Low Homocysteine Levels: What are The Consequences?
Homocysteine is an amino acid derivative that serves as an intermediate in the synthesis of methionine and cysteine. It contains a sulfhydryl group that serves as an important branch in the formation of important biological compounds such as glutathione (GSH) and S-adenosylmethionine (SAM). GSH is formed through the transsulfuration (TS) pathway with the formation of cysteine from homocysteine by a stepwise process by the enzymes cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CGL), and by subsequent formation of GSH by glutathione synthetase. SAM is formed by methylation of homocysteine to form methionine by the enzyme N5,N10-methylenetetrahydrofolate reductase (MTHFR) and subsequent condensation of methionine with adenosine triphosphate (ATP) to form SAM.
Low homocysteine levels, or hypohomocysteinemia, is the result of several factors. It can be a result of a metabolic insult which prompts the body to produce more GSH than normal, low intake of the amino acids methionine and cysteine (methionine predominantly comes from meat protein so those that don’t eat meat or eat too little may be at higher risk), an inherently low level of the enzyme MTHFR, low intake of vitamins folate and B12, or increased detoxification of xenobiotics through the phase II liver reaction sulfation. These factors will result in low homocysteine levels, which would then lead to a variety of clinical disorders.
Hypohomocysteinemia has been shown to play a role in the malnutrition-inflammation-cachexia syndrome with which low dietary intake of methionine would lead to worsening of chronic kidney disease, with which homocysteine can be a variable in determining survivability of the patient. Hypohomocysteinemia is also a cause of the progression of atherosclerosis in cardiovascular diseases.
Since hypohomocysteinemia may also present with a lack of cysteine levels, it can be due to the role that the liver plays. Synthesis of GSH requires cysteine, in which the formation of GSH will get homocysteine from the reservoir to support the body in times of oxidative stress, in which GSH may be able to mediate and prevent oxidative damage to cells. The synthesis of GSH would therefore favor the TS pathway. So basically this means if there is a low level of antioxidants, the body will steal cysteine from homocysteine to support glutathione production. So low homocysteine may be a sign of oxidative stress.Formation of more cysteine from homocysteine would then deplete the homocysteine pool to support the formation of GSH to combat the free radicals.
Another factor that would deplete homocysteine levels would be the detoxification pathway sulfation. Sulfation is a phase II or conjugation reaction in which cysteine donates a sulfur group to the xenobiotic forming a xenobiotic-sulfate, allowing it to be excreted from the system. Apart from sulfation, cysteine is also employed in the formation of bile acids such as taurine. Taurine is especially synthesized when the body takes in fat and alcohol. Synthesis of taurine would also deplete homocysteine levels by promoting the TS pathway in the formation of cysteine. These homocysteine-depleting mechanisms are prevented if there are adequate amounts of methionine and cysteine from the diet.
Low dietary intake of vitamins folate and B12 can also lead to hypohomocysteinemia. Folate is an important component of the methylation pathway as it forms the structure of N5,N10-methylenetetrahydrofolate and would therefore be an important substrate for the transmethylation pathway involving the formation of SAM by transferring a methyl group from N5,N10-methylenetetrahydrofolate to homocysteine forming methionine, catalyzed by the enzyme MTHFR. Folate is important in regulating gene expression by regulating levels of SAM.3
Vitamin B12 is another vitamin that is important in gene expression and DNA synthesis. Methylcobalamin which serves as a cofactor in the methylation cycle, is involved in the production of methionine from homocysteine by the action of MTHFR. Low dietary intake of either or both folate and vitamin B12 will result in low methionine levels, which would ultimately inhibit the formation of homocysteine.4
MTHFR deficiency may also lead to low homocysteine levels in the body. MTHFR is the enzyme responsible for the transfer of a methyl group from N5,N10-methylenetetrahydrofolate to homocysteine forming methionine. Defects in the gene, most notably the C677T gene polymorphism, may result in low 5-MTHF levels, resulting in hypohomocysteinemia.5
The effects of having hypohomocysteinemia are mainly due to the prolonged depletion of cysteine. That said, the effects of hypohomocysteinemia would be the prolonged inflammatory insults experienced by the body due to the increased formation of free radicals with the lack of GSH to counteract the effect. Inflammation can lead to several disorders that may affect the cardiovascular system, nervous system, and even the renal system. Atherosclerosis is a major concern due to the inflammatory nature of the disease. Inflammation will induce the misfolding of the proteins in the brain causing Alzheimer’s disease. Chronic renal failure may result in the increased inflammation of the tubular system. GSH plays a central role in mediating the effects of oxidative stress, preventing damage to the organs. That said, GSH production relies heavily on the pool of homocysteine to fuel its synthesis.
- Ganguly, P. & Alam, S.F. Role of homocysteine in the development of cardiovascular disease. USA: Nutrition Journal. January 2015; Vol. 14, No. 6.
- Lord, R. & Fitzgerald, K. Significance of Low Plasma Homocysteine. USA: Metametrix Laboratory Department of Science and Education. 2006. Retrieved http://www.drkendalstewart.com/wp-content/uploads/2011/09/Significance-of-Low-Plasma-Homocysteine.pdf
- Blom, H. & Smulders, Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. USA: Journal of Inherited Metabolic Disorders. February 2011; Vol. 34, No. 1. pp. 75-81.
- O’Leary, F. & Samman, S. Vitamin B12 in Health and Disease. USA: Nutrients. March 2010; Vol. 2, No. 3. pp. 299-316.
- Leclerc, D. et al. Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR) and Overview of Mutations/Polymorphisms. Madame Curie Bioscience Database.