Homocysteine and Methyltransferase Capacity (B105)

High homocysteine levels are associated with an increased risk of dementia, metabolic syndrome, and all-cause mortality. Homocysteine is a biomarker of methyltransferase activity and function. 

To access the FREE seminars with full presentations and videos please visit Dr. Goodenowe’s resource site here. This is the article for seminar B105, Blood Tests and Biomarkers (Series B).

The methyltransferase system is a critical nexus for multiple essential biochemical systems. Its core purpose is to efficiently utilize the terminal methyl group from the essential amino acid methionine as a methyl source for numerous biological processes. The two main methylation pathways are choline synthesis for biological membranes and neurotransmitter synthesis and creatine synthesis for muscle building and maintenance. Choline plasmalogens are exclusively made via the methyltransferase system. 

The key components of the system are a non-deficient supply of methionine and key vitamins and cofactors such as B12, B6, and folate; efficient recycling of methionine to preserve and reduce daily dietary methionine demands; and sufficient dietary supply of the main methyltransferase products choline and creatine to reduce the endogenous synthesis load. 

Methionine is converted to S-adenosylmethionine (SAM), which is the actual methyl donor. SAM is used by numerous enzyme systems throughout the body. Regardless of the enzyme system that uses SAM, after it donates its methyl group it is converted to S-adenosylhomocysteine (SAH). SAH is then metabolized to homocysteine. Homocysteine is essentially a biomarker of SAH. 

Methionine is an essential dietary amino acid because of the body’s reliance on it for numerous methyltransferase reactions. To prevent methionine depletion caused by overactive methyltransferase activity, the body need to be able to sense the amount of methyltransferase occurring and shut it down if it is overactive. SAH serves this purpose. SAH is a very potent methyl transferase inhibitor. If SAH builds up, methyltransferase activity is shut down. Therefore, to maintain methyltransferase reserve capacity, you need low resting SAH levels – as measured by low homocysteine.  

Homocysteine can either be converted back to methionine (the preferred path) or metabolized further to cysteine, which is then used to make glutathione. The conversion of homocysteine to cysteine irreversibly depletes methionine. 

Homocysteine recycling enzymes require methyl-tetrahydrofolate (mTHF), vitamin B12, and vitamin B6. Deficiencies in these cofactors result in inefficient recycling of homocysteine. Excessive methylation demand results in depletion of these vitamins and cofactors.  

Dietary supply of choline and creatine naturally reduces methyltransferase demand and naturally lowers SAH and homocysteine. Lowering homocysteine by solely increasing homocysteine recycling using high dietary mTHF and vitamin B6/12 eliminates the diagnostic utility of homocysteine and potentially exacerbates the negative effects of overactive methylation. 

Dietary supplementation of methionine should be approached with caution. Supplementation with N-acetylcysteine is preferred as it preserves and prevents excessive conversion of homocysteine to cysteine and ensures healthy glutathione levels.  

Phosphatidylcholine (PC) is the second nexus in this system. PC is essential and critical, and the body will sacrifice other systems to ensure adequate levels. PC is used to create sphingomyelin (SM), which is another critical membrane lipid that also contains choline. PC combines with ceramides to create SM. SM is broken down to create PC and ceramides. 

High homocysteine is associated with increased dementia, metabolic syndrome, and all-cause mortality risk. 

Elevated ceramide levels are associated with increased risk of cardiovascular disease and neurodegenerative disease. 

Higher levels of PC and SM are associated with reduced risk of neurodegenerative diseases. 

ProdromeScan measures PE, PC, SM, ceramides, and homocysteine to obtain an objective evaluation of the methyltransferase system function and reserve capacity. 

Dr. Goodenowe explains the relevant research and literature regarding blood homocysteine levels in seminar B105 – Homocysteine and Methyltransferase Capacity.