Importance of Homocysteine

Summary:

Homocysteine (Hcy) is a sulfur-containing amino acid generated during methionine metabolism. Physiological levels are determined primarily by dietary intake and vitamins.

Elevated plasma Hcy levels may be due to a deficiency of vitamin B12 or folate. Hyperhomocysteinemia may be responsible for various systemic and neurological diseases.

-Discussion:

Congenital homocystinuria. In 1962, researchers found that individuals with a rare genetic condition called homocystinuria, in which a dysfunctional enzyme (CBS mutations) was found.

Which leads to a buildup of homocysteine, were at risk for serious cardiovascular disease in adolescence and in their 20s.

However, homocysteine has been considered a risk factor for systemic atherosclerosis and cardiovascular disease (CVD) and in many neurological disorders, including cognitive impairment and stroke.

It is independent of long-recognized factors such as hyperlipidemia, hypertension, diabetes mellitus and smoking.

Hyperhomocysteinemia is typically defined as levels > 15 micromol/L. Treatment of hyperhomocysteinemia with folic acid and B vitamins appears to be effective in preventing the development of atherosclerosis, CVD and stroke.

Oxidative stress induced by Hyperhomocysteinemia, are endothelial dysfunction, inflammation, smooth muscle cell proliferation and endoplasmic reticulum (ER) stress play an important role in the pathogenesis of several diseases, including atherosclerosis and stroke.

Homocysteine Metabolism

The path of metabolism of a carbon activates units of a carbon, usually serine, producing, 5-methyltetrahydrofolate which is the substrate for methyl homocysteine, using vitamin B12 and folate as cofactors.

During the transulfuration pathway, homocysteine is irreversibly degraded to cysteine. Cysteine is a precursor of glutathione, the most vital endogenous antioxidant.

In most tissues, homocysteine is re-methylated or exported out of the cell.

The liver is the main organ of degradation of excess methionine and maintenance of homocysteine at adequate levels.

Excess methionine causes further degradation of homocysteine through the transulfuration pathway.

The lack of methionine preserves homocysteine, through re-methylation, back to methionine.

Whenever there is a deficit of methionine, homocysteine can be re-methylated to form methionine, through the use of methylenetrahydrofolate.

If there is an adequate amount of methionine, homocysteine is used for the production of cysteine, mediated by a synthetase, with pyridoxine as a co-factor.

Physiological levels of homocysteine in a healthy population are determined primarily by dietary intake of methionine (an essential amino acid), folate, and vitamin B12.

Hyperhomocysteinemia is typically defined as levels > 15 mol/L in published studies; levels between 15 and 30 are considered moderate, levels 30 to 100 micromol/L are considered serious, and levels above 100 micromol/L are considered lethal.

Several other factors such as age, sex (men have higher levels because of muscle mass creatine), plasma concentrations of folate and vitamin B12, serum creatinine, alcohol consumption, and dietary restrictions.

Various pathological conditions (diabetes, hypertension, kidney failure) may be associated with elevated plasma homocysteine levels.

If folate is not circulated, the synthesis of purines and thymidine is limited, due to a severe alteration and inhibition of the trans-methylation pathway.

Cyanocobalamin deficiencies should be excluded before beginning folate supplementation, or if necessary, supplementation with folate and vitamin B12 together should be appropriate.

-Conclusions:

Homocysteine is a sulfur-containing amino acid, closely related to methionine metabolism.

Factors causing homocysteine accumulation may be different due to different genetic defects, mutation of the enzyme cascade, or deficiencies in vitamin B12 and folate during human life.

In fact, an increase of homocysteine is produced in the brain and CSF, and in the plasma, within the aging process and within several neurological diseases, compromising the hematoencephalic barrier.

Moreover, hyperhomocysteinemia accelerates the death of dopaminergic cells, increase of amyloid and tau protein.

NO (nitric oxide) levels decrease and this fact, which has been associated with high homocysteine levels, promotes endothelial damage. Endothelial damage is mediated by one of the precursors, hydrogen sulfide (H2S), which is formed during the transulfuration process.

Endothelial dysfunction is the result of altered cellular integrity, leading to altered endothelium-dependent relaxation due primarily to reduced bioavailability of NO.

NO is produced from its precursor L-arginine by endothelial nitric oxide synthetase. Under physiological conditions, after production.

NO diffuses through the endothelial cell membrane into vascular smooth muscle cells to activate guanylate cyclase, leading to cyclic vasodilation.

The production of ROS (reactive oxygen species) induced by hyperhomcysteinemia decreases the production of NO and bioavailability causing an increase in redox signaling and activating the inflammation cascade, with increased TNF-alpha, and interleukins, etc.

Apart from B12, folic acid, vitamin B6 and antioxidants like vitamin E and C decrease the production of ROS.

References:

-Nichols J. Testing for homocysteine in clinical practice. Nutrition Health. 2017;23:13-15. doi: 10.1177/0260106016686094. (PubMed).

-Int J Mol Sci. 2018 Mar 17;19(3):891. doi: 10.3390/ijms19030891.Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization. Norimichi Shirafuji 1 2, Tadanori Hamano 3 4 5, Shu-Hui Yen 6, Nicholas M Kanaan 7, Hirotaka Yoshida 8, Kouji PMID: 29562600 PMCID: PMC5877752 DOI: 10.3390/ijms19030891

Keywords: Homocysteine and cardiovascular risk, Homocysteine and TAU protein, Homocysteine and oxidative stress, vitamin B12 and homocysteine, folate and homocysteine, oxidative stress and E and C viatamins, ROS production and homocysteine, homocysteinuria in childhood, homocysteinemia and nitric oxide, amyloid and homocysteine.

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