Creatine and Creatinine Metabolism

F. Hoffmann-La Roche, Vitamins and Fine Chemicals Division, Basel, Switzerland.
Physiological Reviews (Impact Factor: 27.32). 08/2000; 80(3):1107-213.
Source: PubMed


The goal of this review is to present a comprehensive survey of the many intriguing facets of creatine (Cr) and creatinine metabolism, encompassing the pathways and regulation of Cr biosynthesis and degradation, species and tissue distribution of the enzymes and metabolites involved, and of the inherent implications for physiology and human pathology. Very recently, a series of new discoveries have been made that are bound to have distinguished implications for bioenergetics, physiology, human pathology, and clinical diagnosis and that suggest that deregulation of the creatine kinase (CK) system is associated with a variety of diseases. Disturbances of the CK system have been observed in muscle, brain, cardiac, and renal diseases as well as in cancer. On the other hand, Cr and Cr analogs such as cyclocreatine were found to have antitumor, antiviral, and antidiabetic effects and to protect tissues from hypoxic, ischemic, neurodegenerative, or muscle damage. Oral Cr ingestion is used in sports as an ergogenic aid, and some data suggest that Cr and creatinine may be precursors of food mutagens and uremic toxins. These findings are discussed in depth, the interrelationships are outlined, and all is put into a broader context to provide a more detailed understanding of the biological functions of Cr and of the CK system.

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    • "GAA has an interaction with GABA A receptors in in vitro studies, contributing to the seizures and movement disorder seen in GAMT deficiency (Neu et al., 2002). Creatine deficiency in brain proton magnetic resonance spectroscopy ( 1 H-MRS), and elevated GAA levels in urine, blood and cerebral spinal fluid (CSF) are the biochemical hallmarks of the GAMT deficiency (Stöckler et al., 1996b; Wyss and Kaddurah-Daouk, 2000). Clinical features include global developmental delay (GDD), hypotonia and seizures in infants and intellectual disability, movement disorder, epilepsy and behavioral problems in children (Mercimek-Mahmutoglu et al., 2009; Viau et al., 2013). "
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    ABSTRACT: GAMT deficiency is an autosomal recessive disorder of creatine biosynthesis causing developmental delays or intellectual disability in untreated patients as a result of irreversible brain damage occurring prior to diagnosis. Normal neurodevelopmental outcome has been reported in patients treated from neonatal period highlighting the importance of early treatment. Five hundred anonymized newborns from the National Newborn Screening Program of The Netherlands were included into this pilot study. Direct sequencing of the coding region of the GAMT gene was applied following DNA extraction. The disease causing nature of novel missense variants in the GAMT gene was studied by overexpression studies. GAA and creatine was measured in blood dot spots. We detected two carriers, one with a known common (c.327G>A) and one with a novel mutation (c.297_309dup (p.Arg105Glyfs*) in the GAMT gene. The estimated incidence of GAMT deficiency was 1:250,000. We also detected five novel missense variants. Overexpression of these variants in GAMT deficient fibroblasts did restore GAMT activity and thus all were considered rare, but not disease causing variants including the c.131G>T (p.Arg44Leu) variant. Interestingly, this variant was predicted to be pathogenic by in silico analysis. The variants were included in the Leiden Open Variation Database (LOVD) database ( The average GAA level was 1.14μmol/L±0.45 standard deviations. The average creatine level was 408 μmol/L±106. The average GAA/creatine ratio was 2.94±01.36. The estimated incidence of GAMT deficiency is 1:250,000 newborns based on our pilot study. The newborn screening for GAMT deficiency should be implemented to identify patients at the asymptomatic stage to achieve normal neurodevelopmental outcome for this treatable neurometabolic disease. Biochemical investigations including GAA, creatine and GAMT enzyme activity measurements are essential to confirm the diagnosis of GAMT deficiency. According to availability, all missense variants can be assessed functionally, as in silico prediction analysis of missense variants is not sufficient to confirm the pathogenicity of missense variants. Copyright © 2015. Published by Elsevier B.V.
    Gene 08/2015; DOI:10.1016/j.gene.2015.08.045 · 2.14 Impact Factor
    • "This result may reflect, at least in part, the immaturity of the neonatal kidney [19]. Creatinine is a breakdown product of creatine phosphate in muscle [21]. Changes in the creatinine content followed a similar trend in urines of AGA, IUGR, and LGA, decreasing over time. "
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    ABSTRACT: Under conditions of non-optimal supply of nutrients, maternal diet during gestation can alter the balance between anabolic and catabolic pathways of fetus and triggers an effect of programming to the metabolic syndrome. Metabolomics is an analytical technique that has been recently attracting increasing interest for the identification of biomarkers of dietary exposure. In this study, a NMR-based metabolomic approach was employed for an explorative analysis of the time-related urinary metabolic profiles of three groups of newborns receiving a different fetal nutrition: adequate for gestational age (AGA), with intrauterine growth retardation (IUGR), and large for gestational age (LGA). Urine samples were collected over the first week of life. Application of orthogonal projection to latent structure discriminant analysis (OPLS-DA) evidenced similar time-related modifications in the metabolic profiles of the three classes of infants, consisting mainly of changes in levels of taurine, creatinine, betaine, and glycine. Furthermore, alterations in the content of citrate and myo-inositol were found to be characteristic of IUGR and LGA, whole levels were higher with respect to controls, while higher contents of betaine and succinate were noted in AGA. Our results positively support the application of the metabolomic approach in the study of the metabolic pathways associated to fetal malnutrition. Copyright © 2015. Published by Elsevier B.V.
    Clinica chimica acta; international journal of clinical chemistry 08/2015; DOI:10.1016/j.cca.2015.08.008 · 2.82 Impact Factor
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    • "Both sufficient availability of CK substrates (e.g. creatine, phosphocreatine, ATP) and functional catalysis are traditionally considered prerequisites for normal cellular bioenergetics (Wyss and Kaddurah-Daouk 2000). Many studies have reported disturbed energy metabolism, and structural and physiological abnormalities in different disorders of creatine biosynthesis and/or transport (Nasrallah et al. 2010). "
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    ABSTRACT: Guanidinoacetic acid (GAA) is a natural precursor of creatine, and a possible substrate for the creatine kinase (CK) enzyme system, serving as a creatine mimetic. Its direct role in cellular bioenergetics has been confirmed in several studies, however GAA utilization by CK seems to be a second-rate as compared to creatine, and compartment-dependent. Here we discuss various factors that might affect GAA use in high-energy phosphoryl transfer in the cytosol and mitochondria.
    Journal of Bioenergetics 08/2015; DOI:10.1007/s10863-015-9619-7 · 3.21 Impact Factor
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