Transsulfuration Pathway Products and H2S-Donors in Hyperhomocysteinemia: Potential Strategies Beyond Folic Acid

Abstract

The transsulfuration pathway plays a central role in the regulation of sulfur metabolism and contributes to the maintenance of cellular homeostasis. Starting from homocysteine, a sulfur-containing amino acid derived from methionine via the methionine cycle, this metabolic pathway supports the biosynthesis of cysteine and other downstream products, such as taurine, serine, reduced glutathione and the gasotransmitter hydrogen sulfide (H₂S). The most common disruption of this pathway leads to hyperhomocysteinemia (HHcy), a well-known risk factor for the development of cardiometabolic diseases and other pathological conditions. In this context, identifying effective pharmacological strategies is crucial. Based on both preclinical and clinical evidence, this review provides an updated overview on the role of folates in restoring transsulfuration balance in HHcy and explores the potential effects of downstream products (such as serine, taurine, and precursors of glutathione) under HHcy conditions. Finally, it examines the pharmacological properties of H₂S-donors in cultured cells exposed to HHcy and in animal models of HHcy. This summary of the literature offers new perspectives for the treatment of HHcy and the prevention of its associated multiorgan complications.

Keywords: homocysteine; hydrogen sulfide; hyperhomocysteinemia; sulfur compounds; transsulfuration pathway.

Figure 1

Schematic representation of the folate cycle, methionine cycle and transsulfuration pathway. Abbreviations: 3-MST, 3-mercaptopyruvate sulfurtransferase; BHMT, betaine-homocysteine methyltransferase; CAT, cysteine aminotransferase; CBS, cystathionine β-synthase; CDO, cysteine dioxygenase enzyme; CSA, cysteine sulfinic acid; CSAD, cysteine sulfinic acid decarboxylase; CSE, cystathionine γ-liase; Cys, cysteine; DMG, dimethylglycine; Glut, glutamate; GS, glutathione synthetase; GSH, reduced glutathione; H₂S, hydrogen sulfide; Hcy, homocysteine; HTAU-DH, hypotaurine dehydrogenase; Met, methionine; MS, methionine synthase; MTHFR, methylenetetrahydrofolate reductase; SAH, S-adenosyl homocysteine; SAM, S-adenosyl methionine; THF, tetrahydrofolate; γ-GCS, γ-glutamyl cysteine synthetase; γ-Glu-Cys, γ-glutamyl cysteine.

Figure 2

Classification of hyperhomocysteinemia (HHcy) severity based on plasma homocysteine (Hcy) concentrations in humans.

Figure 3

Hyperhomocysteinemia, the most common alteration of the transsulfuration pathway (red plot), contributes to multiorgan damage. This imbalance can potentially be restored (green plot) through supplementation/treatment with (a) folic acid and non-sulfur amino acids (i.e., serine), (b) sulfur-containing products of the transsulfuration pathway (i.e., cysteine, taurine, glutathione, or cystine), and (c) hydrogen sulfide (H₂S)-donors. Abbreviations: CSA, cysteine sulfinic acid; Cys, cysteine; DMG, dimethylglycine; GSH, reduced glutathione; Hcy, homocysteine; HHcy, hyperhomocysteinemia; Met, methionine; SAH, S-adenosyl homocysteine; SAM, S-adenosyl methionine; THF, tetrahydrofolate; γ-Glu-Cys, γ-glutamyl cysteine.