthesis (which occurs primarily in the liver, kidneys, and pancreas), through methylation of guanidinoacetate, employing S-adenosylmethionine (SAM) as methyl donor [99]. Although likely under-diagnosed [100], GAMT deficiency is a rare disease with a prevalence of < 1/1,000,000 [101]. Numerous loss-of-function mutations (mainly of missense type) are scattered throughout the gene [102]. GAMT deficiency is characterized, from a biochemical standpoint, by low levels of Cr, which plays an essential role in energy homeostasis, and by the concomitant accumulation in tissues and bodily fluids of its precursor GAA, whose toxicity, mainly for the brain, has been implicated in the pathophysiology of the disorder [99,103,104].
Effects of Creatine Supplementation on Muscle Fatigue in Rats Receiving Doxorubicin Treatment
Published in Nutrition and Cancer, 2020
Zoltan A. Torok, Raquel B. Busekrus, David S. Hydock
Supplementing the diet with creatine monohydrate (Cr) is one such therapy. Creatine, or N-aminoiminomethyl-N-methylglycine, is an endogenously formed amino acid that is taken up in diets containing fresh meat or fish. Biosynthesis of creatine takes place in the liver and begins with the transfer of the amindino group of arginine (synthesized in the kidneys) to glycine to yield L-ornithine and guanidinoacetic acid, catalyzed by L-arginine:glycine amindinotransferase. The enzyme S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase then methylates the amidino group on guanidinoacetic acid and forms creatine. Creatine is then distributed throughout the body, with 95% of Cr found in skeletal muscle and the other 5% in brain, liver, kidney, and testes (7).