Which Amino Acids Make Creatine? A Guide to Natural Synthesis

December 17, 2025 •

4 min read

Approximately half of the body's creatine is produced internally from amino acids, while the other half comes from diet. To understand how the body manufactures this vital compound, it's essential to know which amino acids make creatine and the specific roles they play in this crucial biological pathway.

Quick Summary

The body synthesizes creatine from the amino acids arginine, glycine, and methionine, primarily within the kidneys and liver, to create an essential energy-buffering compound.

Key Points

Core Ingredients: Creatine is synthesized from three specific amino acids: arginine, glycine, and methionine.
Two-Part Process: The synthesis is a two-step process involving the kidneys and liver, with the pancreas also playing a minor role.
Methyl Group Donor: Methionine is the precursor for S-adenosylmethionine (SAM), which donates the crucial methyl group in the final synthesis step.
Dietary vs. Endogenous: The body produces some creatine, but dietary sources, primarily meat and fish, provide a significant portion for omnivores.
Energy Buffer: The final creatine molecule is stored in high-energy tissues, predominantly skeletal muscle, and is converted into phosphocreatine for rapid energy regeneration.
Supports High-Demand Tissues: Organs with high energy needs, including the brain and skeletal muscle, are the primary storage sites for creatine.

The Three Key Amino Acids for Creatine Synthesis

Creatine is an amino acid derivative, not a standard protein-building amino acid itself. Instead, it is synthesized from three precursor amino acids in a two-step enzymatic process. Understanding each component's role is key to grasping the overall synthesis pathway.

Arginine

Arginine is a conditionally essential amino acid and plays a pivotal role in the first step of creatine synthesis. Its amidino group, which is a key part of its structure, is transferred to glycine to begin the formation of the creatine molecule. This initial reaction is carried out by the enzyme L-arginine:glycine amidinotransferase (AGAT).

Glycine

Glycine is the simplest of all amino acids and acts as the receiver molecule in the first synthetic step. It accepts the amidino group from arginine, creating an intermediate compound called guanidinoacetic acid (GAA). Glycine is readily synthesized by the body, so its metabolism typically isn't heavily burdened by this process.

Methionine

Methionine's contribution is critical but indirect. It is a precursor to a high-energy molecule called S-adenosylmethionine (SAM). In the second and final step of creatine synthesis, SAM acts as the methyl group donor, attaching a methyl group to the newly formed GAA molecule. This methylation reaction is what completes the formation of creatine from GAA. The process places an appreciable burden on methionine and the body's methyl group metabolism.

The Two-Step Biosynthesis Process

The production of creatine in the body is a prime example of inter-organ metabolism, where different organs work together to complete a single biosynthetic pathway.

Step 1: In the Kidneys

The first reaction of creatine synthesis takes place primarily in the kidneys. The enzyme AGAT catalyzes the transfer of an amidino group from arginine to glycine, forming guanidinoacetic acid (GAA) and ornithine. This newly synthesized GAA is then released into the bloodstream to be transported to the next location.

Step 2: In the Liver

The GAA from the kidneys travels to the liver. Here, another enzyme, guanidinoacetate N-methyltransferase (GAMT), catalyzes the final reaction. Using S-adenosylmethionine (SAM) derived from methionine as a methyl donor, GAMT converts GAA into creatine. Once synthesized, creatine is released into the bloodstream for storage in target tissues with high energy demands.

Comparison of Creatine Sources

The body can obtain creatine from two primary sources: endogenous synthesis and dietary intake. The balance between these sources can vary significantly based on an individual's diet.


Feature	Endogenous Synthesis	Dietary Intake
Primary Location	Produced in kidneys, liver, pancreas.	Consumed via food (meat, fish) or supplements.
Amino Acids Used	Arginine, glycine, methionine.	None directly (consumed as creatine).
Daily Production	Approximately 1 gram per day.	Varies greatly based on diet; significant for omnivores.
Methyl Group Burden	Places significant demand on methionine metabolism.	Does not require methionine as a methyl donor.
Impact on Vegans/Vegetarians	Must produce all creatine internally; lower muscle levels common.	Very low or non-existent; often requires supplementation.

Storage and Function of Creatine

Once synthesized or consumed, creatine is taken up by tissues with high energy demands, with approximately 95% being stored in skeletal muscles. The remainder is found in the brain, heart, and testes.

Within these cells, creatine is phosphorylated by the enzyme creatine kinase to form phosphocreatine (PCr). The PCr system acts as a rapid energy buffer. During short, intense bursts of activity, like weightlifting or sprinting, ATP is rapidly broken down to ADP. The PCr then donates its phosphate group to ADP, converting it back to ATP to fuel muscle contraction. This process is crucial for performance in power-based sports.

Conclusion: The Integrated Pathway of Creatine

Creatine's synthesis is a fascinating and crucial biochemical process that highlights the interconnectedness of amino acid metabolism. Beginning with arginine, glycine, and methionine, the body orchestrates a complex, multi-organ pathway to create a vital compound for energy storage and rapid ATP regeneration. While natural production provides a baseline supply, both dietary intake and supplementation can significantly influence the body's creatine stores, especially in athletes or those with specific dietary restrictions. For a deeper dive into the metabolic basis of creatine, its synthesis, and its broader role in health and disease, you can refer to this authoritative publication: Metabolic Basis of Creatine in Health and Disease.

Key Stages of Creatine Synthesis

Initial Combination: The amidino group from arginine is combined with glycine in the kidneys.
GAA Formation: This first step produces the intermediate compound guanidinoacetic acid (GAA).
Methylation Step: GAA is transported to the liver, where it is methylated using a methyl group from S-adenosylmethionine (SAM).
Final Product: The methylation process yields the final creatine molecule.
Energy Buffer Function: The synthesized creatine is stored mainly in muscles and phosphorylated to phosphocreatine to replenish ATP during high-intensity exercise.

Frequently Asked Questions

The three amino acids required for the endogenous synthesis of creatine are arginine, glycine, and methionine.

Methionine is converted into S-adenosylmethionine (SAM), which acts as the essential methyl group donor needed for the final methylation step of creatine synthesis in the liver.

The kidneys and the liver are the primary organs involved in producing creatine, although the pancreas also contributes.

Creatine is naturally found primarily in animal products like meat and fish. Vegans and vegetarians have little to no dietary intake of creatine and may have lower muscle creatine levels, often benefiting from supplementation.

Yes, genetic defects in the enzymes (AGAT and GAMT) or the transporter (SLC6A8) responsible for creatine metabolism can lead to rare but serious cerebral creatine deficiency syndromes.

Guanidinoacetic acid (GAA) is an intermediate compound formed from arginine and glycine during the first enzymatic step of creatine synthesis.

Creatine is not a protein-building amino acid itself but an amino acid derivative. It is synthesized from other amino acids and functions as an energy buffer, not as a building block for proteins.