Guanidinoacetic acid deficiency: a new entity in clinical medicine?

Ostojić, Sergej M.; Rátgéber, László; Oláh, A.; Betlehem, József; Ács, Pongrác

doi:10.7150/ijms.47757

Cited by 14 publications

(11 citation statements)

References 46 publications

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“…However, several pathological conditions can affect GAA production-utilization circle, including kidney dysfunction, neurological diseases, or inherited metabolic disorders (for a detailed review, see Ref. [ 11 ]). Besides serving as an immediate precursor of creatine, GAA can also have several non-creatine-related metabolic roles, including the stimulation of hormonal release and neuromodulation, alteration of metabolic utilization of amino acids, vasodilation, and oxidant–antioxidant tuning (for a detailed review, see Ref.…”

Section: Gaa Physiology Biomolecular Interactions and Pathwaysmentioning

confidence: 99%

Safety of Dietary Guanidinoacetic Acid: A Villain of a Good Guy?

Ostojić

2021

Nutrients

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Guanidinoacetic acid (GAA) is a natural amino acid derivative that is well-recognized for its central role in the biosynthesis of creatine, an essential compound involved in cellular energy metabolism. GAA (also known as glycocyamine or betacyamine) has been investigated as an energy-boosting dietary supplement in humans for more than 70 years. GAA is suggested to effectively increase low levels of tissue creatine and improve clinical features of cardiometabolic and neurological diseases, with GAA often outcompeting traditional bioenergetics agents in maintaining ATP status during stress. This perhaps happens due to a favorable delivery of GAA through specific membrane transporters (such as SLC6A6 and SLC6A13), previously dismissed as un-targetable carriers by other therapeutics, including creatine. The promising effects of dietary GAA might be countered by side-effects and possible toxicity. Animal studies reported neurotoxic and pro-oxidant effects of GAA accumulation, with exogenous GAA also appearing to increase methylation demand and circulating homocysteine, implying a possible metabolic burden of GAA intervention. This mini-review summarizes GAA toxicity evidence in human nutrition and outlines functional GAA safety through benefit-risk assessment and multi-criteria decision analysis.

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Section: Gaa Physiology Biomolecular Interactions and Pathwaysmentioning

confidence: 99%

Safety of Dietary Guanidinoacetic Acid: A Villain of a Good Guy?

Ostojić

2021

Nutrients

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“…The elevation of 2-ketobutyric acid and L-methionine after SCI may suggest that the antioxidant system and energy supply system of the injured microenvironment are impaired and have toxic effects on neurons. Guanidoacetic acid, synthesized de novo from glycine and arginine, is the natural precursor of creatine in vertebrates ( Ostojic et al, 2020 ). Normally, creatine can form phosphocreatine under the action of creatine kinase and then participate in the production of adenosine triphosphate (ATP) for energy supply ( Kazak and Cohen, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Integrated transcriptomic and metabolomic profiling reveals dysregulation of purine metabolism during the acute phase of spinal cord injury in rats

Zeng

Jiang

et al. 2022

Front. Neurosci.

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IntroductionSpinal cord injury (SCI) results in drastic dysregulation of microenvironmental metabolism during the acute phase, which greatly affects neural recovery. A better insight into the potential molecular pathways of metabolic dysregulation by multi-omics analysis could help to reveal targets that promote nerve repair and regeneration in the future.Materials and methodsWe established the SCI model and rats were randomly divided into two groups: the acute-phase SCI (ASCI) group (n = 14, 3 days post-SCI) and the sham group with day-matched periods (n = 14, without SCI). In each group, rats were sacrificed at 3 days post-surgery for histology study (n = 3), metabolome sequencing (n = 5), transcriptome sequencing (n = 3), and quantitative real-time polymerase chain reaction (n = 3). The motor function of rats was evaluated by double-blind Basso, Beattie, and Bresnahan (BBB) Locomotor Scores at 0, 1, 2, 3 days post-SCI in an open field area. Then the transcriptomic and metabolomic data were integrated in SCI model of rat to reveal the underlying molecular pathways of microenvironmental metabolic dysregulation.ResultsThe histology of the microenvironment was significantly altered in ASCI and the locomotor function was significantly reduced in rats. Metabolomics analysis showed that 360 metabolites were highly altered during the acute phase of SCI, of which 310 were up-regulated and 50 were down-regulated, and bioinformatics analysis revealed that these differential metabolites were mainly enriched in arginine and proline metabolism, D-glutamine and D-glutamate metabolism, purine metabolism, biosynthesis of unsaturated fatty acids. Transcriptomics results showed that 5,963 genes were clearly altered, of which 2,848 genes were up-regulated and 3,115 genes were down-regulated, and these differentially expressed genes were mainly involved in response to stimulus, metabolic process, immune system process. Surprisingly, the Integrative analysis revealed significant dysregulation of purine metabolism at both transcriptome and metabolome levels in the acute phase of SCI, with 48 differential genes and 16 differential metabolites involved. Further analysis indicated that dysregulation of purine metabolism could seriously affect the energy metabolism of the injured microenvironment and increase oxidative stress as well as other responses detrimental to nerve repair and regeneration.DiscussionOn the whole, we have for the first time combined transcriptomics and metabolomics to systematically analyze the potential molecular pathways of metabolic dysregulation in the acute phase of SCI, which will contribute to broaden our understanding of the sophisticated molecular mechanisms of SCI, in parallel with serving as a foundation for future studies of neural repair and regeneration after SCI.

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“…The reference serum and urinary GAA levels are 2.3 μmol/L (mixed), 31.2 mmol/mol creatinine (male), and 53.1 (female) mmol/mol creatinine in healthy humans aged over 15 years, respectively (Joncquel‐Chevalier Curt et al, 2013 ), with GAA also detected in human milk, saliva, and cerebrospinal liquor. GAA synthesis and utilization could be compromised in various pathological conditions, with creatine deficiency syndromes being most featured (for a detailed review, see Ostojic, Ratgeber, et al, 2020 ).…”

Section: Gaa Metabolismmentioning

confidence: 99%

Guanidinoacetic acid in human nutrition: Beyond creatine synthesis

Ostojić

Jorga²

2023

Food Science & Nutrition

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Guanidinoacetic acid (GAA) is a nutrient that has been used in human nutrition since the early 1950s. Recommended for its role in creatine biosynthesis, GAA demonstrated beneficial energy‐boosting effects in various clinical conditions. Dietary GAA has also been suggested to trigger several creatine‐independent mechanisms. Besides acting as a direct precursor of high‐energy phosphagen creatine, dietary GAA is suggested to reduce blood glucose concentration by acting as an insulinotropic food compound, spare amino acid arginine for other metabolic purposes (including protein synthesis), modulate taste, and perhaps alter methylation and fat deposition in various organs including the liver. GAA as a food component can have several important metabolic roles beyond creatine biosynthesis; future studies are highly warranted to address GAA overall role in human nutrition.

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Guanidinoacetic acid deficiency: a new entity in clinical medicine?

Cited by 14 publications

References 46 publications

Safety of Dietary Guanidinoacetic Acid: A Villain of a Good Guy?

Safety of Dietary Guanidinoacetic Acid: A Villain of a Good Guy?

Integrated transcriptomic and metabolomic profiling reveals dysregulation of purine metabolism during the acute phase of spinal cord injury in rats

Guanidinoacetic acid in human nutrition: Beyond creatine synthesis

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