Creatine

For the use of creatine to increase athletic performance, see Creatine supplements.

Not to be confused with creatinine.

Creatine
IUPAC name 2-(Methylguanidino)ethanoic acid
Systematic name 2-(1-Methylcarbamimidamido)acetic acid[citation needed]
Other names Creatin Kreatin (α-Methylguanido)acetic acid
Identifiers
CAS number	57-00-1 Y
PubChem	586
ChemSpider	566 Y
UNII	MU72812GK0 Y
EC number	200-306-6
DrugBank	DB00148
KEGG	C00300 Y
MeSH	Creatine
ChEBI	CHEBI:16919 N
ChEMBL	CHEMBL283800 Y
RTECS number	MB7706000
ATC code	C01EB06
Beilstein Reference	907175
Gmelin Reference	240513
3DMet	B00084
Jmol-3D images	Image 1 Image 2
SMILES CN(CC(O)=O)C(N)=N [H]/N=C(\N)/N(C)CC(=O)O
InChI InChI=1S/C4H9N3O2/c1-7(4(5)6)2-3(8)9/h2H2,1H3,(H3,5,6)(H,8,9) Y Key: CVSVTCORWBXHQV-UHFFFAOYSA-N Y InChI=1/C4H9N3O2/c1-7(4(5)6)2-3(8)9/h2H2,1H3,(H3,5,6)(H,8,9) Key: CVSVTCORWBXHQV-UHFFFAOYAV
Properties
Molecular formula	C4H9N3O2
Molar mass	131.13 g mol−1
Exact mass	131.069476547 g mol-1
Density	1.3 (monohydrate),[1]
Melting point	255 °C, 528 K, 491 °F
Solubility in water	13.3 g dm-3 (at 18 °C)
Solubility	non-soluble in ethanol and ether [2]
log P	-0.2
Acidity (pKa)	3.429
Basicity (pKb)	10.568
Isoelectric point	8.47
Hazards
EU classification	Xi
R-phrases	R36/37/38
S-phrases	S26, S36
N (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Creatine is a nitrogenous organic acid that occurs naturally in vertebrates and helps to supply energy to all cells in the body, primarily muscle. This is achieved by increasing the formation of Adenosine triphosphate (ATP). Creatine was identified in 1832 when Michel Eugène Chevreul discovered it as a component of skeletal muscle, which he later named creatine after the Greek word for meat, κρέας (kreas). In solution, creatine is in equilibrium with creatinine.^[3]

Biosynthesis

Creatine is naturally produced in the human body from amino acids primarily in the kidney and liver. It is transported in the blood for use by muscles. Approximately 95% of the human body's total creatine is located in skeletal muscle.^[4]

Creatine is not an essential nutrient, as it is manufactured in the human body from L-arginine, glycine, and L-methionine.^[5]

In humans and animals, approximately half of stored creatine originates from food (mainly from meat). A study, involving 18 vegetarians and 24 non-vegetarians, on the effect of creatine in vegetarians showed that total creatine was significantly lower than in non-vegetarians. Since vegetables do not represent the primary source of creatine, vegetarians can be expected to show lower levels of directly derived muscle creatine. However, the subjects happened to show the same levels after using supplements.^[6] Given the fact that creatine can be synthesized from the above mentioned amino acids, protein sources rich in these amino acids can be expected to provide adequate capability of native biosynthesis in the human body.^[5]

The enzyme GATM (L-arginine:glycine amidinotransferase (AGAT), EC 2.1.4.1) is a mitochondrial enzyme responsible for catalyzing the first rate-limiting step of creatine biosynthesis, and is primarily expressed in the kidneys and pancreas.^[7]

The second enzyme in the pathway (GAMT, guanidinoacetate N-methyltransferase, EC:2.1.1.2) is primarily expressed in the liver and pancreas.^[7]

Genetic deficiencies in the creatine biosynthetic pathway lead to various severe neurological defects.^[8]

The pathway for the synthesis of creatine
Arg - Arginine; GATM - Glycine amidinotransferase; GAMT - Guanidinoacetate N-methyltransferase; Gly - Glycine; Met - Methionine; SAH - S-adenosyl homocysteine; SAM - S-adenosyl methionine.

The color scheme is as follows:enzymes, coenzymes and the Met part, substrate names, the Gly part, the Arg part

The phosphocreatine system

Creatine, synthesized in the liver and kidney, 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.^[9] Fortunately, 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 with the enzyme creatine kinase (CK). 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.^[9] 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.^[10] For a review of the creatine kinase system and the pleiotropic actions of creatine and creatine supplementation see ^[11].

Health effects

Use as food supplement

Main article: Creatine supplements

Creatine supplements are sometimes used by athletes, bodybuilders, wrestlers, sprinters and others who wish to gain muscle mass, typically consuming 2 to 3 times the amount that could be obtained from a very-high-protein diet. A survey of long-term use gives the creatine content of several foods.^[12] The Mayo Clinic states that creatine has been associated with asthmatic symptoms and warns against consumption by persons with known allergies.^[13]

While there was once some concern that creatine supplementation could affect hydration status and heat tolerance and lead to muscle cramping and diarrhea, recent studies have shown these concerns to be unfounded.^[14][15]

There are reports of kidney damage with creatine use, such as interstitial nephritis; patients with kidney disease should avoid use of this supplement.^[13] In similar manner, liver function may be altered, and caution is advised in those with underlying liver disease although studies have shown little or no adverse impact on kidney or liver function from oral creatine supplementation.^[16] In 2004 the European Food Safety Authority (EFSA) published a record which stated that oral long-term intake of 3g pure creatine per day is risk-free.^[17] The reports of damage to the kidneys by creatine supplementation have been scientifically refuted.^[18][19][20]

Long-term administration of large quantities of creatine is reported to increase the production of formaldehyde, which has the potential to cause serious unwanted side-effects. However, this risk is largely theoretical because urinary excretion of formaldehyde, even under heavy creatine supplementation, does not exceed normal limits.^[21]

Extensive research over the last decade has shown that oral creatine supplementation at a rate of 5 to 20 grams per day appears to be very safe and largely devoid of adverse side-effects,^[22] while at the same time effectively improving the physiological response to resistance exercise, increasing the maximal force production of muscles in both men and women.^[23][24]

Pharmacokinetics

Endogenous serum or plasma creatine concentrations in healthy adults are normally in a range of 2–12 mg/L. A single 5 g (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. After the "loading dose" period (1–2 weeks, 12-24 g a day), it is no longer necessary to maintain a consistently high serum level of creatine. As with most supplements, each person has their own genetic "preset" amount of creatine they can hold. The rest is eliminated out of the body as waste. Creatine is consumed by the body fairly quickly, and if one wishes to maintain the high concentration of creatine, Post-loading dose, 2-5 g daily is the standard amount to intake.^[25][26][27]

Pregnancy and breastfeeding

Creatine cannot be recommended during pregnancy or breastfeeding due to a lack of scientific information. Pasteurized cow's milk contains higher levels of creatine than human milk.^[28][29]

Treatment of diseases

Creatine has been demonstrated to cause modest increases in strength in people with a variety of neuromuscular disorders.^[30] Creatine supplementation has been, and continues to be, investigated as a possible therapeutic approach for the treatment of muscular, neuromuscular, neurological and neurodegenerative diseases (arthritis, congestive heart failure, Parkinson's disease, disuse atrophy, gyrate atrophy, McArdle's disease, Huntington's disease, miscellaneous neuromuscular diseases, mitochondrial diseases, muscular dystrophy, and neuroprotection).^{[citation needed]}

A study demonstrated that creatine is twice as effective as the prescription drug riluzole in extending the lives of mice with the degenerative neural disease amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease). The neuroprotective effects of creatine in the mouse model of ALS may be due either to an increased availability of energy to injured nerve cells or to a blocking of the chemical pathway that leads to cell death.^[31] A similarly promising result has been obtained in prolonging the life of transgenic mice affected by Huntington's disease. Creatine treatment lessened brain atrophy and the formation of intranuclear inclusions, attenuated reductions in striatal N-acetylaspartate, and delayed the development of hyperglycemia.^[32]

Cognitive ability

A placebo-controlled double-blind experiment found that a group of subjects composed of vegetarians and vegans who took 5 grams of creatine per day for six weeks showed a significant improvement on two separate tests of fluid intelligence, Raven's Progressive Matrices, and the backward digit span test from the WAIS. The treatment group was able to repeat longer sequences of numbers from memory and had higher overall IQ scores than the control group. The researchers concluded that "supplementation with creatine significantly increased intelligence compared with placebo."^[33] A subsequent study found that creatine supplements improved cognitive ability in the elderly.^[34] A study on young adults (0.03 g/kg/day for six weeks, e.g., 2 g/day for a 70-kilogram (150 lb) individual) failed to find any improvements.^[35]

See also

• Adenosine triphosphate
• Beta-alanine
• Creatine phosphate

References

1. ^ www.sciencelab.com/msds.php?msdsId=9923566
2. ^ http://chemyq.com/en/xz/xz1/9019vbolx.htm
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7. ^ ^{a b} ETH ETH E-Collection: Methylglyoxal, creatine and mitochondrial micro-compartments - ETH E-Collection. E-collection.ethbib.ethz.ch. 2008-04-19. doi:10.3929/ethz-a-004636659.. http://e-collection.ethbib.ethz.ch/ecol-pool/diss/fulltext/eth15180.pdf. Retrieved 2010-08-16. 
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External links

• NCBI Online Mendelian Inheritance In MAN (OMIM) GATM human mutation record
• Creatine Supplementation, Beth Lulinski, Quackwatch
• Creatine 'boosts brain power', BBC News, 12 August 2003
• Creatine: From Muscle to Brain, Peter W. Schutz, The Science Creative Quarterly, 2009
• Creatine Supplementation A primer for athletes
• Creatine during Pregnancy and Protection of Babies against Anoxia A mouse study
• "The creatine kinase system and pleiotropic effects of creatine" in: Amino Acids. 2011 May;40(5):1271-96 A recent Review from May 2011