creatine creatine creatine skeletal formula of neutral form of creatine skeletal formula of one of zwitterionic forms of creatine ball and stick model of one of zwitterionic forms of creatine names systematic iupac name 2-acetic acid other names n-carbamimidoyl-n-methylglycine; methylguanidoacetic acid identifiers cas number 57-00-1 y 3d model (jsmol) interactive image 3dmet b00084 beilstein reference 907175 chebi chebi:16919 y chembl chembl283800 y chemspider 566 y drugbank db00148 y echa infocard 100.000.278 ec number 200-306-6 gmelin reference 240513 kegg c00300 y mesh creatine pubchem cid 586 rtecs number mb7706000 unii mu72812gk0 y comptox dashboard (epa) dtxsid1040451 inchi inchi=1s/c4h9n3o2/c1-7(4(5)6)2-3(8)9/h2h2,1h3,(h3,5,6)(h,8,9) ykey: cvsvtcorwbxhqv-uhfffaoysa-n y smiles cn(cc(=o)o)c(=n)n properties chemical formula c4h9n3o2 molar mass 131.135 g·mol−1 appearance white crystals odor odourless melting point 255 °c (491 °f; 528 k) solubility in water 13.3 g l−1 (at 18 °c) log p −1.258 acidity (pka) 3.429 basicity (pkb) 10.568 isoelectric point 8.47 thermochemistry heat capacity (c) 171.1 j k−1 mol−1 (at 23.2 °c) std molarentropy (s⦵298) 189.5 j k−1 mol−1 std enthalpy offormation (δfh⦵298) −538.06–−536.30 kj mol−1 std enthalpy ofcombustion (δch⦵298) −2.3239–−2.3223 mj mol−1 pharmacology atc code c01eb06 (who) pharmacokinetics: biological half-life 3 hours hazards ghs labelling: pictograms signal word warning hazard statements h315, h319, h335 precautionary statements p261, p305+p351+p338 related compounds related alkanoic acids sarcosinedimethylglycineglycocyaminen-methyl-d-aspartic acidbeta-methylamino-l-alanineguanidinopropionic acid related compounds dimethylacetamide except where otherwise noted, data are given for materials in their standard state (at 25 °c , 100 kpa). n verify (what is yn ?) infobox references creatine (/ˈkriːətiːn/ or /ˈkriːətɪn/) is an organic compound with the nominal formula (h2n)(hn)cn(ch3)ch2co2h. it exists in various tautomers in solutions (among which are neutral form and various zwitterionic forms). creatine is found in vertebrates where it facilitates recycling of adenosine triphosphate (atp), primarily in muscle and brain tissue. recycling is achieved by converting adenosine diphosphate (adp) back to atp via donation of phosphate groups. creatine also acts as a buffer. history creatine was first identified in 1832 when michel eugène chevreul isolated it from the basified water-extract of skeletal muscle. he later named the crystallized precipitate after the greek word for meat, κρέας (kreas). in 1928, creatine was shown to exist in equilibrium with creatinine. studies in the 1920s showed that consumption of large amounts of creatine did not result in its excretion. this result pointed to the ability of the body to store creatine, which in turn suggested its use as a dietary supplement. in 1912, harvard university researchers otto folin and willey glover denis found evidence that ingesting creatine can dramatically boost the creatine content of the muscle. in the late 1920s, after finding that the intramuscular stores of creatine can be increased by ingesting creatine in larger than normal amounts, scientists discovered phosphocreatine (creatine phosphate), and determined that creatine is a key player in the metabolism of skeletal muscle. the substance creatine is naturally formed in vertebrates. the discovery of phosphocreatine was reported in 1927. in the 1960s, creatine kinase (ck) was shown to phosphorylate adp using phosphocreatine (pcr) to generate atp. it follows that atp, not pcr is directly consumed in muscle contraction. ck uses creatine to "buffer" the atp/adp ratio. while creatine's influence on physical performance has been well documented since the early twentieth century, it came into public view following the 1992 olympics in barcelona. an august 7, 1992 article in the times reported that linford christie, the gold medal winner at 100 meters, had used creatine before the olympics. an article in bodybuilding monthly named sally gunnell, who was the gold medalist in the 400-meter hurdles, as another creatine user. in addition, the times also noted that 100 meter hurdler colin jackson began taking creatine before the olympics. phosphocreatine relays phosphate to adp. at the time, low-potency creatine supplements were available in britain, but creatine supplements designed for strength enhancement were not commercially available until 1993 when a company called experimental and applied sciences (eas) introduced the compound to the sports nutrition market under the name phosphagen. research performed thereafter demonstrated that the consumption of high glycemic carbohydrates in conjunction with creatine increases creatine muscle stores. the cyclic derivative creatinine exists in equilibrium with its tautomer and with creatine. metabolic role creatine is a naturally occurring non-protein compound and the primary constituent of phosphocreatine, which is used to regenerate atp within the cell. 95% of the human body's total creatine and phosphocreatine stores are found in skeletal muscle, while the remainder is distributed in the blood, brain, testes, and other tissues. the typical creatine content of skeletal muscle (as both creatine and phosphocreatine) is 120 mmol per kilogram of dry muscle mass, but can reach up to 160 mmol/kg through supplementation. approximately 1–2% of intramuscular creatine is degraded per day and an individual would need about 1–3 grams of creatine per day to maintain average (unsupplemented) creatine storage. an omnivorous diet provides roughly half of this value, with the remainder synthesized in the liver and kidneys. creatine is not an essential nutrient. it is an amino acid derivative, naturally produced in the human body from the amino acids glycine and arginine, with an additional requirement for s-adenosyl methionine (a derivative of methionine) to catalyze the transformation of guanidinoacetate to creatine. in the first step of the biosynthesis, the enzyme arginine:glycine amidinotransferase (agat, ec:2.1.4.1) mediates the reaction of glycine and arginine to form guanidinoacetate. this product is then methylated by guanidinoacetate n-methyltransferase (gamt, ec:2.1.1.2), using s-adenosyl methionine as the methyl donor. creatine itself can be phosphorylated by creatine kinase to form phosphocreatine, which is used as an energy buffer in skeletal muscles and the brain. a cyclic form of creatine, called creatinine, exists in equilibrium with its tautomer and with creatine. phosphocreatine system proposed creatine kinase/phosphocreatine (ck/pcr) energy shuttle. crt = creatine transporter; ant = adenine nucleotide translocator; atp = adenine triphosphate; adp = adenine diphosphate; op = oxidative phosphorylation; mtck = mitochondrial creatine kinase; g = glycolysis; ck-g = creatine kinase associated with glycolytic enzymes; ck-c = cytosolic creatine kinase; ck-a = creatine kinase associated with subcellular sites of atp utilization; 1 – 4 sites of ck/atp interaction. creatine is transported through the blood and taken up by tissues with high energy demands, such as the brain and skeletal muscle, through an active transport system. the concentration of atp in skeletal muscle is usually 2–5 mm, which would result in a muscle contraction of only a few seconds. during times of increased energy demands, the phosphagen (or atp/pcr) system rapidly resynthesizes atp from adp with the use of phosphocreatine (pcr) through a reversible reaction catalysed by the enzyme creatine kinase (ck). the phosphate group is attached to an nh center of the creatine. in skeletal muscle, pcr concentrations may reach 20–35 mm or more. additionally, in most muscles, the atp regeneration capacity of ck is very high and is therefore not a limiting factor. although the cellular concentrations of atp are small, changes are difficult to detect because atp is continuously and efficiently replenished from the large pools of pcr and ck. a proposed representation has been illustrated by krieder et al. creatine has the ability to increase muscle stores of pcr, potentially increasing the muscle's ability to resynthesize atp from adp to meet increased energy demands. creatine supplementation appears to increase the number of myonuclei that satellite cells will 'donate' to damaged muscle fibers, which increases the potential for growth of those fibers. this increase in myonuclei probably stems from creatine's ability to increase levels of the myogenic transcription factor mrf4. genetic deficiencies genetic deficiencies in the creatine biosynthetic pathway lead to various severe neurological defects. clinically, there are three distinct disorders of creatine metabolism. deficiencies in the two synthesis enzymes can cause l-arginine:glycine amidinotransferase deficiency caused by variants in gatm and guanidinoacetate methyltransferase deficiency, caused by variants in gamt. both biosynthetic defects are inherited in an autosomal recessive manner. a third defect, creatine transporter defect, is caused by mutations in slc6a8 and inherited in a x-linked manner. this condition is related to the transport of creatine into the brain. vegetarians some studies suggest that total muscle creatine is significantly lower in vegetarians than non-vegetarians. it is postulated that this finding is due to an omnivorous diet being the primary source of creatine. research shows that supplementation is needed to raise the concentration of creatine in the muscles of lacto-ovo vegetarians and vegans up to non-vegetarian levels. studies have shown that they have lower creatine concentrations in muscle and blood, but not brain. pharmacokinetics most of the research to-date on creatine has predominantly focused on the pharmacological properties of creatine, yet there is a lack of research into the pharmacokinetics of creatine. studies have not established pharmacokinetic parameters for clinical usage of creatine such as volume of distribution, clearance, bioavailability, mean residence time, absorption rate, and half life. a clear pharmacokinetic profile would need to be established prior to optimal clinical dosing. loading phase an approximation of 0.3 g/kg/day divided into 4 equal spaced intervals has been suggested since creatine needs may vary based on body weight. it has also been shown that taking a lower dose of 3 grams a day for 28 days can also increase total muscle creatine storage to the same amount as the rapid loading dose of 20 g/day for 6 days. however, a 28 day loading phase does not allow for ergogenic benefits of creatine supplementation to be realized until fully saturated muscle storage. supplementing creatine with carbohydrates or carbohydrates and protein has been shown to augment creatine retention. this elevation in muscle creatine storage has been correlated with ergogenic benefits discussed in the research section. however, higher doses for longer periods of time are being studied to offset creatine synthesis deficiencies and mitigating diseases. maintenance phase after the 5–7 day loading phase, muscle creatine stores are fully saturated and supplementation only needs to cover the amount of creatine broken down per day. this maintenance dose was originally reported to be around 2–3 g/day (or 0.03 g/kg/day), however, some studies have suggested 3–5 g/day maintenance dose to maintain saturated muscle creatine. absorption this graph shows the mean plasma creatine concentration (measured in μmol/l) over an 8-hour period following ingestion of 4.4 grams of creatine in the form of creatine monohydrate (crm), tri-creatine citrate (crc), or creatine pyruvate (crpyr). endogenous serum or plasma creatine concentrations in healthy adults are normally in a range of 2–12 mg/l. a single 5 gram (5000 mg) oral dose in healthy adults results in a peak plasma creatine level of approximately 120 mg/l at 1–2 hours post-ingestion. creatine has a fairly short elimination half life, averaging just less than 3 hours, so to maintain an elevated plasma level it would be necessary to take small oral doses every 3–6 hours throughout the day. clearance it has been shown that once supplementation of creatine stops, muscle creatine stores return to baseline in 4–6 weeks. exercise and sport creatine supplements are marketed in ethyl ester, gluconate, monohydrate, and nitrate forms. creatine supplementation for sporting performance enhancement is considered safe for short-term use but there is a lack of safety data for long term use, or for use in children and adolescents. a 2018 review article in the journal of the international society of sports nutrition said that creatine monohydrate might help with energy availability for high-intensity exercise. creatine use can increase maximum power and performance in high-intensity anaerobic repetitive work (periods of work and rest) by 5% to 15%. creatine has no significant effect on aerobic endurance, though it will increase power during short sessions of high-intensity aerobic exercise. a survey of 21,000 college athletes showed that 14% of athletes take creatine supplements to try to improve performance. non-athletes report taking creatine supplements to improve appearance. research cognitive performance creatine is reported to have a beneficial effect on brain function and cognitive processing, although the evidence is difficult to interpret systematically and the appropriate dosing is unknown. the greatest effects appears to be in individuals who are stressed (due, for instance, to sleep deprivation) or cognitively impaired. muscular disease a meta-analysis found that creatine treatment increased muscle strength in muscular dystrophies, and potentially improved functional performance. creatine treatment does not appear to improve muscle strength in people who have metabolic myopathies. high doses of creatine lead to increased muscle pain and an impairment in activities of daily living when taken by people