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.

Dear Editor, 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]. Sulfur in the form of sulfane sulfur or hydrogen sulfide (H2S) has been shown to have numerous regulatory effects in several biological systems. The author addresses the hypothesis that the sulfur atom could also be involved in vitamin B12-dependent methyl group transfer. The impairment of this metabolic pathway leads to decreased methionine synthesis, decreased S-adenosylmethionine (SAM) availability, and ultimately to hypomethylation of essential sites. The methylation of molecules such as creatine, DNA, RNA, phosphatidylcholine, and many neurotransmitters occurs through a transmethylation process. The final donor of methyl groups in this pathway is usually SAM, and the end-product of methyl group transfer from SAM is homocysteine which is remethylated by B12-dependent methyltetrahydrofolate (CH3-THF)-homocysteine S-methyltransferase, also called methionine synthase (MS). SAM-mediated methylation reactions are indirectly dependent on the B12-dependent methylation of homocysteine [2]. During the metabolism of homocysteine to cysteine by the enzymes cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE), H2S is also produced as a side product. H2S is an angiogenic agent with antioxidant and vasorelaxing properties. Hyperhomocysteinemia causes downregulation of CBS and CSE, resulting in H2S depletion, which in turn leads to vascular damage, vascular disease, and subsequently to deterioration of endothelial function [3]. At each stage of chronic kidney disease (CKD), the risk of cardiovascular mortality is increased several-fold compared to that of the general population, particularly when CKD progresses to end-stage renal disease (ESRD) [4]. Various possible underlying pathophysiological pathways have been proposed to account for this excess mortality. Hyperhomocysteinemia occurs in about 85% of CKD patients because of altered renal metabolism and impaired excretion [5]. Homocysteine is currently regarded as an independent predictor of cardiovascular morbidity and mortality in ESRD patients [6,7]. Folic acid and vitamins B12 and B6 are important regulators of homocysteine metabolism. Vascular cells—in particular vascular endothelial cells—are believed to be particularly susceptible to elevated