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      Phosphocyclocreatine is the dominant form of cyclocreatine in control and creatine transporter deficiency patient fibroblasts

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          Creatine transporter deficiency (CTD) is a metabolic disorder resulting in cognitive, motor, and behavioral deficits. Cyclocreatine (cCr), a creatine analog, has been explored as a therapeutic strategy for the treatment of CTD. We developed a rapid, selective, and accurate HILIC ultra‐performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS) method to simultaneously quantify the intracellular concentrations of cCr, creatine (Cr), creatine‐d3 (Cr‐d3), phosphocyclocreatine (pcCr), and phosphocreatine (pCr). Using HILIC‐UPLC‐MS/MS, we measured cCr and Cr‐d3 uptake and their conversion to the phosphorylated forms in primary human control and CTD fibroblasts. Altogether, the data demonstrate that cCr enters cells and its dominant intracellular form is pcCr in both control and CTD patient cells. Therefore, cCr may replace creatine as a therapeutic strategy for the treatment of CTD.

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          Most cited references 15

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          Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans.

          Arginine:glycine amidinotransferase (AGAT) catalyzes the first step of creatine synthesis, resulting in the formation of guanidinoacetate, which is a substrate for creatine formation. In two female siblings with mental retardation who had brain creatine deficiency that was reversible by means of oral creatine supplementation and had low urinary guanidinoacetate concentrations, AGAT deficiency was identified as a new genetic defect in creatine metabolism. A homozygous G-A transition at nucleotide position 9297, converting a tryptophan codon (TGG) to a stop codon (TAG) at residue 149 (T149X), resulted in undetectable cDNA, as investigated by reverse-transcription PCR, as well as in undetectable AGAT activity, as investigated radiochemically in cultivated skin fibroblasts and in virus-transformed lymphoblasts of the patients. The parents were heterozygous for the mutant allele, with intermediate residual AGAT activities. Recognition and treatment with oral creatine supplements may prevent neurological sequelae in affected patients.
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            The Effect of the Creatine Analogue Beta-guanidinopropionic Acid on Energy Metabolism: A Systematic Review

            Background Creatine kinase plays a key role in cellular energy transport. The enzyme transfers high-energy phosphoryl groups from mitochondria to subcellular sites of ATP hydrolysis, where it buffers ADP concentration by catalyzing the reversible transfer of the high-energy phosphate moiety (P) between creatine and ADP. Cellular creatine uptake is competitively inhibited by beta-guanidinopropionic acid. This substance is marked as safe for human use, but the effects are unclear. Therefore, we systematically reviewed the effect of beta-guanidinopropionic acid on energy metabolism and function of tissues with high energy demands. Methods We performed a systematic review and searched the electronic databases Pubmed, EMBASE, the Cochrane Library, and LILACS from their inception through March 2011. Furthermore, we searched the internet and explored references from textbooks and reviews. Results After applying the inclusion criteria, we retrieved 131 publications, mainly considering the effect of chronic oral administration of beta-guanidinopropionic acid (0.5 to 3.5%) on skeletal muscle, the cardiovascular system, and brain tissue in animals. Beta-guanidinopropionic acid decreased intracellular creatine and phosphocreatine in all tissues studied. In skeletal muscle, this effect induced a shift from glycolytic to oxidative metabolism, increased cellular glucose uptake and increased fatigue tolerance. In heart tissue this shift to mitochondrial metabolism was less pronounced. Myocardial contractility was modestly reduced, including a decreased ventricular developed pressure, albeit with unchanged cardiac output. In brain tissue adaptations in energy metabolism resulted in enhanced ATP stability and survival during hypoxia. Conclusion Chronic beta-guanidinopropionic acid increases fatigue tolerance of skeletal muscle and survival during ischaemia in animal studies, with modestly reduced myocardial contractility. Because it is marked as safe for human use, there is a need for human data.
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              X-linked creatine transporter deficiency: clinical aspects and pathophysiology.

              Creatine transporter deficiency was discovered in 2001 as an X-linked cause of intellectual disability characterized by cerebral creatine deficiency. This review describes the current knowledge regarding creatine metabolism, the creatine transporter and the clinical aspects of creatine transporter deficiency. The condition mainly affects the brain while other creatine requiring organs, such as the muscles, are relatively spared. Recent studies have provided strong evidence that creatine synthesis also occurs in the brain, leading to the intriguing question of why cerebral creatine is deficient in creatine transporter deficiency. The possible mechanisms explaining the cerebral creatine deficiency are discussed. The creatine transporter knockout mouse provides a good model to study the disease. Over the past years several treatment options have been explored but no treatment has been proven effective. Understanding the pathogenesis of creatine transporter deficiency is of paramount importance in the development of an effective treatment.

                Author and article information

                Pharmacol Res Perspect
                Pharmacol Res Perspect
                Pharmacology Research & Perspectives
                John Wiley and Sons Inc. (Hoboken )
                20 December 2019
                December 2019
                : 7
                : 6 ( doiID: 10.1002/prp2.v7.6 )
                [ 1 ] National Center for Advancing Translational Sciences National Institutes of Health Bethesda MD USA
                [ 2 ] Division of Medical Genetics Department of Pediatrics University of Utah Salt Lake City UT USA
                [ 3 ] Associated Regional and University Pathologists (ARUP) Laboratories Salt Lake City UT USA
                [ 4 ] Lumos Pharma Austin TX USA
                Author notes
                [* ] Correspondence

                Kirill Gorshkov, Amy Q. Wang and Wei Zheng, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.

                Email: kirill.gorshkov@ 123456nih.gov (K. G.); amy.wang@ 123456nih.gov (A. Q. W.) and wzheng@ 123456mail.nih.gov (W. Z.)

                © 2019 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 7, Tables: 1, Pages: 10, Words: 11289
                Funded by: National Institutes of Health Intramural Research Program , open-funder-registry 10.13039/100000002;
                Funded by: Lumos Pharma
                Original Article
                Early Career Researcher Themed Issue
                Custom metadata
                December 2019
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.3 mode:remove_FC converted:20.12.2019


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