Creatine and energy production within the cell

The penultimate step in energy production within the cell is the transfer of ATP across the mitochondrial membrane via the enzyme creatine-kinase, to an awaiting creatine molecule in the cytoplasm of the cell to make the high energy phosphate donor Creatine-Phosphate. Without this step, the generation of ATP within the mitochondria is futile. Thus, the creatine/phosphocreatine shuttle system is an essential component of transport of energy, produced in the mitochondria, into the cytoplasm of the cell (Sacks et al, 1978) . As such, it is thought to be essential for storing of high phosphate-bound energy, particularly in those cells with high energy demand. Creatine levels are high in tissues such as muscles, the brain, and are also very high in the oligodendrocytes Braissant etal, 2007; 2008; 2011) and astrocytes. It has been known for some time that Creatine-kinase mRNA levels are high in oligodendrocytes and astrocytes Molloy etal, 1992. The methylating enzyme GAMT, which is involved in the final step in creatine synthesis is similarly found in these cells Tachikawa etal, 2004). Whist originally it was thought that most of the Creatine in the brain was of peripheral origin, more recently evidence suggests that the ability of creatine to cross the blood brain barrier is very poor, and hence the majority of Creatine used in the brain comes from endogenous synthesis (Braissant etal, 2007; 2008; 2011). This, then, potentially creates a problem in functional vitamin B12 deficiency, because the synthesis of Creatine in the brain will also require an active methylation cycle locally in the brain, to provide the methyl donor SAM for use by GAMT in the synthesis of Creatine.

Modified from Beard and Braissant, 2010.

CK - Creatine Kinase mCK - mitochondrial Creatine Kinase, CAC - citric acid cycle, AGAT - Arginine-Glycine AmidinoTransferase, GAMT - GaunidinoAcetate-MethylTransferase, SAM - S-Adenosylmethionine, AcCoA - AcetylCoA.

Synthesis of Creatine

Synthesis of creatine occurs in two steps

The requirement of GAMT/GNMT for SAM, means that there is a co-requirement for an effective methylation cycle, which in turn requires sufficient active MethylCo(III)B12. Hence in functional B12 deficiency, you will also have functional deficiency in the GAMT/GNMT enzyme, and will therefore have reduced production of creatine. A deficiency of vitamin B12 in the peripheral organs is relatively easy to fix, BUT, loading a deficient brain with vitamin B12 is much harder.

Levels of Creatine Kinase expression vary between cells in the brain, with levels 17-fold higher in oligodendrocytes, and 14-fold higher in astrocytes than in normal neurons (Molloy etal, 1992). Olidogendrocytes are the main source of endogenously synthesised creatine, and loss or lowering of creatine synthesis leads to delayed myelination, and lead to intellectual delays (seen in absolute B12 deficiency), seizures, and autistic behaviour (Rosko et al, 2023)

Deficiency of GAMT/GNMT activity and Autism

Lack of activity of the enzyme GAMT has been shown to give rise to many of the symptoms of autism. In addition lack of activity of GAMT leads to prolonged fatigue, similar to that in Chronic Fatigue Syndrome. Lack of activity of GAMT enzyme is associated with many symptoms associated with Autism and Alzheimer's Disease. In children GAMT deficiency can cause severe developmental and mental retardation, speech delay, recurrent seizures (and TICS), behavioral changes, and movement disorders, including Muscular hypotonia, mild spasticity, and coordination disturbances (Braissant etal, 2011; Longo etal, 2011; Pacheva etal, 2016; Stöckler et al, 1994; Mercimek-Mahmutoglu et al, 2006; Stockler-Ipsiroglu  et al, 2014; Mercimek-Mahmutoglu et al 2014; O'Rourke et al, 2009; Araújo  et al, 2005; Lion-François  et al, 2006; Mercimek-Mahmutoglu  et al, 2009; Leuzzi  et al, 2013 Schulze  et al, 2006;Verbruggen et al 2007; Morris  et al, 2007; Item etal, 2004.

Lack of methylation, due to functional methyl B12 deficiency, can lead to toxic build up of Guandinoacetate in the brain, which can in turn lead to symptoms of epilepsy. Deficiency of activity of GAMT leads to greatly decreased levels of Creatine in the brain (Braissant et al, 2011; 2008) and CNS which is the main organ affected by Creatine deficiency (Stöckleretal, 1994; Schulze et al, 1997; Schulze and Battini 2007; Salomons et al, 2001).

Despite the inextricable linkage between methyl B12, the methylation cycle, the production of SAM, and the need for GAMT to use SAM in the final step in the production of Creatine, not one review on GAMT and creatine production, that we could find ever cited it, and in fact ever mentioned vitamin B12. This is despite the frequent association between vitamin B12 deficiency and conditions such as autism, AD, and CFS!!

Creatine supplementation and Improvement in Cognition

Studies on Vegan subjects given 5 gm per day creatine-monohydrate, showed a significant improvement in cognitive scores after 4 weeks of supplementation. The mechanism was presumed to be greater uptake of creatine into the brain and neuronal cells (Rae etal, 2003). A similar improvement was seen cognition by Hammet and co-workers (2010). See review by Candow (2023)

Methylation, Neurodevelopment and Autism

Apart from the obvious requirement of Methyl B12 for energy production in oligodendrocytes, methylB12 has a secondary role in the production of melatonin. Thus, Melatonin, together with vitamin D, stimulates neuronal stem cells to differentiate into oligodendrocytes, which are the cells in the brain that are responsible for myelination of the nerves in the brain. Hence a deficiency in methyl B12 would result in lower stimulation of differentiation of neuronal stem cells into oligodendrocytes, and lack of production of creatine, would in turn lead to lower energy within the oligodendrocytes, lower myelination and a greater chance of developmental and mental retardation.

Dietary supplements that may help increase creatine, Neurodevelopment and Autism

The last step in creatine synthesis involves SAM, which is a conjugate of Adenosine and Methionine. Potentially foods high in methionine may aid in increasing levels of SAM, such as dried egg whites, dried spirulina, lean beef, brazil nuts, lean lamb, bacon, parmesan cheese, chicken breast and tuna. Of note, in functional B12 deficiency, the continued use of dietary methionine to supply SAM will eventually lead to high levels of homocysteine. Whilst the majority of those on an omnivore diet obtain around half their daily creatine requirements from red meat, those on a vegan or vegetarian diet obtain very little from their food and so must rely on local synthesis (da Silve etal, 2009). Dietary creatine has limitations in the very little of the material crosses the blood brain barrier.

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