How does the body make creatine according to Brosnan 2007?

Brosnan et al. (2007) described creatine synthesis as a two-organ process. The kidneys produce guanidinoacetate (GAA) from arginine and glycine using the enzyme AGAT. GAA is then transported to the liver where the enzyme GAMT methylates it to form creatine, which is released into the bloodstream.

How much creatine does the body produce daily?

The body synthesizes approximately 1-2 g of creatine per day endogenously. This accounts for roughly half of the daily creatine requirement, with the other half ideally coming from dietary sources such as meat and fish. Vegetarians rely entirely on endogenous synthesis.

Why does creatine synthesis matter for supplementation?

Understanding endogenous synthesis explains why vegetarians have lower creatine stores and benefit most from supplementation. It also clarifies that supplementation reduces the metabolic burden of creatine synthesis, sparing methyl groups and amino acids for other biochemical processes.

Brosnan et al. 2007: The Inter-Organ Metabolism and Synthesis of Creatine

TL;DR — Brosnan et al. 2007

Brosnan and Brosnan published a comprehensive review on the inter-organ metabolism of creatine, detailing how the body synthesizes this critical molecule through a coordinated process involving the kidneys, liver, and pancreas. The paper quantified the metabolic cost of creatine synthesis, showing that it consumes approximately 40% of all S-adenosylmethionine (SAM) methyl groups. This finding highlighted the significant metabolic burden of endogenous creatine production and provided a biochemical rationale for dietary creatine intake and supplementation.

~40%

of all SAM methyl groups are consumed by creatine synthesis

Brosnan & Brosnan, 2007

Background

Creatine is not merely a supplement — it is an essential metabolite that the body produces endogenously. Understanding how the body makes creatine provides critical context for why supplementation is beneficial, particularly for populations with low dietary creatine intake.

The creatine kinase system, reviewed comprehensively by Wallimann et al. (2011), is central to cellular energy homeostasis (T et al., 2011) . However, the upstream synthesis pathway received comparatively less attention in the sports nutrition literature despite its importance.

The Two-Step Synthesis Pathway

Step 1: Kidneys produce GAA

The first step occurs primarily in the kidneys, where the enzyme AGAT (arginine:glycine amidinotransferase) catalyzes the transfer of an amidino group from arginine to glycine, producing guanidinoacetate (GAA) and ornithine.

Step 2: Liver methylates GAA to creatine

GAA is released into the bloodstream and taken up by the liver, where GAMT (guanidinoacetate N-methyltransferase) transfers a methyl group from S-adenosylmethionine (SAM) to GAA, producing creatine.

The newly formed creatine is then released into the blood and taken up primarily by skeletal muscle and the brain via the creatine transporter (SLC6A8).

1-2 g

creatine produced endogenously per day by the human body

Brosnan & Brosnan, 2007

Key Insights

1. Creatine synthesis is metabolically expensive

The methylation step consumes approximately 40% of all SAM-derived methyl groups in the body. This is a remarkable metabolic investment, larger than any other single methylation reaction. It means creatine synthesis competes with other critical methylation processes including DNA methylation and neurotransmitter synthesis.

2. Dietary creatine reduces the synthetic burden

When creatine is obtained from diet (meat, fish) or supplements, endogenous synthesis downregulates. This spares methyl groups, arginine, and glycine for other metabolic needs. This provides a biochemical rationale for supplementation beyond simply increasing muscle creatine stores.

3. Vegetarians bear the full synthetic cost

Without dietary creatine, vegetarians must synthesize their entire daily requirement endogenously. This explains the lower creatine stores consistently observed in vegetarians and their robust response to supplementation, as demonstrated by Harris et al. (1992) (RC et al., 1992) .

Practical Implications

Creatine is semi-essential: While the body can make it, dietary intake significantly reduces the metabolic burden of synthesis
Vegetarians especially benefit: Supplementation offsets the increased demand on methylation pathways in those without dietary creatine
Methyl group sparing: Creatine supplementation may indirectly benefit other methylation-dependent processes
The standard 3-5 g/day dose is rational: This approximates the combined endogenous and dietary creatine turnover rate (RB et al., 2017)

Malaysian Relevance

Malaysia has a diverse dietary landscape including significant vegetarian populations within the Indian-Malaysian and Buddhist communities. Understanding that vegetarians bear a higher metabolic cost for creatine synthesis reinforces the value of supplementation for these groups. The biochemistry also explains why meat-eating Malaysians may have adequate baseline creatine but can still benefit from supplementation for athletic and cognitive performance.

Full Citation

Brosnan JT, Brosnan ME. Creatine: endogenous metabolite, dietary, and therapeutic supplement. Annual Review of Nutrition. 2007;27:241-261. doi:10.1146/annurev.nutr.27.061406.093621

Study Design and Methodology

Understanding how a study was designed helps assess the strength of its conclusions. Key methodological factors to evaluate include:

Sample size — larger studies (n=50+) provide more reliable results than small studies (n=10-15). Small sample sizes increase the risk of false positives and limit the ability to detect moderate effect sizes
Study duration — creatine research requires adequate duration for muscle saturation (minimum 4 weeks for maintenance dosing, 1 week for loading). Studies shorter than this may miss the full effect
Blinding — double-blind, placebo-controlled designs (where neither researchers nor participants know who receives creatine) are the gold standard for minimising bias
Population studied — results from trained athletes may not fully apply to untrained individuals, and vice versa. Age, sex, and dietary habits (particularly vegetarian status) also influence creatine response
Outcome measures — direct measures (muscle biopsy, MRS imaging) are more informative than indirect proxies (blood markers, performance tests) for assessing creatine uptake and metabolism

Clinical Implications and Practical Relevance

This research contributes to our understanding of creatine in several practical ways:

For athletes and fitness enthusiasts: The findings support the use of creatine monohydrate as a safe, effective ergogenic aid. The standard dosing protocol of 3-5g daily remains well-supported by the cumulative evidence base including this study.

For healthcare professionals: Understanding the specific mechanisms and safety data from studies like this helps clinicians provide evidence-based guidance to patients who ask about creatine supplementation. The research consistently shows a favourable safety profile at recommended doses.

For the Malaysian context: While most creatine research is conducted in Western populations, the fundamental biochemistry (ATP-phosphocreatine system) is universal. Malaysian consumers can apply these findings with confidence, adjusting for local factors like tropical climate (increased hydration needs) and halal dietary requirements (synthetic creatine monohydrate is permissible).

How This Fits Into the Broader Evidence

No single study should be used to make definitive claims about creatine supplementation. Instead, this research should be viewed as one piece of a much larger evidence base:

The ISSN Position Stand (2017) synthesises hundreds of studies into comprehensive recommendations
Multiple systematic reviews and meta-analyses confirm creatine’s effects on strength, power, and lean mass
Long-term safety data spanning up to 5 years shows no adverse effects at recommended doses

For a complete overview of the evidence, explore our Research Library which covers 60+ landmark creatine studies.

Sources & References

This article is based on the review by Brosnan and Brosnan published in Annual Review of Nutrition (2007) and contextualized with Wallimann et al. (2011), Harris et al. (1992), and Kreider et al. (2017). All citations reference PubMed-indexed publications.