Possible Involvement of Hydrosulfide in B12-Dependent Methyl Group Transfer.

Evidence from several fields of investigation lead to the hypothesis that the sulfur atom is involved in vitamin B12-dependent methyl group transfer. To compile the evidence, it is necessary to briefly review the following fields: methylation, the new field of sulfane sulfur/hydrogen sulfide (S°/H2S), hydrosulfide derivatives of cobalamins, autoxidation of hydrosulfide radical, radical S-adenosylmethionine methyl transfer (RSMT), and methionine synthase (MS). Then, new reaction mechanisms for B12-dependent methyl group transfer are proposed; the mechanisms are facile and overcome difficulties that existed in previously-accepted mechanisms. Finally, the theory is applied to the effect of S°/H2S in nerve tissue involving the "hypomethylation theory" that was proposed 50 years ago to explain the neuropathology resulting from deficiency of vitamin B12 or folic acid. The conclusions are consistent with emerging evidence that sulfane sulfur/hydrogen sulfide may be beneficial in treating Alzheimer's disease.

Thiosulfoxide (sulfane) sulfur: new chemistry and new regulatory roles in biology.

The understanding of sulfur bonding is undergoing change. Old theories on hypervalency of sulfur and the nature of the chalcogen-chalcogen bond are now questioned. At the same time, there is a rapidly expanding literature on the effects of sulfur in regulating biological systems. The two fields are inter-related because the new understanding of the thiosulfoxide bond helps to explain the newfound roles of sulfur in biology. This review examines the nature of thiosulfoxide (sulfane, S0) sulfur, the history of its regulatory role, its generation in biological systems, and its functions in cells. The functions include synthesis of cofactors (molybdenum cofactor, iron-sulfur clusters), sulfuration of tRNA, modulation of enzyme activities, and regulating the redox environment by several mechanisms (including the enhancement of the reductive capacity of glutathione). A brief review of the analogous form of selenium suggests that the toxicity of selenium may be due to over-reduction caused by the powerful reductive activity of glutathione perselenide.

Sulfur amino acids in diet-induced fatty liver: a new perspective based on recent findings.

The relationship of sulfur amino acids to diet-induced fatty liver was established 80 years ago, with cystine promoting the condition and methionine preventing it. This relationship has renewed importance today because diet-induced fatty liver is relevant to the current epidemics of obesity, non-alcoholic fatty liver disease, metabolic syndrome, and type 2 diabetes. Two recent papers provide the first evidence linking sulfane sulfur to diet-induced fatty liver opening a new perspective on the problem. This review summarizes the early data on sulfur amino acids in fatty liver and correlates that data with current knowledge of sulfur metabolism. Evidence is reviewed showing that the lipotropic effect of methionine may be mediated by sulfane sulfur and that the hepatosteatogenic effect of cystine may be related to the removal of sulfane sulfur by cysteine catabolites. Possible preventive and therapeutic strategies are discussed.

Sulfur metabolism in AIDS: cystamine as an anti-HIV agent.

Numerous reports have documented disturbances of sulfur metabolism in AIDS patients. There is a generalized loss of sulfur from the body, measured as cysteine and glutathione. The enzyme, cystathionase, has been shown to be greatly decreased in the liver of AIDS patients. Cystathionase is known to catalyze beta elimination of cystine giving rise to sulfane sulphur, which has potent stimulatory properties for lymphocytes. When both cystine and cystathionase are deficient in AIDS, the lymphocytes would lack this important regulator, which might be replenished by giving cystamine. Cystamine is a small disulfide that gives rise to sulfane sulfur when it undergoes oxidation catalyzed by diamine oxidase (a ubiquitous enzyme in animals). Cystamine has been shown to cause marked suppression of HIV replication in cultured lymphocytes and macrophages; the inference is that the cystamine/diamine oxidase system may replace the cystine/cystathionase system as a source of sulfane sulfur. Sulfane sulfur could have two beneficial effects: (1) it could increase the vigor and resistance of the lymphocytes and (2) it could interfere with the HIV replication process. A clinical trial of cystamine in AIDS is indicated.

Dehydroascorbic acid as an anti-cancer agent.

Three discoveries together point the way to a potential treatment for cancer. In 1982, Poydock and colleagues found that dehydroascorbic acid has the remarkable ability to eliminate the aggressive mouse tumours, L1210, P388, Krebs sarcoma, and Ehrlich carcinoma. In 1993, Jakubowski found that cancer cells (but not normal cells) contain measurable quantities of homocysteine thiolactone. Recently, the author found that dehydroascorbic acid reacts with homocysteine thiolactone converting it to the toxic compound, 3-mercaptopropionaldehyde. Taken together, these findings suggest that rapidly-dividing tumour cells make unusually large amounts of homocysteine thiolactone and that administered dehydroascorbic acid enters the cells and converts the thiolactone to mercaptopropionaldehyde which kills the cancer cells. The effectiveness of dehydroascorbic acid might be further increased by combining it with methionine and/or methotrexate to increase the homocysteine concentration in cancer cells.

Homocysteine toxicity in connective tissue: theories, old and new.

Hyperhomocysteinemia causes connective tissue pathology. Several theories on the mechanism of homocysteine toxicity in connective tissue are reviewed briefly. A possible new mechanism was revealed recently in the discovery of a reaction in which homocysteine thiolactone is converted to mercaptopropionaldehyde. The reaction is the Strecker degradation of amino acids in which ninhydrin is replaced by the structurally similar dehydroascorbic acid. The reaction may occur in vivo and may be pathogenic to connective tissue in four ways: (1) the reaction may deplete ascorbic acid that is required for collagen synthesis, (2) the mercaptoaldehyde product may interfere with collagen synthesis, (3) the mercaptoaldehyde may cause abnormal cross-linking of collagen molecules, and (4) the mercaptoaldehyde may attach to collagen molecules rendering them antigenic and triggering an autoimmune response.

Mercaptopropionaldehyde from homocysteine: implications for Alzheimer's disease.

There has been evidence for a causal relationship between homocysteine and Alzheimer's disease for several years but the mechanism is unclear. In vivo, some homocysteine is converted to the thiolactone. This report describes a novel reaction between homocysteine thiolactone and dehydroascorbic acid in which the homocysteine thiolactone is converted to 3-mercaptopropionaldehyde. This product is shown to react with proteins causing their precipitation (probably by cross-linking). The two reactions are extremely facile and appear to be physiologically compatible suggesting a mechanism by which homocysteine may promote the deposition of proteins in nerve cells as amyloid plaques and fibrillary tangles.

Vitamin B12 and methionine synthesis: a critical review. Is nature's most beautiful cofactor misunderstood?

The mechanism by which Vitamin B12 prevents demyelination of nerve tissue is still not known. The evidence indicates that the critical site of B12 function in nerve tissue is in the enzyme, methionine synthase, in a system which requires S-adenosylmethionine. In recent years it has been recognized that S-adenosylmethionine gives rise to the deoxyadenosyl radical which catalyzes many reactions including the rearrangement of lysine to beta-lysine. Evidence is reviewed which suggests that there is an analogy between the two systems and that S-adenosyl methionine may catalyze a rearrangement of homocysteine on methionine synthase giving rise to iso- or beta-methionine. The rearranged product is readily degraded to CH3-SH, providing a mechanism for removing toxic homocysteine.