Crucial role of methyla0on on SAMe and Oxida0ve Stress

Crucial role of methyla0on on SAMe and Oxida0ve Stress

Consequences of Reduced SAMe

Crea9ne Methylcobalamin Phospha9dylcholine Coenzyme Q10 Carni9ne SAMe is involved in the synthesis of: Methyla9on by SAMe is a cri9cal step in the stabiliza9on of many proteins including myelin.

www.tamu.edu/classes/bich/bmiles/ lectures/biosynaa.pdf

and I would suggest we should also include oxida0ve stress

methionine SAH SAMe X SAMe homocysteine adenosine

SAH methyltransferase Less fluid membrane High adenosine Less receptor recycling

Since damaged SAMe also can lead to increased SAH and adenosine can start to see the importance of this on a more global level methionine SAH SAMe X SAMe homocysteine adenosine

Lack of methyla9on (ie decreased PCMT) Ability to repair protein damage due to oxida9on, which in turn may cause damage to SAMe SAMe X which then generates more SAH end we end up in a catch 22

So high levels of protein damage can deplete SAMe and throw off the SAMe/SAH ra9o

Oxida9ve stress affects >>> SAMe/ SAH ra9o Also NOS/BH4 rela9onship

DNA damage 8 hydroxy 2 deoxyguanosine

Fuchs, Schroecksnadel and Frick make the interes9ng and important observa9on that oxida9ve stress may have an addi9onal impact on the methionine synthase reac9on by irreversibly oxidizing methyl folate. We agree that this would contribute to methionine synthase inac9va9on. Following our publica9on, we learned that the zinc site in methionine synthase, essen9al for binding and ac9va9ng homocysteine, might also be oxidized. Current experiments in E.coli indicate that this site is readily oxidized on treatment of cells to induce oxida9ve stress [1]. It seems likely that, for a variety of reasons, the methionine synthase reac9on will be physiologically compromised by oxida9ve stress. The differen9al effects of such stress on this enzyme and cystathionine beta synthase may explain the observed age related decline in methionine synthase ac9vity and the switch from methionine conserva9on to transsulfura9on with aging [2]. Tissues without an alterna9ve means of metabolizing homocysteine will be par9cularly affected by such stress. Their consequent increased cellular export of homocysteine might contribute to elevated plasma levels. Neurones and vascular endothelium both lack an intact transsulfura9on pathway and also lack the B12 and folate independent enzyme betaine:homocysteine methyltransferase. Homocysteine levels in these 9ssues should therefore prove to be an excellent marker of oxida9ve stress. Rather than cons9tu9ng a risk factor for vascular disease, demen9a and other neurological condi9ons, elevated plasma homocysteine might best be considered a risk marker signifying the effects of oxida9ve stress in such diseases. 1) E. Manning and R. G. Mabhews, unpublished data. 2) J.Finkelstein. Regula9on of Homocysteine Metabolism. In: Carmel R, Jacobsen DW, eds. Homocysteine in Health and Disease. Cambridge University Press, 2001: 92 99.

We read with interest the hypothesis by McCaddon et al [1] in which oxida9ve stress discussed underlying moderate hyperhomocysteinemia in AD. It is suggested that the oxida9on sensi9ve intermediate form of vitamin B12 (cob[i]alamin) will be destroyed thereby impairing remethyla9on of homocysteine and giving rise to moderate hyperhomocysteinemia. The authors further speculate that cerebral oxida9ve stress plays a major role. These assump9ons confirm our findings that oxida9ve stress may underlie moderate hyperhomocysteinemia. [2,3] Not only the intermediate form of vitamin B12 but also methyl tetrahydrofolate, the second necessary cofactor in the remethyla9on of homocysteine, is very sensi9ve to oxida9on and as a 6 subs9tuted pteridinederiva9ve is irreversibly degraded once oxidized. This may impact other clinical condi9ons such as atherosclerosis, depression and even cancer, [2 4] which are ojen associated with moderate hyperhomocysteinemia. Interes9ngly, folate deficiency is detected more ojen in pa9ents than vitamin B12 deficiency, further suppor9ng the concept that also degrada9on of folate is important. The results confirm a state of chronic immune ac9va9on in pa9ents with AD. [5] Homocysteine concentra9ons correlate with the degree of immune ac9va9on as measured by, for example, neopterin concentra9ons. [3] This associa9on is also found in other clinical condi9ons with hyperhomocysteinemia. [3,4] Ac9va9on of immunocompetent cells like T lymphocytes and macrophages is associated with the produc9on of large amounts of oxidizing compounds, indica9ng oxida9ve stress. The immunopathogene9c background of oxida9ve stress resul9ng in vitamin deple9on and thus hyperhomocysteinemia is likely and would confirm the concept proposed by McCadden et al. References 1. McCaddon A, Regland B, Hudson P, Davies G. Func9onal vitamin B(12) deficiency and Alzheimer disease. Neurology 2002;58:1395 9. 2. Widner B, Fuchs D, Leblhuber F, Sperner Unterweger B. Does disturbed homocysteine and folate metabolism in depression result from enhanced oxida9ve stress? J Neurol Neurosurg Psych 2001;70:419. 3. Fuchs D, Jaeger M, Widner B, Wirleitner B, Artner Dworzak E, Leblhuber F. Is hyperhomocysteinemia due to oxida9ve deple9on of folate rather than insufficient dietary intake. Clin Chem Lab Med 2001;39:691 4. 4. Frick B, Schröcksnadel K, Fuchs D. Folate and homocysteine levels in head and neck squamous cell carcinoma. Cancer (in press). 5. Leblhuber F, Walli J, Demel U, Tilz GP, Widner B, Fuchs D: Increased serum neopterin concentra9ons in pa9ents with Alzheimer's disease. Clin Chem Lab Med 1999;37: 429 31.