1. Creatine biosynthesis and transport in health and disease.
- Author
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Joncquel-Chevalier Curt M, Voicu PM, Fontaine M, Dessein AF, Porchet N, Mention-Mulliez K, Dobbelaere D, Soto-Ares G, Cheillan D, and Vamecq J
- Subjects
- AMP-Activated Protein Kinases metabolism, Amidinotransferases deficiency, Amidinotransferases genetics, Amino Acid Metabolism, Inborn Errors diagnosis, Amino Acid Metabolism, Inborn Errors enzymology, Amino Acid Metabolism, Inborn Errors genetics, Amino Acid Metabolism, Inborn Errors metabolism, Amino Acid Transport Systems, Basic deficiency, Amino Acid Transport Systems, Basic genetics, Amino Acid Transport Systems, Basic metabolism, Animals, Biological Transport, Active, Brain Diseases, Metabolic, Inborn diagnosis, Brain Diseases, Metabolic, Inborn enzymology, Brain Diseases, Metabolic, Inborn genetics, Brain Diseases, Metabolic, Inborn metabolism, Creatine biosynthesis, Creatine deficiency, Creatine genetics, Developmental Disabilities diagnosis, Developmental Disabilities enzymology, Developmental Disabilities genetics, Developmental Disabilities metabolism, Energy Metabolism, Guanidinoacetate N-Methyltransferase deficiency, Guanidinoacetate N-Methyltransferase genetics, Gyrate Atrophy diagnosis, Gyrate Atrophy enzymology, Gyrate Atrophy genetics, Gyrate Atrophy metabolism, Humans, Hyperammonemia diagnosis, Hyperammonemia enzymology, Hyperammonemia genetics, Hyperammonemia metabolism, Intellectual Disability diagnosis, Intellectual Disability enzymology, Intellectual Disability genetics, Intellectual Disability metabolism, Language Development Disorders diagnosis, Language Development Disorders enzymology, Language Development Disorders genetics, Language Development Disorders metabolism, Mental Retardation, X-Linked diagnosis, Mental Retardation, X-Linked enzymology, Mental Retardation, X-Linked genetics, Mental Retardation, X-Linked metabolism, Methylation, Mitochondrial Membrane Transport Proteins, Movement Disorders congenital, Movement Disorders diagnosis, Movement Disorders enzymology, Movement Disorders genetics, Movement Disorders metabolism, Mutation, Nerve Tissue Proteins deficiency, Nerve Tissue Proteins genetics, Ornithine deficiency, Ornithine genetics, Ornithine metabolism, Plasma Membrane Neurotransmitter Transport Proteins deficiency, Plasma Membrane Neurotransmitter Transport Proteins genetics, Prenatal Diagnosis, S-Adenosylmethionine metabolism, Speech Disorders diagnosis, Speech Disorders enzymology, Speech Disorders genetics, Speech Disorders metabolism, Urea Cycle Disorders, Inborn diagnosis, Urea Cycle Disorders, Inborn enzymology, Urea Cycle Disorders, Inborn genetics, Urea Cycle Disorders, Inborn metabolism, Amidinotransferases metabolism, Creatine metabolism, Guanidinoacetate N-Methyltransferase metabolism, Nerve Tissue Proteins metabolism, Plasma Membrane Neurotransmitter Transport Proteins metabolism
- Abstract
Creatine is physiologically provided equally by diet and by endogenous synthesis from arginine and glycine with successive involvements of arginine glycine amidinotransferase [AGAT] and guanidinoacetate methyl transferase [GAMT]. A specific plasma membrane transporter, creatine transporter [CRTR] (SLC6A8), further enables cells to incorporate creatine and through uptake of its precursor, guanidinoacetate, also directly contributes to creatine biosynthesis. Breakthrough in the role of creatine has arisen from studies on creatine deficiency disorders. Primary creatine disorders are inherited as autosomal recessive (mutations affecting GATM [for glycine-amidinotransferase, mitochondrial]) and GAMT genes) or X-linked (SLC6A8 gene) traits. They have highlighted the role of creatine in brain functions altered in patients (global developmental delay, intellectual disability, behavioral disorders). Creatine modulates GABAergic and glutamatergic cerebral pathways, presynaptic CRTR (SLC6A8) ensuring re-uptake of synaptic creatine. Secondary creatine disorders, addressing other genes, have stressed the extraordinary imbrication of creatine metabolism with many other cellular pathways. This high dependence on multiple pathways supports creatine as a cellular sensor, to cell methylation and energy status. Creatine biosynthesis consumes 40% of methyl groups produced as S-adenosylmethionine, and creatine uptake is controlled by AMP activated protein kinase, a ubiquitous sensor of energy depletion. Today, creatine is considered as a potential sensor of cell methylation and energy status, a neurotransmitter influencing key (GABAergic and glutamatergic) CNS neurotransmission, therapeutic agent with anaplerotic properties (towards creatine kinases [creatine-creatine phosphate cycle] and creatine neurotransmission), energetic and antioxidant compound (benefits in degenerative diseases through protection against energy depletion and oxidant species) with osmolyte behavior (retention of water by muscle). This review encompasses all these aspects by providing an illustrated metabolic account for brain and body creatine in health and disease, an algorithm to diagnose metabolic and gene bases of primary and secondary creatine deficiencies, and a metabolic exploration by (1)H-MRS assessment of cerebral creatine levels and response to therapeutic measures., (Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)
- Published
- 2015
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