How Your Body Makes Creatine: Endogenous Synthesis from Arginine, Glycine, and Methionine

The Two-Step Pathway

Creatine synthesis occurs in two enzymatic steps, split across two organs. The first reaction takes place primarily in the kidney. The second takes place in the liver. The intermediate product, guanidinoacetate (GAA), travels through the bloodstream between these two sites. This inter-organ relay is one of the more distinctive features of creatine biochemistry.

Walker (1979) provided one of the foundational descriptions of this pathway in his review for Advances in Enzymology, characterizing the enzymology and regulation that subsequent decades of research have refined. Brosnan and Brosnan (2007) published a comprehensive update in the Annual Review of Nutrition that remains the definitive modern review of endogenous creatine synthesis.

Step One: AGAT in the Kidney

The first enzyme is arginine-glycine amidinotransferase, abbreviated AGAT (also known as GATM, the gene name). AGAT catalyzes the transfer of an amidino group from arginine to glycine, producing guanidinoacetate (GAA) and ornithine as a byproduct. This reaction occurs primarily in the renal tubular cells of the kidney, though AGAT expression has also been detected in the pancreas and brain at lower levels.

The substrates are two amino acids: arginine and glycine. Both are conditionally essential, meaning the body can synthesize them but may not produce sufficient quantities under all conditions. Glycine, in particular, has been identified as a potentially limiting substrate for creatine synthesis in some dietary contexts, a point that becomes relevant when discussing vegetarian populations.

AGAT is the rate-limiting step of creatine synthesis. Its activity is subject to feedback inhibition by creatine itself. When intracellular creatine levels are high, whether from dietary intake or supplementation, AGAT activity is downregulated. This feedback mechanism means that exogenous creatine intake reduces, but does not eliminate, endogenous production. The downregulation is reversible: when supplementation ceases, AGAT activity returns to baseline over days to weeks.

The regulatory sensitivity of AGAT has clinical implications. Patients with chronic kidney disease have reduced AGAT capacity, which may contribute to the lower creatine stores observed in this population. This is separate from the kidney's role in creatinine excretion and represents a synthetic rather than excretory impairment.

Step Two: GAMT in the Liver

Guanidinoacetate produced in the kidney enters the bloodstream and is taken up by the liver. There, the enzyme guanidinoacetate N-methyltransferase (GAMT) catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to GAA, producing creatine and S-adenosylhomocysteine (SAH).

This reaction has broad metabolic significance because SAM is the body's primary methyl donor. The GAMT reaction consumes a substantial fraction of total SAM-derived methyl groups. Brosnan and Brosnan (2007) estimated that creatine synthesis accounts for approximately 40% of all SAM-dependent methylation reactions in the body. This makes creatine synthesis the single largest consumer of methyl groups, exceeding the demands of DNA methylation, phosphatidylcholine synthesis, and all other methyltransferase reactions combined.

The methyl donor for SAM is methionine, an essential amino acid obtained exclusively from the diet. Methionine is converted to SAM by methionine adenosyltransferase. After donating its methyl group in the GAMT reaction, SAH is hydrolyzed to homocysteine, which can be remethylated back to methionine (using folate and vitamin B12) or directed into the transsulfuration pathway. This places creatine synthesis at a metabolic crossroads involving methionine, folate, B12, and homocysteine metabolism.

The implication is that creatine supplementation, by reducing endogenous synthesis through AGAT feedback inhibition, spares SAM and methyl groups for other reactions. This methyl-sparing effect has been proposed as a secondary benefit of creatine supplementation, particularly in populations with marginal methionine, folate, or B12 status. Stead and colleagues (2006) provided quantitative evidence for this effect, showing that creatine supplementation reduced plasma homocysteine concentrations, consistent with reduced demand on the methionine-homocysteine cycle.

Synthesis Rate: Approximately 1 Gram Per Day

The human body synthesizes approximately 1 gram of creatine per day through the AGAT-GAMT pathway. This figure, widely cited in the literature, was established through metabolic balance studies and isotope tracer experiments. It represents the production rate needed to replace daily creatine losses.

Creatine is degraded non-enzymatically into creatinine at a rate of approximately 1.7% of the total creatine pool per day. For an individual with a total body creatine pool of approximately 120 grams (the estimated total for a 70 kg male), this translates to roughly 2 grams of creatinine produced daily. Of this, about half is replaced by endogenous synthesis and the remainder by dietary creatine intake in omnivores.

The synthesis rate is not fixed. It adjusts in response to dietary creatine intake through the AGAT feedback mechanism. In individuals consuming no dietary creatine (vegans), endogenous synthesis increases to partially compensate, but may not fully replace what an omnivorous diet provides. In individuals consuming high amounts of meat and fish, endogenous synthesis decreases. This regulatory flexibility means that total body creatine status is determined by the sum of dietary intake and endogenous production, with the two sources existing in a dynamic balance.

Dietary Creatine: Sources and Quantities

Creatine is found naturally in animal tissues, with the highest concentrations in skeletal muscle. Red meat (beef, pork, lamb) and fish are the richest dietary sources, containing approximately 3-5 grams of creatine per kilogram of raw tissue. Cooking reduces creatine content by 15-30%, depending on temperature and duration, because heat converts creatine to creatinine.

A typical omnivorous diet provides approximately 1-2 grams of creatine per day, depending on the quantity and type of animal products consumed. Combined with endogenous synthesis of approximately 1 gram per day, total daily creatine availability for an omnivore is roughly 2-3 grams. Since daily creatine turnover (degradation to creatinine) is approximately 2 grams, this maintains a stable total body pool.

Dairy products and eggs contain very small amounts of creatine. Plant foods contain essentially none. This creates a meaningful difference in creatine status between dietary patterns, which has been quantified in several studies.

Vegetarian and Vegan Creatine Status

Burke and colleagues (2003) compared muscle creatine concentrations between vegetarians and omnivores. Vegetarians had significantly lower intramuscular creatine and phosphocreatine stores. The difference was approximately 20-30% lower total creatine in vegetarians compared to omnivores matched for age, sex, and physical activity level.

This lower baseline is explained by the absence of dietary creatine. Although AGAT upregulates in response to the lack of dietary input, the increased endogenous synthesis does not fully compensate. The body's synthetic capacity has limits set by enzyme expression levels, substrate availability (arginine, glycine, methionine), and the metabolic cost of methylation.

The practical consequence is that vegetarians and vegans tend to show larger absolute and relative responses to creatine supplementation. When supplementation begins, the depleted creatine pool has more room to fill. Benton and Donohoe (2011) found that vegetarians who supplemented with creatine showed greater improvements in cognitive tasks than omnivore supplementers, consistent with a larger relative increase in brain creatine from a lower baseline.

This does not mean that vegetarians are creatine-deficient in a clinical sense. They function normally with lower creatine stores. But they operate further from the theoretical maximum, and supplementation moves them closer to the levels that omnivores maintain through diet alone.

The Creatine Transporter: Getting It Into Cells

Once creatine is synthesized in the liver (or absorbed from the diet through the intestine), it must enter target cells. This requires an active transport process because creatine is a charged molecule that cannot freely cross cell membranes. The sodium- and chloride-dependent creatine transporter, encoded by the SLC6A8 gene, is responsible for this uptake.

SLC6A8 is expressed in skeletal muscle, heart, brain, kidney, and testes, among other tissues. The transporter moves creatine against its concentration gradient using the electrochemical energy of the sodium gradient maintained by the Na+/K+-ATPase. Insulin and insulin-like growth factor 1 (IGF-1) enhance creatine transporter activity, which is why some early supplementation protocols recommended combining creatine with carbohydrate-rich meals to spike insulin.

Genetic deficiency of SLC6A8 causes cerebral creatine deficiency syndrome, a severe condition characterized by intellectual disability, seizures, and speech delay. This rare inborn error of metabolism demonstrates the critical importance of creatine transport to brain function. It also confirms that endogenous brain synthesis alone, which does occur via local AGAT and GAMT expression, is insufficient to meet cerebral creatine demands.

Regulation and Feedback

The creatine synthesis pathway is primarily regulated at the level of AGAT. Creatine itself acts as a feedback inhibitor, reducing AGAT transcription when intracellular creatine concentrations are elevated. This mechanism ensures that endogenous production adjusts to dietary intake, maintaining homeostasis without wasteful overproduction.

The feedback is not instantaneous. When creatine supplementation begins, AGAT downregulation takes several days to weeks to reach a new steady state. When supplementation stops, the restoration of full AGAT activity similarly requires time. This lag explains why muscle creatine stores decline gradually over 4-6 weeks after cessation of supplementation rather than dropping immediately.

GAMT does not appear to be subject to the same degree of product inhibition. Its activity is more consistently determined by substrate availability, particularly GAA concentrations arriving from the kidney. The liver's role is primarily to methylate whatever GAA is delivered to it, making the kidney's AGAT reaction the true gatekeeper of synthesis rate.

Metabolic Cost of Creatine Synthesis

The endogenous production of 1 gram of creatine per day requires approximately 1 gram each of arginine, glycine, and methionine (as the methyl donor via SAM). This amino acid cost is non-trivial. Brosnan and Brosnan estimated that creatine synthesis places a meaningful demand on the body's amino acid economy, particularly for glycine and methionine.

Glycine is used in numerous biosynthetic reactions including glutathione production, heme synthesis, nucleotide synthesis, and collagen formation. De Koning and colleagues (2003) argued that glycine availability may be conditionally limiting in some populations, particularly during growth, pregnancy, and in individuals with low protein intake. If creatine synthesis competes with these other glycine-dependent processes, exogenous creatine supplementation could free glycine for alternative uses.

Methionine demand for creatine synthesis feeds into the broader one-carbon metabolism network. Inadequate folate or B12 status impairs the remethylation of homocysteine to methionine, potentially creating a bottleneck that affects creatine synthesis alongside other methylation-dependent processes. This interconnection is one reason why researchers have proposed creatine supplementation as a component of nutritional strategies targeting homocysteine management.

Clinical Relevance

Understanding endogenous synthesis matters beyond academic biochemistry. Patients with chronic kidney disease may have impaired AGAT function, contributing to muscle wasting and fatigue. Individuals on vegan diets have lower creatine stores and may benefit disproportionately from supplementation. People with inborn errors of creatine metabolism (AGAT deficiency, GAMT deficiency, SLC6A8 deficiency) present with severe neurological symptoms that respond variably to creatine supplementation depending on which step is affected.

For healthy individuals, the synthesis pathway operates quietly and efficiently. The body makes what it needs, adjusts to what you eat, and maintains a stable pool. Supplementation overrides the regulatory system temporarily, saturating stores beyond what diet and synthesis alone achieve. When supplementation stops, the system returns to its baseline set point. The pathway's built-in flexibility is what makes creatine supplementation both effective and reversible.