Hydrogen sulfide is a gasotransmitter, with similarities to nitric oxide and carbon monoxide. Although the enzymes indicated below have multiple enzymatic activities, the focus here is the generation of hydrogen sulphide (H₂S) and the enzymatic characteristics are described accordingly. Cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) are pyridoxal phosphate (PLP)-dependent enzymes. 3-mercaptopyruvate sulfurtransferase (3-MPST) functions to generate H₂S; only CAT is PLP-dependent, while 3-MPST is not. Thus, this third pathway is sometimes referred to as PLP-independent. CBS and CSE are predominantly cytosolic enzymes, while 3-MPST is found both in the cytosol and the mitochondria. For an authoritative review on the pharmacological modulation of H₂S levels, see Szabo and Papapetropoulos, 2017 [7].

* Key recommended reading is highlighted with an asterisk

* Asimakopoulou A, Panopoulos P, Chasapis CT, Coletta C, Zhou Z, Cirino G, Giannis A, Szabo C, Spyroulias GA, Papapetropoulos A. (2013) Selectivity of commonly used pharmacological inhibitors for cystathionine β synthase (CBS) and cystathionine γ lyase (CSE). Br J Pharmacol, 169 (4): 922-32. [PMID:23488457]

Bełtowski J. (2015) Hydrogen sulfide in pharmacology and medicine--An update. Pharmacol Rep, 67 (3): 647-58. [PMID:25933982]

Kanagy NL, Szabo C, Papapetropoulos A. (2017) Vascular biology of hydrogen sulfide. Am J Physiol, Cell Physiol, 312 (5): C537-C549. [PMID:28148499]

Kashfi K, Olson KR. (2013) Biology and therapeutic potential of hydrogen sulfide and hydrogen sulfide-releasing chimeras. Biochem Pharmacol, 85 (5): 689-703. [PMID:23103569]

Kimura H. (2011) Hydrogen sulfide: its production, release and functions. Amino Acids, 41 (1): 113-21. [PMID:20191298]

Kolluru GK, Shen X, Bir SC, Kevil CG. (2013) Hydrogen sulfide chemical biology: pathophysiological roles and detection. Nitric Oxide, 35: 5-20. [PMID:23850632]

Li L, Rose P, Moore PK. (2011) Hydrogen sulfide and cell signaling. Annu Rev Pharmacol Toxicol, 51: 169-87. [PMID:21210746]

Meng G, Zhao S, Xie L, Han Y, Ji Y. (2018) Protein S-sulfhydration by hydrogen sulfide in cardiovascular system. Br J Pharmacol, 175 (8): 1146-1156. [PMID:28432761]

Nagy P, Pálinkás Z, Nagy A, Budai B, Tóth I, Vasas A. (2014) Chemical aspects of hydrogen sulfide measurements in physiological samples. Biochim Biophys Acta, 1840 (2): 876-91. [PMID:23769856]

Singh S, Banerjee R. (2011) PLP-dependent H(2)S biogenesis. Biochim Biophys Acta, 1814 (11): 1518-27. [PMID:21315854]

* Szabo C, Papapetropoulos A. (2017) International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors. Pharmacol Rev, 69 (4): 497-564. [PMID:28978633]

Wang R. (2012) Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev, 92 (2): 791-896. [PMID:22535897]

Wang R, Szabo C, Ichinose F, Ahmed A, Whiteman M, Papapetropoulos A. (2015) The role of H2S bioavailability in endothelial dysfunction. Trends Pharmacol Sci, 36 (9): 568-78. [PMID:26071118]

1. Asimakopoulou A, Panopoulos P, Chasapis CT, Coletta C, Zhou Z, Cirino G, Giannis A, Szabo C, Spyroulias GA, Papapetropoulos A. (2013) Selectivity of commonly used pharmacological inhibitors for cystathionine β synthase (CBS) and cystathionine γ lyase (CSE). Br J Pharmacol, 169 (4): 922-32. [PMID:23488457]

2. Chen X, Jhee KH, Kruger WD. (2004) Production of the neuromodulator H2S by cystathionine beta-synthase via the condensation of cysteine and homocysteine. J Biol Chem, 279 (50): 52082-6. [PMID:15520012]

3. Croppi G, Zhou Y, Yang R, Bian Y, Zhao M, Hu Y, Ruan BH, Yu J, Wu F. (2020) Discovery of an Inhibitor for Bacterial 3-Mercaptopyruvate Sulfurtransferase that Synergistically Controls Bacterial Survival. Cell Chem Biol, 27 (12): 1483-1499.e9. [PMID:33186540]

4. Druzhyna N, Szczesny B, Olah G, Módis K, Asimakopoulou A, Pavlidou A, Szoleczky P, Gerö D, Yanagi K, Törö G et al.. (2016) Screening of a composite library of clinically used drugs and well-characterized pharmacological compounds for cystathionine β-synthase inhibition identifies benserazide as a drug potentially suitable for repurposing for the experimental therapy of colon cancer. Pharmacol Res, 113 (Pt A): 18-37. [PMID:27521834]

5. Hanaoka K, Sasakura K, Suwanai Y, Toma-Fukai S, Shimamoto K, Takano Y, Shibuya N, Terai T, Komatsu T, Ueno T et al.. (2017) Discovery and Mechanistic Characterization of Selective Inhibitors of H₂S-producing Enzyme: 3-Mercaptopyruvate Sulfurtransferase (3MST) Targeting Active-site Cysteine Persulfide. Sci Rep, 7: 40227. [PMID:28079151]

6. Nagahara N, Okazaki T, Nishino T. (1995) Cytosolic mercaptopyruvate sulfurtransferase is evolutionarily related to mitochondrial rhodanese. Striking similarity in active site amino acid sequence and the increase in the mercaptopyruvate sulfurtransferase activity of rhodanese by site-directed mutagenesis. J Biol Chem, 270 (27): 16230-5. [PMID:7608189]

7. Szabo C, Papapetropoulos A. (2017) International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors. Pharmacol Rev, 69 (4): 497-564. [PMID:28978633]

8. Zuhra K, Panagaki T, Randi EB, Augsburger F, Blondel M, Friocourt G, Herault Y, Szabo C. (2020) Mechanism of cystathionine-β-synthase inhibition by disulfiram: The role of bis(N,N-diethyldithiocarbamate)-copper(II). Biochem Pharmacol, 182: 114267. [PMID:33035509]

Subcommittee members: Andreas Papapetropoulos (Co-chairperson) Drug Discovery & Pharmacology Group Department of Pharmaceutical Chemistry Faculty of Pharmacy University of Athens Athens 15771, Greece Csaba Szabo, MD, PhD (Co-chairperson) Department of Anesthesiology The University of Texas Medical Branch at Galveston 601 Harborside Drive Galveston, TX 77555, USA Timothy R. Billiar Department of Surgery University of Pittsburgh Pittsburgh, PA, USA Giuseppe Cirino Department of Experimental Pharmacology University of Naples-Federico II Via Domenico Montesano 49 80131, Naples, Italy David Fulton Vascular Biology Center Georgia Regents University Sanders Building, CB 3940 Augusta, Georgia, USA Roberto Motterlini Director of Research (DR2) Equipe 12 INSERM U955, Faculty of Medicine University of Paris Est Creteil 94010 Creteil France