Here I make statements and give references.
Homocysteine is involved in two pathways: remethylation to methionine, which requires folate and vitamin B12 (or betaine in an alternative reaction); and transsulfuration to cystathionine, which requires pyridoxal-5-phosphate. The two pathways are coordinated by S-adenosylmethionine, which acts as an allosteric inhibitor of the methylene tetrahydrofolate reductase reaction and as an activator of cystathionine ?-synthase.
Target is to get levels down to 8umol/L or less.
When we look closely at the role of the interplay between folate, B12 and homocysteine, we see why it is important to attain optimal levels.
Folate and its metabolites are important for purine metabolism, but also in production of the pyrimidine base, thymine.
When homocysteine is methylated into methionine it enables the production of methionine and S-adenosyl methionine (SAMe), which plays a role in serotonin metabolism, in conversion of phosphatidyl ehanolamine into phosphatidyl choline (a stepping stone to make acetyl choline.)
Creatine synthesis is a major use of methyl groups.
Methylation of nucleotides and their use in forming methylated RNA and DNA is also protective.
A deficiency in B12 impairs the formation of methionine, increases methyl malonyl CoA and methyl malonic acid.
The are variation is individual requirements, but higher B12 and folate levels decrease DNA and RNAS damage. (M Fenech, CSIRO)
Increased plasma MMA was seen when plasma vitamin B12 was < 400 pmol/L. (Vogiatzoglou et al, 2009)
High homocysteine is associated with faster shortening of telomeres (used for DNA repair)
Homocysteine seems to increase the expression of vascular adhesion molecules
The detrimental T allele exerted an additive effect to increase sVCAM and decrease NOx concentrations, which may contribute to atherosclerosis. (JUO et al, 2007)
Also the high pKa of the sulfhydryl group (pKa, 10.0) of homocysteine underlies its ability to form stable disulfide bonds with protein cysteine residues, and in the process, alters or impairs the function of the protein. Studies in this laboratory have identified albumin, fibronectin, transthyretin, and metallothionein as targets for homocysteinylation. In the case of albumin, the mechanism of targeting has been elucidated.
Homocysteinylation of the cysteine residues of fibronectin impairs its ability to bind to fibrin. Homocysteinylation of the cysteine residues of metallothionein disrupts zinc binding by the protein and abrogates inherent superoxide dismutase activity.
Thus, S-homocysteinylation of protein cysteine residues may explain mechanistically the cytotoxicity of elevated homocysteine.
(Glushchenko et al, 2007)
Several authors highlight the importance of looking at both homocysteine production and removal in understanding these regulations. (Brosnan et al 2004)
Hyperhomocysteinemia (HHcy) is a risk factor for neuroinflammatory and neurodegenerative diseases. Homocysteine (Hcy) induces redox stress, in part, by activating matrix metalloproteinase-9 (MMP-9), which degrades the matrix and leads to blood-brain barrier dysfunction. Hcy competitively binds to gamma-aminbutyric acid (GABA) receptors, which are excitatory neurotransmitter receptors.( Neetu Tyagi, 2009)
Further implications
Plasma HC levels in L-dopa treated Parkinson’s patients are about 50% higher than in controls.
Clin Chem. 2009 Oct 15. [Epub ahead of print]
Links
Determinants of Plasma Methylmalonic Acid in a Large Population: Implications for Assessment of Vitamin B12 Status.
Vogiatzoglou A, Oulhaj A, Smith AD, Nurk E, Drevon CA, Ueland PM, Vollset SE, Tell GS, Refsum H.
Atherosclerosis. 2008 Feb 14 [Epub ahead of print]
Links
Homocysteine levels and leukocyte telomere length.
Richards JB, Valdes AM, Gardner JP, Kato BS, Siva A, Kimura M, Lu X, Brown MJ, Aviv A, Spector TD.
Centre for Twin Research and Genetic Epidemiology Unit, St. Thomas’ Hospital, King’s College London School of Medicine, London SE1 7EH, UK.
Methylation demand: a key determinant of homocysteine
metabolism
John T. Brosnan1 , Rene L. Jacobs2, Lori M. Stead1 and Margaret E. Brosnan1
1Department of Biochemistry, Memorial University of Newfoundland, St. John’s, Canada;
2CIHR Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Canada
Molecular mechanisms of homocysteine toxicity.
Biochemistry (Mosc). 2009 Jun;74(6):589–98
Biological Faculty, Lomonosov Moscow State University, Moscow, 119992, Russia. alexander.boldyrev@gmail.com
Hyperhomocysteinemia is a risk factor for a number of cardiovascular and neurodegenerative processes as well as a complicating factor in normal pregnancy. Toxic effects of homocysteine and the product of its spontaneous oxidation, homocysteic acid, are based on their ability to activate NMDA receptors, increasing intracellular levels of ionized calcium and reactive oxygen species. Even a short-term exposure of cells to homocysteic acid at concentrations characteristic of hyperhomocysteinemia induces their apoptotic transformation. The discovery of NMDA receptors both in neuronal tissue and in several other tissues and organs (including immunocompetent cells) makes them a target for toxic action of homocysteine. The neuropeptide carnosine was found to protect the organism from homocysteine toxicity.
Treatment of pregnant rats with carnosine under conditions of alimentary hyperhomocysteinemia increases viability and functional activity of their progeny.
