Creatine synthesis is required in adult animals to replace creatine that is spontaneously converted to creatinine and excreted in the urine. Additionally, in growing animals it is necessary to provide creatine to the expanding tissue mass. Creatine synthesis requires three amino acids: glycine, methionine and arginine, and three enzymes: l-arginine:glycine amidinotransferase (AGAT), methionine adenosyltransferase (MAT) and guanidinoacetate methyltransferase (GAMT). The entire glycine molecule is consumed in creatine synthesis but only the methyl and amidino groups, respectively, from methionine and arginine. Creatinine loss averages approximately 2 g (14.6 mmol) for 70 kg males in the 20- to 39-year age group. Creatinine loss is lower in females and in older age groups because of lower muscle mass. Approximately half of this creatine lost to creatinine can be replaced, in omnivorous individuals, by dietary creatine. However, since dietary creatine is only provided in animal products, principally in meat and fish, virtually all of the creatine loss in vegetarians must be replaced via endogenous synthesis. Creatine synthesis does not appear to place a major burden on glycine metabolism in adults since this amino acid is readily synthesized. However, creatine synthesis does account for approximately 40% of all of the labile methyl groups provided by S-adenosylmethionine (SAM) and, as such, places an appreciable burden on the provision of such methyl groups, either from the diet or via de novo methylneogenesis. Creatine synthesis consumes some 20–30% of arginine’s amidino groups, whether provided in the diet or synthesized within the body. Creatine synthesis is, therefore, a quantitatively major pathway in amino acid metabolism and imposes an appreciable burden on the metabolism of methionine and of arginine.
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Almeida LS, Salomons GS, Hogenboom F, Jakobs C, Schoffelmeer AN (2006) Exocytotic release of creatine in rat brain. Synapse 60:118–123
Arias A, Garcia-Villoria J, Ribes A (2004) Guanidinoacetate and creatine/creatinine levels in controls and patients with urea cycle defects. Mol Genet Metab 82:220–223
Brosnan JT, Brosnan ME (2007) Creatine: endogenous metabolite, dietary, and therapeutic supplement. Annu Rev Nutr 27:241–261
Brosnan JT, Brosnan ME (2010) Creatine metabolism and the urea cycle. Mol Genet Metab 100(Suppl 1):S49–S52
Brosnan JT, Wijekoon EP, Warford-Woolgar L, Trottier NL, Brosnan ME, Brunton JA, Bertolo RF (2009) Creatine synthesis is a major metabolic process in neonatal piglets and has important implications for amino acid metabolism and methyl balance. J Nutr 139:1292–1297
Brusilow SW (1984) Arginine, an indispensable amino acid for patients with inborn errors of urea synthesis. J Clin Invest 74:2144–2148
Castillo L, Chapman TE, Sanchez M, Yu YM, Burke JF, Ajami AM, Vogt J, Young VR (1993a) Plasma arginine and citrulline kinetics in adults given adequate and arginine-free diets. Proc Natl Acad Sci USA 90:7749–7753
Castillo L, Chapman TE, Yu YM, Ajami A, Burke JF, Young VR (1993b) Dietary arginine uptake by the splanchnic region in adult humans. Am J Physiol 265:E532–E539
Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41
Da Silva RP, Nissim I, Brosnan ME, Brosnan JT (2009) Creatine synthesis: hepatic metabolism of guanidinoacetate and creatine in the rat in vitro and in vivo. Am J Physiol Endocrinol Metab 296:E256–E261
Dhanakoti SN, Brosnan JT, Herzberg GR, Brosnan ME (1990) Renal arginine synthesis: studies in vitro and in vivo. Am J Physiol 259:E437–E442
Edison EE, Brosnan ME, Meyer C, Brosnan JT (2007) Creatine synthesis: production of guanidinoacetate by the rat and human kidney in vivo. Am J Physiol Renal Physiol 293:F1799–F1804
Food and Nutrition Board (2005) Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids. The National Academies Press, Washington
Fukagawa NK, Martin JM, Wurthmann A, Prue AH, Ebenstein D, O’Rourke B (2000) Sex-related differences in methionine metabolism and plasma homocysteine concentrations. Am J Clin Nutr 72:22–29
Goping IS, Lagacé M, Shore GC (1992) Factors interacting with the rat carbamyl phosphate synthetase promoter in expressing and nonexpressing tissues. Gene 118:283–287
Guthmiller P, Van Pilsum JF, Boen JR, McGuire DM (1994) Cloning and sequencing of rat kidney l-arginine:glycine amidinotransferase. Studies on the mechanism of regulation by growth hormone and creatine. J Biol Chem 269:17556–17560
Harris RC, Nevill M, Harris DB, Fallowfield JL, Bogdanis GC, Wise JA (2002) Absorption of creatine supplied as a drink, in meat or in solid form. J Sports Sci 20:147–151
Kan HE, van der Graaf M, Klomp DW, Vlak MH, Padberg GW, Heerschap A (2006) Intake of 13C–4 creatine enables simultaneous assessment of creatine and phosphocreatine pools in human skeletal muscle by 13C MR spectroscopy. Magn Reson Med 56:953–957
Kasumov T, Gruca LL, Dasarathy S, Kalhan SC (2009) Simultaneous assay of isotopic enrichment and concentration of guanidinoacetate and creatine by gas chromatography-mass spectrometry. Anal Biochem 395:91–99
Levillain O, Diaz JJ, Reymond I, Soulet D (2000) Ornithine metabolism along the female mouse nephron: localization of ornithine decarboxylase and ornithine aminotransferase. Pflugers Arch 440:761–769
MacNeil L, Hill L, MacDonald D, Keefe L, Cormier JF, Burke DG, Smith-Palmer T (2005) Analysis of creatine, creatinine, creatine-d3 and creatinine-d3 in urine, plasma, and red blood cells by HPLC and GC-MS to follow the fate of ingested creatine-d3. J Chromatogr B Analyt Technol Biomed Life Sci 827:210–215
McGuire DM, Gross MD, Elde RP, van Pilsum JF (1986) Localization of l-arginine-glycine amidinotransferase protein in rat tissues by immunofluorescence microscopy. J Histochem Cytochem 34:429–435
Melendez-Hevia E, De Paz-Lugo P, Cornish-Bowden A, Cardenas ML (2009) A weak link in metabolism: the metabolic capacity for glycine biosynthesis does not satisfy the need for collagen synthesis. J Biosci 34:853–872
Mudd SH, Brosnan JT, Brosnan ME, Jacobs RL, Stabler SP, Allen RH, Vance DE, Wagner C (2007) Methyl balance and transmethylation fluxes in humans. Am J Clin Nutr 85:19–25
Riedijk MA, Stoll B, Chacko S, Schierbeek H, Sunehag AL, van Goudoever JB, Burrin DG (2007) Methionine transmethylation and transsulfuration in the piglet gastrointestinal tract. Proc Natl Acad Sci USA 104:3408–3413
Roze E, Azuar C, Menuel C, Häberle J, Guillevin R (2007) Usefulness of magnetic resonance spectroscopy in urea cycle disorders. Pediatr Neurol 37:222–225
Schulze A (2003) Creatine deficiency syndromes. Mol Cell Biochem 244:143–150
Smith AD (2008) The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull 29(2 Suppl):S143–S172
Tizianello A, De Ferrari G, Garibotto G, Gurreri G, Robaudo C (1980) Renal metabolism of amino acids and ammonia in subjects with normal renal function and in patients with chronic renal insufficiency. J Clin Invest 65:1162–1173
Van Pilsum JF, Stephens GC, Taylor D (1972) Distribution of creatine, guanidinoacetate and the enzymes for their biosynthesis in the animal kingdom. Implications for phylogeny. Biochem J 126:325–345
Venderley AM, Campbell WW (2006) Vegetarian diets: nutritional considerations for athletes. Sports Med 36:293–305
Walzel B, Speer O, Boehm E, Kristiansen S, Chan S, Clarke K, Magyar JP, Richter EA, Wallimann T (2002) New creatine transporter assay and identification of distinct creatine transporter isoforms in muscle. Am J Physiol Endocrinol Metab 283:E390–E401
Wilmore D (2004) Enteral and parenteral arginine supplementation to improve medical outcomes in hospitalized patients. J Nutr (10 Suppl) 134:2863S–2867S
Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80:1107–1213
Yu YM, Ryan CM, Castillo L, Lu XM, Beaumier L, Tompkins RG, Young VR (2001) Arginine and ornithine kinetics in severely burned patients: increased rate of arginine disposal. Am J Physiol Endocrinol Metab 280:E509–E517
The authors’ work was supported by Grant # MOP 97851 from the Canadian Institutes of Health Research.
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Brosnan, J.T., da Silva, R.P. & Brosnan, M.E. The metabolic burden of creatine synthesis. Amino Acids 40, 1325–1331 (2011). https://doi.org/10.1007/s00726-011-0853-y
- S-Adenosyl methionine
- Methyl balance