Author Background: Alikhan Serikuly grew up in Kazakhstan and currently attends Haileybury Almaty in Almaty, Kazakhstan. His Pioneer research concentration was in the field of chemistry and was titled “Chemistry of Foods”.

1. Introduction

The synthesis of creatine takes place naturally in organs such as the liver, kidney, and pancreas, and creatine’s primary storage location is within skeletal muscle. It can be obtained through the consumption of animal-based foods or synthesized naturally within the human body. It plays a vital role in the energy metabolism of most vertebrates by capturing and storing high-energy phosphate groups and donating them to adenosine diphosphate (ADP) to restore depleted adenosine triphosphate (ATP) levels. This reversible process is facilitated by creatine kinase (CK). Following their initial introduction to the general public in the 1990s, creatine supplements have gained significant popularity and are predominantly utilized by athletes as an ergogenic aid (Close et al., 2o16). However, whole-body creatine deficiency most strongly affects the nervous system, with the potential to cause cognitive dysfunction, seizures, and behavioral impairments (Mercimek-Andrews & Salomons, 2009). Emerging research has provided evidence of additional positive effects of creatine supplementation on the health of non-athletes, thereby suggesting its potential use for the general public. The purpose of this research paper is to provide an in-depth exploration of the biochemical properties of creatine and its potential as a dietary supplement for the general public. This paper aims to investigate the synthesis, chemical properties, metabolism, and transportation of creatine, as well as its effects on sports performance, cognitive function, and potential applications in cancer treatment and antiviral activity. By reviewing existing literature and incorporating recent research findings, this paper aims to provide a comprehensive understanding of creatine and its potential benefits for individuals seeking to enhance physical performance, cognitive abilities, and overall health.

Figure 1. Creatine 3D structure (PubChem)

2. Chemical Structure.

Creatine is a non-proteinogenic amino acid and a glycine derivative with the chemical formula C4H9N3O2. At room temperature, creatine is slightly soluble in water (13 g/L). Like all amino acids, it contains carboxyl and amino functional groups. Due to charge separation and the presence of O-H and N-H bonds, creatine can form hydrogen bonds that play an essential role in protein binding (Colas et al., 2020). The crystal structure of creatine contains hydrogen bonds between guanidine and carboxyl groups as well as charge attraction interactions. The lone pairs on all three nitrogen atoms are delocalized, explaining the trigonal planar geometry on the nitrogen atoms and equal lengths of C-N bonds of the guanidine group. The zwitterionic form is highly stabilized by resonance and is the major species at physiological pH (7.3), with pKa values of amino and carboxylic acid moieties estimated to be 12.7 and 3.8, respectively (PubChem). Owing to charge separation, creatine is a relatively reactive molecule.

Figure 2. Creatine bond angles and lengths (Arlin et al., 2014) in Mercury (Macrae et al., 2020)

Figure 3. Creatine crystal structure (Arlin et al., 2014) in Mercury (Macrae et al., 2020)

3. Biosynthesis

Creatine is naturally synthesized in the kidney and liver through the conversion of glycine and arginine, facilitated by the enzyme arginine:glycine amidinotransferase (AGAT). Guanidinoacetate (GAA), formed from the reaction between glycine and arginine, is then methylated by guanidinoacetate N-methyltransferase (GAMT), using S-adenosyl methionine (SAM) as the methyl donor. The result is creatine. Creatine’s cyclic form, creatinine, exists in equilibrium with its tautomer and creatine itself (Joncquel-Chevalier Curt et al., 2015).

Figure 4. Creatine biosynthesis pathway

4. Transportation and Transporter Protein Binding

Figure 5. Creatinine tautomerization

Creatine is transported through the bloodstream and taken up into the cell by the transmembrane protein creatine transporter, CreaT. Malfunctions or mutations of CreaT can result in creatine deficiency within the brain. Such a deficiency has the potential to cause extreme neurological disorders such as epilepsy and intellectual disability (Passi et al., 2022). CreaT belongs to the solute carrier transporter 6 family (SLC6), specifically the subgroup of GABA transporters (GATs).  These transporters, including CreaT, are considered symporters as they transport Na⁺ ions along with their respective substrates in the same direction, utilizing the electrical potential gradient across the cellular membrane.

Colas and fellow researchers created homology models of CreaT based on the structurally similar serotonin transporter (hSERT) that shed light on the structural factors characterizing ligand binding to the active site of CreaT. One discovered feature is that transmembrane helix 10 (TM10) has a π helix that provides a specific conformation to the binding site and is believed to influence the substrate selectivity among proteins in the SLC6 family. Another feature is the deprotonated cysteine (C144), located on TM3, that is specific to CreaT. This cysteine plays an essential role in CreaT ligand binding because it allows for S-H-N hydrogen bonding with the guanidine group of the substrate. Complexes of CreaT with different ligands were studied, and it was revealed that optimal binding occurs when the distance between carboxylate and guanidine groups is approximately 4.5 – 5 Å, which corresponds to a linker with 2-3 carbon atoms (Colas et al., 2020).

Figure 6. Creatine binding to CreaT (Colas et al., 2020)

 

5. Metabolic Role.

About two-thirds of the total creatine in the body is stored in the form of phosphocreatine (PCr). PCr is created by creatine phosphorylation catalyzed by CK and serves as an energy buffer in skeletal muscles and the brain by supplying high-energy phosphates to convert ADP to ATP when needed. The enzymatic breakdown of PCr into Cr and inorganic phosphate (Pi) provides energy that is used to synthesize ATP from ADP and Pi.

Maintaining adequate ATP availability is crucial in situations where ATP levels have been depleted due to high energy demands. The capacity to restore depleted ATP levels assumes significance in sustaining optimal ATP availability. Approximately 95% of creatine is stored in skeletal muscle, with the remaining 5% distributed among other tissues, notably the brain  (Balsom et al., 1994). The breakdown of creatine into creatinine occurs at a rate of approximately 1-2% per day. The degradation process is more pronounced in more physically active individuals, as well as individuals exhibiting higher lean muscle mass  (Hultman et al., 1996). As a result, a person of average size may require a daily intake of 2-3 grams of creatine to maintain normal levels in their muscles. This requirement can vary depending on factors such as diet, muscle mass, and physical activity levels. Creatine stores in individuals following either a normal omnivorous diet or a vegan diet are usually not saturated. Therefore, to promote overall health, the recommended daily dietary intake of creatine may range from 2 to 4 grams per person (R. B. Kreider et al., 2017; R. B. Kreider & Stout, 2021).

Figure 7. Phosphocreatine structure

6. Effects of Creatine Supplementation on Sports Performance

Improved exercise performance associated with creatine supplementation is caused by an increase in muscle creatine and PCr levels  (Buford et al., 2007). Studies have shown that individuals who take creatine experience a performance increase of approximately 10-20% in various high-intensity activities, including fitness and weight training (Izquierdo et al., 2002; R. Kreider et al., 1998; Wiroth et al., 2001). These benefits have been observed in both men and women across different age groups. Consequently, it is widely acknowledged among scientists that creatine supplementation is an important and valuable ergogenic aid for athletes. The quickest and most effective way to elevate muscle creatine levels is to consume 5 g of creatine four times a day for 5-7 days (R. B. Kreider & Stout, 2021).

7. Effects on Cognitive Function

The brain is an organ with a high energy demand, which implies that creatine may offer potential cognitive benefits. Indeed, creatine supplementation boosts brain bioenergetics and reduces mental fatigue (Braissant et al., 2011). It has also been observed to enhance extended cognitive abilities in healthy individuals (Van Cutsem et al., 2020) and alleviate the decline in skill execution that arises from lack of sleep (Cook et al., 2011).

8. Creatine’s Role in Cancer

Creatine plays a complex role in the development and progression of cancer, because its benefits can be used by both tumor cells and healthy cells. It has demonstrated potential anti-cancer effects, acting as a power source for T cell activities (Campos-Ferraz et al., 2016; Di Biase et al., 2019) and similar effects have been observed with cyclocreatine (Miller et al., 1993). However, recent studies have unveiled the protumor effects of creatine, specifically in promoting cancer metastasis  (Papalazarou et al., 2020; Zhang et al., 2021). Additionally, elevated levels of CK have been observed in certain cancers, such as lung cancer (Gazdar & et al., 1981) and prostate carcinoma  (Feld & Witte, 1977). Inhibition of the SLC6A8 gene, responsible for creatine transport, has been shown to reduce PCr and ATP levels in cells and induce tumor apoptosis (Kurth et al., 2021). Despite ongoing research, the complete understanding of creatine’s role in cancer remains elusive. Therefore, caution is advised when considering creatine supplementation in the context of cancer.

9. Antiviral Properties: Computational Study of Creatine Binding to SARS-CoV-2 Main Protease

Calculations were performed using (1) the Main Protease crystal structure coordinates as obtained from the Protein Data Bank (PDB) with PDBID: 6Y84 (Owen et al., 2023) and (2) the creatine crystal structure atomic coordinates downloaded from the Cambridge crystallographic database (CSD) CSD code: JOHJIB01 (Arlin et al., 2014). We used software from Biovia (Dassault Systèmes, San Diego, CA, USA). Docking studies were performed with the CDOCKER package in Discovery Studio 2020 version  (Wu et al., 2003). Standard dynamics cascade protocol in Discovery Studio allows optimization of atomic coordinates and was also applied to the selected poses.

Figure 8. Creatine binding to SARS-CoV-2 main protease active site amino acids

This computational analysis uncovers the potential of creatine to intricately bind to the active site of SARS-CoV-2 main protease, suggesting its capacity as an inhibitor of this protease, which is known to play an essential role in viral replication by cleaving polyproteins to form multiple functional proteins, including those responsible for RNA replication (Qiao et al., 2021). Additionally, creatine has the potential to prevent the protease from dimerizing, which is necessary for its function. Despite the study’s reliance on computational analysis, these findings pave the way for the exploration of creatine as a promising candidate for effectively targeting and inhibiting the protease and therefore the activity of the virus.

10. Interactions with Other Substances

Research indicates a potential exacerbation of liver damage caused by ethanol when taken together with creatine (Marinello et al., 2019). Despite previous suppositions, research has shown that neither anhydrous caffeine nor coffee hinders the performance boost from creatine, but simultaneous ingestion may cause digestive discomfort (Trexler et al., 2016).

11. Safety and Side Effects

Creatine monohydrate (CM) supplementation has been associated with anecdotal claims of side effects such as cramping or fluid balance disruption, but scientific research suggests that these concerns are largely unfounded (Dalbo et al., 2008; Lopez et al., 2009). In fact, Greenwood and others discovered that football players who supplemented with creatine experienced significantly less cramping, dehydration, muscle tightness and strains during training (Greenwood et al., 2003). Creatine has also been speculated to have a negative effect on kidney function. Certain fears about creatine and renal function stemmed from a case study involving a man with pre-existing kidney disease (Koshy et al., 1999; Pritchard & Kalra, 1998). Some concerns have centered around increased serum creatinine levels, which are often used as an indicator of kidney health. However, large-sample studies conducted over several years have not found any significant side effects, including adverse effects on renal function, resulting from CM supplementation in healthy athletes (Groeneveld et al., 2005; R. B. Kreider et al., 2003; Lugaresi et al., 2013; Poortmans & Francaux, 1999). To conclude, current evidence suggests that CM supplementation is safe within recommended guidelines.

12. Conclusions

In conclusion, creatine supplementation offers various benefits in terms of sports performance enhancement, cognitive function improvement, and potential anticancer properties without any known adverse side effects. Furthermore, our computational study reveals creatine’s potential as an antiviral agent that arises from its ability to bind to the SARS-CoV-2 main protease. Creatine’s wide availability and relatively low cost make it an intriguing research target to investigate as a SARS-CoV-2 treatment. While further research is needed to explore its full range of applications and mechanisms of action, the current evidence supports the use of creatine as a valuable nutritional supplement for both athletes and the general population.

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