Serine + Vitamin B6: The Best Way To Reduce Homocysteine? (Also, Homocysteine Activates mTORC1)

[Mike Lustgarten]

 

 

[InquilineKea]

https://www.sciencedirect.com/science/article/abs/pii/S0887233316300716 (serine and glycine can prevent its intracellular accumulation and damage, possibly, even if they dont decrease Hcy)

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https://pubs.acs.org/doi/10.1021/acs.analchem.3c00822

https://www.frontiersin.org/articles/10.3389/fnut.2023.1179807/full

I still have a hard time having a "disgust" function towards homocysteine the same way I have for glucose.

 

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In addition, vascular endothelium and neuronal tissue are both particularly sensitive to oxidative stress, and it is possible the observed relationships might reflect the effects of redox status on homocysteine metabolism. To fully understand this, one needs to consider the mechanism of the methionine synthase reaction in relation to vitamin B12 and its various oxidation states.

Vitamin B12 comprises a cobalt atom at the center of a tetrapyrrole ring with a variable upper axial ligand, such as a methyl, adenosyl, hydroxo, or cyano group (93). Dimethylbenzimidazole is bonded to one pyrrole and usually coordinates to cobalt as the lower axial ligand. The cobalt atom exists in three different oxidation states. In the cob(III)alamin state it is co-ordinated to the pyrrole ring as well as the upper and lower ligands. When cobalt is coordinated to the pyrrole ring alone, it is in a cob(I)alamin state. Removal of one or other axial ligands leaves cobalt in an intermediate cob(II)alamin state. In the primary turnover cycle of the MS reaction homocysteine reacts with the methyl group of methionine synthase-bound methylcobalamin to produce methionine and an unstable intermediate form, cob(I)alamin. Cob(I)alamin then reacts with 5-methyltetrahydrofolate to generate tetrahydrofolate and regenerate methylcobalamin. Vitamin B12 shuttles between methylcobalamin and cob(I)alamin states. However, cob(I)alamin is occasionally deactivated by oxidation to cob(II)alamin. Return to the primary turnover cycle requires a reactivation step in which SAM is the methyl donor. This deactivation and reactivation occur every few hundred cycles in vitro. AD and age-related oxidative stress likely augment this process (94). In addition, the homocysteine binding site of methionine synthase can also be oxidized, and folate itself can undergo irreversible oxidation. It is also likely that intracellular reduction of vitamin B12 to its active state, which requires reduced glutathione (95), might also be compromised under such conditions.

Thus, homocysteine probably compromises neuronal homeostasis by multiple, divergent routes. Assessing the relative importance of these mechanisms will be an exciting and hopefully fruitful aspect of future research. This is discussed further below.

 

 

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5.6. Protein homocysteinylation

Homocysteinylation mainly targets proteins and is classified as S-homocysteinylation and N-homocysteinylation, N-homocysteinylation is mainly discussed here. When plasma Hcy level is elevated, N-homocysteinylation of numerous proteins in cells occurs due to the interaction between the highly reactive homocysteine thiolactone (HTL) and lysine residues of a target protein. Also, when HHcy is present in atherosclerotic patients, protein homocysteinylation is enhanced (22). HTL is a cyclic thioester generated during protein biosynthesis because of error-editing reaction of Hcy with methionyl-tRNA synthetase (MetRS) (7). The N-homocysteinylation of proteins can lead to abnormal protein structure and biochemical function, which is closely involved in the injury of vascular intima caused by HHcy (109). Cellular protein quality control (PQC) is an important event in maintaining cellular homeostasis to maintain proteome integrity and cell viability, which include unfolded protein response (UPR), autophagy, ubiquitin-proteasome system (UPS), and chaperones (110–113). Numerous studies suggest that HHcy can damage PQC by activating UPR, impairing autophagy, and reducing chaperone level (114).

High-density lipoproteins is considered to have endothelial repair function, and then it was found that when HDL is homocysteinylated by N-homocysteine, it reduces ECs migration and attenuates HDL-mediated endothelial healing compared with control (109). One study found that angiotensin-converting enzyme (ACE) could be directly homocysteinylated by Hcy, which enhances ACE reactivity toward angiotensin II (ANG II)-NADPH oxidase-superoxide-dependent endothelial injury (115). Therefore, finding more proteins with specific and sensitive homocysteine changes in endothelial injury is of great value for the diagnosis and treatment of AS.

 

 

Edited January 17 by InquilineKea