Creatine biosynthesis and transport in health and disease

Biochimie. 2015 Dec;119:146-65. doi: 10.1016/j.biochi.2015.10.022. Epub 2015 Nov 2.

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.

Keywords: AGAT; AMP activated protein kinase; CRTR; Creatine; GAMT; SLC6A8; Secondary creatine disorders.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Amidinotransferases / deficiency
  • Amidinotransferases / genetics
  • Amidinotransferases / metabolism*
  • 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
  • Creatine / metabolism*
  • Developmental Disabilities / diagnosis
  • Developmental Disabilities / enzymology
  • Developmental Disabilities / genetics
  • Developmental Disabilities / metabolism
  • Energy Metabolism
  • Guanidinoacetate N-Methyltransferase / deficiency
  • Guanidinoacetate N-Methyltransferase / genetics
  • Guanidinoacetate N-Methyltransferase / metabolism*
  • 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
  • Nerve Tissue Proteins / metabolism*
  • Ornithine / deficiency
  • Ornithine / genetics
  • Ornithine / metabolism
  • Plasma Membrane Neurotransmitter Transport Proteins / deficiency
  • Plasma Membrane Neurotransmitter Transport Proteins / genetics
  • Plasma Membrane Neurotransmitter Transport Proteins / metabolism*
  • 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

Substances

  • Amino Acid Transport Systems, Basic
  • Mitochondrial Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Plasma Membrane Neurotransmitter Transport Proteins
  • SLC25A15 protein, human
  • SLC6A8 protein, human
  • S-Adenosylmethionine
  • Ornithine
  • GAMT protein, human
  • Guanidinoacetate N-Methyltransferase
  • Amidinotransferases
  • glycine amidinotransferase
  • AMP-Activated Protein Kinases
  • Creatine

Supplementary concepts

  • Arginine-Glycine Amidinotransferase Deficiency
  • Creatine deficiency, X-linked
  • Guanidinoacetate methyltransferase deficiency
  • HHH syndrome