Background
Homocysteine (HCY) is a sulfur-containing amino acid formed after the demethylation of methionine and is an intermediate product of the methionine cycle. Homocysteine cannot be synthesized in the body and can only be converted from methionine. Methionine cannot be synthesized in the human body and must be supplied by food. In normal plasma, 80% of homocysteine is bound to proteins through disulfide bonds. Most of the unconjugated homocysteine exists as cystine or cysteine-homocysteine, with only a small portion free. Homocysteine, whether in bound or free form, is collectively referred to as total homocysteine. The main factors that affect homocysteine levels are genetics and dietary deficiencies. Homocysteine metabolism requires vitamin B6, vitamin B12, and folic acid. If the concentration of vitamin B12, vitamin B6, and folic acid in the blood is too low, the concentration of homocysteine in the blood will increase. The first reports of homocysteine metabolism disorders came from the observation of homocystinuria in patients with congenital cystathionine synthase deficiency. Since then, several other metabolic disorders caused by changes in enzymes or coenzymes involved in HCY metabolism have been discovered. In recent years, with the improvement of measurement technology and methods, it has been possible to measure HCY existing in various forms in normal human plasma. Studies have found that HCY metabolic disorders exist in patients with heart, brain and peripheral vascular diseases, chronic renal insufficiency, dermatophytes, vitamin By2 deficiency and other diseases.
Figure 1. Homocysteine (Hcy) metabolic pathway.(Source: Alexey Chubarov. 2021)
HCY comes from methionine in the daily diet. It is the product of the hydrolysis reaction of S-adenosine HCY in the methionine cycle. At the same time, it is the substrate for the synthesis of cystathionine by cystathionine beta synthase. The total HCY in the blood includes three forms: HCY, HCY disulfide and cystine-HCY. Most of them exist in protein-bound form, and a small part is in a free state. There are three metabolic pathways for HCY. 1. HCY is remethylated into methionine, also known as the remethylation pathway. The remethylation reaction requires the participation of methionine synthase and vitamin B12 as a coenzyme. Under these conditions, HCY synthesizes methionine and tetrahydrofolate with 5'-methyltetrahydrofolate. There is another remethylation pathway in the liver, which uses betaine as a methyl donor and synthesizes methionine and dimethylglycine under the catalysis of betaine HCY methyltransferase. 2. The reaction of condensation of HCY and serine into cystathionine, also known as the transsulfurization pathway. The reaction is catalyzed by cystathionine synthase, with vitamin Br as a coenzyme, and is condensed into cystathionine and water. This reaction is irreversible under physiological conditions and is beneficial to the transport of HCY. The generated cystathionine is cleaved into cysteine and α-ketobutyric acid by γ-cystathionase. 3. Directly released into the extracellular fluid. This part is closely related to plasma concentration. Increased release of HCY outside cells reflects disturbances in its production and metabolism. Studies have shown that the concentration of methionine can affect the release of HCY from cells. At low concentrations, cellular release is affected by methionine synthase; while at high concentrations, cellular release is affected by cystathionine synthase.
Elevated homocysteine levels are found in atherosclerotic vascular disease, stroke, rheumatoid arthritis, various cancers, etc. Elevated levels of homocysteine produce superoxide and peroxide, which can cause damage to vascular endothelial cells and oxidation of low-density lipoprotein, leading to sustained contraction of vascular smooth muscle and hypoxia, accelerating the process of atherosclerosis. It can also disrupt normal clotting mechanisms and increase the risk of thrombosis. If homocysteine levels are elevated due to inadequate intake of vitamin B6, vitamin B12 and folic acid, you can reduce plasma homocysteine levels through diet or increase intake of B vitamins and folic acid, thereby reducing the risk of cardiovascular and cerebrovascular disease.
Alternative Names
L-Homocysteine
Thiohomocysteine
Hcy
References
- 1. Alexey Chubarov. Homocysteine Thiolactone: Biology and Chemistry. Encyclopedia. 2021, 1(2):445-459.
References
Homocysteine thiolactone: metabolic origin and protein homocysteinylation in humans
J Nutr.
Authors: Jakubowski H.
Abstract
Homocysteine thiolactone, an intramolecular thioester of homocysteine, is synthesized by methionyl-tRNA synthetase in an error-editing reaction that prevents translational incorporation of homocysteine into proteins. The synthesis of thiolactone occurs in all human cell types investigated. An increase in homocysteine levels leads to elevation of thiolactone levels in human cells. In cultured human cells and in human serum, homocysteine thiolactone reacts with proteins by a mechanism involving homocysteinylation of protein lysine residues. The homocysteinylation leads to protein damage. A calcium-dependent homocysteine thiolactonase, tightly associated with HDL in human serum, may prevent protein damage by detoxifying thiolactone.
Homocysteine metabolism in diabetes
Homocysteine metabolism in diabetes
Authors: Wijekoon EP, Brosnan ME, Brosnan JT.
Abstract
An increase in the plasma level of Hcy (homocysteine), an intermediate in the catabolism of methionine, has been identified as a risk factor for many diseases including CVD (cardiovascular disease). CVD is the major cause of death in patients with diabetes mellitus. Therefore the study of Hcy metabolism in diabetes mellitus has been a major focus of current research. Studies conducted in our laboratory were able to show that in both Type 1 and Type 2 diabetes with no renal complications, the plasma Hcy levels were lower than in controls. In Type 1 diabetes, increased activities of the trans-sulfuration enzymes were the major cause for the reduction in plasma Hcy. In Type 2 diabetes, BHMT (betaine:homocysteine methyltransferase) was also observed to play a major role in the increased catabolism of Hcy in addition to the trans-sulfuration enzymes. We were also able to demonstrate the direct effect of insulin and the counter-regulatory hormones on the regulation of cystathionine beta-synthase and BHMT, which accounts for the changes in the activities of these two enzymes seen in diabetes mellitus.
Homocysteine as a risk factor for atherosclerosis
Ann Pharmacother
Authors: Temple ME, Luzier AB, Kazierad DJ.
Abstract
Objective: To review the role of homocysteine as a risk factor in the pathogenesis of atherosclerosis and to provide recommendations for the treatment of hyperhomocysteinemia.
Data sources: A MEDLINE search using key terms such as homocysteine, atherosclerosis, folic acid, vitamin B6, and vitamin B12 was conducted for the time period 1966 through January 1999.
Study selection: An article was selected for inclusion in this review if it assessed the relationship and proposed mechanisms of hyperhomocysteinemia on the vasculature, physiologic changes due to hyperhomocysteinemia, and outcomes due to hyperhomocysteinemia, such as morbidity and mortality. In addition, studies that assessed the treatment outcomes of hyperhomocysteinemia were evaluated.
Data synthesis: Studies of patients with cerebral vascular disease reveal elevated homocysteine concentrations in 30-40% of patients compared with controls. Many studies demonstrate a correlation between elevated homocysteine concentrations, risk of myocardial infarction, and mortality. In addition, hyperhomocysteinemia and decreased folic acid concentrations have been identified in end-stage renal disease (ESRD) and type 2 diabetic patients, while both concentrations remained normal in healthy controls. Studies using folic acid 650 microg/d reduced homocysteine concentrations to within normal therapeutic range after two weeks of treatment. Studies with vitamins B6 and B12 have demonstrated that the use of either alone is ineffective, but when combined or administered with folic acid, homocysteine concentrations return to normal. All therapies must be given for the lifetime of the patient. In addition, patients must use discretion in their diet, as common beverages, such as coffee, have a strong correlation with hyperhomocysteinemia, while foods high in folic acid, vitamin B6 and vitamin B12 may reduce homocysteine concentrations. Additional prospective studies are needed to determine effects of treatment of hyperhomocysteinemia and various diets on atherosclerotic morbidity and mortality.
Conclusions: Studies demonstrate a positive correlation between hyperhomocysteinemia and atherosclerosis. The treatment of choice for hyperhomocysteinemia is folic acid. Although the optimal dose is not known, 650 microg/d is the minimum effective dose. To date, no studies have assessed the effects on morbidity and mortality when treating high homocysteine concentrations in atherosclerotic patients.