Possible Involvement of Hydrosulfide in B12-Dependent Methyl Group Transfer

Abstract

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.

Is Hydrogen Sulfide a Concern During Treatment of Lung Adenocarcinoma With Ammonium Tetrathiomolybdate?

“…In fact, it has been documented that high VitB 12 can raise the risk of lung cancer (17). H 2 S can also facilitate VitB 12 -induced SAM generation (16) that is the first substrate of METTTL3/14 complex. These findings further support H 2 S-induced m 6 A methylation promotes LUAD tumor growth.…”

“…Both increased METTL3 and decreased FTO strongly suggest that LUAD tissues exhibit high m 6 A levels. However, no direct evidence has shown H 2 S can regulate m 6 A methylation, although H 2 S enhances SAM generation (16), a cofactor of METTL3/14 complex. We therefore hypothesize that m 6 A methylation is likely to be affected by H 2 S derived from ATTM and participate in LUAD development.…”

“…Some studies showed that elevated H 2 S can induce angiogenesis and tumor cell proliferation, thereby contributing to cancer development (13)(14)(15). H 2 S was also involved in VitB 12 -induced S-adenosylmethionine (SAM) generation (16), and high VitB 12 has been found to raise the risk of lung cancer (17). Notably, in lung cancer tissues, endogenous H 2 S and its producing enzymes, like cystathionine beta-synthase (CBS), cystathionine gamma lyase (CSE, also known as CTH) and 3-mercaptopyruvate sulfurtransferase (3-MST), are highly expressed thereby benefiting cancer development (18,19).…”

The Hydrogen Sulfide-Vitamin B12-Folic Acid Axis: An Intriguing Issue in Chronic Kidney Disease. A Comment on Toohey JI: “Possible Involvement of Hydrosulfide in B12-Dependent Methyl Group Transfer”. Molecules 2017, 22, 582, pii: E582

“…We read with great interest the recent article by John I. Toohey entitled “Possible Involvement of Hydrosulfide in B12-Dependent Methyl Group Transfer”, recently published in Molecules 2017, and we wish to discuss some additional insights raised by this important issue into the nephrological area [ 1 ].…”

Atomic Sulfur: An Element for Adaptation to an Oxidative Environment

“…Toohey [ 32 ] has discussed the roles of hydrosulfide and hypothesized that the sulfur atom was involved in vitamin B 12 -dependent methyl group transfer. He further proposed that sulfane sulfur/hydrogen sulfide may be beneficial in treating Alzheimer’s disease.…”