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.

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.

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.

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 sulfur, 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 lymphocyes and (2) it could interfere with the HIV replication process. A clinical trial of cystamine in AIDS is indicated.