BACKGROUND AND PURPOSE: Homocystinurias are rare genetic defects characterized by altered fluxes of sulfur compounds including homocysteine and cysteine. We explored whether the severely perturbed sulfur amino acid metabolism in patients with homocystinurias affects the metabolism of hydrogen sulfide. EXPERIMENTAL APPROACH: We studied 10 treated patients with a block in the conversion of homocysteine to cysteine due to cystathionine β-synthase deficiency (CBSD) and six treated patients with remethylation defects (RMD) and an enhanced flux of sulfur metabolites via transsulfuration. Control groups for CBSD and RMD patients consisted of 22 patients with phenylketonuria on a low-protein diet and of 12 healthy controls respectively. Plasma and urine concentrations of selected sulfur compounds were analysed by HPLC and LC-MS/MS. KEY RESULTS: Patients with CBSD exhibited plasma concentrations of monobromobimane-detected sulfide similar to appropriate controls. Urinary homolanthionine and thiosulfate in CBSD were increased significantly 1.9 and 3 times suggesting higher hydrogen sulfide synthesis by γ-cystathionase and detoxification respectively. Surprisingly, patients with RMD had significantly lower plasma sulfide levels (53 and 64% of controls) with lower sulfite concentrations, and higher taurine and thiosulfate levels suggesting enhanced cysteine oxidation and hydrogen sulfide catabolism respectively. CONCLUSION AND IMPLICATIONS: The results from this study suggest that severe inherited defects in sulfur amino acid metabolism may be accompanied by only moderately perturbed hydrogen sulfide metabolism and lends support to the hypothesis that enzymes in the transsulfuration pathway may not be the major contributors to the endogenous hydrogen sulfide pool. LINKED ARTICLES: This article is part of a themed section on Chemical Biology of Reactive Sulfur Species. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.4/issuetoc.

Department of Molecular Immunology and Toxicology National Institute of Oncology Budapest Hungary

Department of Paediatrics and Adolescent Medicine Charles University 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic

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Akaike T, Ida T, Wei FY, Nishida M, Kumagai Y, Alam MM et al (2017). Cysteinyl‐tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics. Nat Commun 8: 1177. PubMed PMC

Alexander SP, Fabbro D, Kelly E, Marrion NV, Peters JA, Faccenda E et al (2017). The Concise Guide to PHARMACOLOGY 2017/18: Enzymes. Br J Pharmacol 174: S272–S359. PubMed PMC

Augustyn KD, Jackson MR, Jorns MS (2017). Use of tissue metabolite analysis and enzyme kinetics to discriminate between alternate pathways for hydrogen sulfide metabolism. Biochemistry 56: 986–996. PubMed PMC

Awwad HM, Geisel J, Obeid R (2016). Determination of trimethylamine, trimethylamine N‐oxide, and taurine in human plasma and urine by UHPLC‐MS/MS technique. J Chromatogr B Analyt Technol Biomed Life Sci 1038: 12–18. PubMed

Bogdándi V, Ida T, Sutton TR, Bianco C, Ditrói T, Koster G et al (2019). Speciation of reactive sulfur species and their reactions with alkylating agents: have we got a clue of what is inside the cell? Br J Pharmacol 176: 646–670. PubMed PMC

Carter RN, Morton NM (2016). Cysteine and hydrogen sulphide in the regulation of metabolism: insights from genetics and pharmacology. J Pathol 238: 321–332. PubMed PMC

Doka E, Pader I, Biro A, Johansson K, Cheng Q, Ballago K et al (2016). A novel persulfide detection method reveals protein persulfide‐ and polysulfide‐reducing functions of thioredoxin and glutathione systems. Sci Adv 2: e1500968. PubMed PMC

Harding SD, Sharman JL, Faccenda E, Southan C, Pawson AJ, Ireland S et al (2018). The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY. Nucl Acids Res 46: D1091–D1106. PubMed PMC

Hargreaves IP, Lee PJ, Briddon A (2002). Homocysteine and cysteine – albumin binding in homocystinuria: assessment of cysteine status and implications for glutathione synthesis? Amino Acids 22: 109–118. PubMed

Huemer M, Diodato D, Schwahn B, Schiff M, Bandeira A, Benoist JF et al (2017). Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency. J Inherit Metab Dis 40: 21–48. PubMed PMC

Ji AJ, Savon SR, Jacobsen DW (1995). Determination of total serum sulfite by HPLC with fluorescence detection. Clin Chem 41: 897–903. PubMed

Kabil O, Banerjee R (2014). Enzymology of H2S biogenesis, decay and signaling. Antioxid Redox Signal 20: 770–782. PubMed PMC

Kasinath BS, Feliers D, Lee HJ (2018). Hydrogen sulfide as a regulatory factor in kidney health and disease. Biochem Pharmacol 149: 29–41. PubMed

Kohl JB, Mellis AT, Schwarz G (2019). Homeostatic impact of sulfite and hydrogen sulfide on cysteine catabolism. Br J Pharmacol 176: 554–570. PubMed PMC

Kozich V, Krijt J, Sokolova J, Melenovska P, Jesina P, Vozdek R et al (2016). Thioethers as markers of hydrogen sulfide production in homocystinurias. Biochimie 126: 14–20. PubMed

Kožich V, Morris AAM, Blom HJ (2016). Disorders of sulfur amino acid metabolism In: Saudubray J‐M, Baumgartner MR, Walter J. (eds). Inborn Metabolic Diseases: Diagnosis and Treatment. Springer Berlin Heidelberg: Berlin, Heidelberg.

Krijt J, Vackova M, Kozich V (2001). Measurement of homocysteine and other aminothiols in plasma: advantages of using tris(2‐carboxyethyl) phosphine as reductant compared with tri‐n‐butylphosphine. Clin Chem 47: 1821–1828. PubMed

Libiad M, Motl N, Akey DL, Sakamoto N, Fearon ER, Smith JL et al. (2018). Thiosulfate Sulfurtransferase like Domain Containing 1 Protein Interacts with Thioredoxin. J Biol Chem 293: 2675–2686. PubMed PMC

Maclean KN, Sikora J, Kozich V, Jiang H, Greiner LS, Kraus E et al (2010). Cystathionine beta‐synthase null homocystinuric mice fail to exhibit altered hemostasis or lowering of plasma homocysteine in response to betaine treatment. Mol Genet Metab 101: 163–171. PubMed PMC

Majors AK, Pyeritz RE (2000). A deficiency of cysteine impairs fibrillin‐1 deposition: implications for the pathogenesis of cystathionine beta‐synthase deficiency. Mol Genet Metab 70: 252–260. PubMed

Majtan T, Krijt J, Sokolova J, Krizkova M, Ralat MA, Kent J et al (2018). Biogenesis of hydrogen sulfide and thioethers by cystathionine beta‐synthase. Antioxid Redox Signal 28: 311–323. PubMed

Mansoor MA, Ueland PM, Svardal AM (1994). Redox status and protein binding of plasma homocysteine and other aminothiols in patients with hyperhomocysteinemia due to cobalamin deficiency. Am J Clin Nutr 59: 631–635. PubMed

Melideo SL, Jackson MR, Jorns MS (2014). Biosynthesis of a central intermediate in hydrogen sulfide metabolism by a novel human sulfurtransferase and its yeast ortholog. Biochemistry 53: 4739–4753. PubMed PMC

Morava E, Rahman S, Peters V, Baumgartner MR, Patterson M, Zschocke J (2015). Quo vadis: the re‐definition of ‘inborn metabolic diseases’. J Inherit Metab Dis 38: 1003–1006. PubMed

Morris AA, Kozich V, Santra S, Andria G, Ben‐Omran TI, Chakrapani AB et al (2017). Guidelines for the diagnosis and management of cystathionine beta‐synthase deficiency. J Inherit Metab Dis 40: 49–74. PubMed PMC

Nagy P, Palinkas Z, Nagy A, Budai B, Toth I, Vasas A (2014). Chemical aspects of hydrogen sulfide measurements in physiological samples. Biochim Biophys Acta 1840: 876–891. PubMed

Nimni ME, Han B, Cordoba F (2007). Are we getting enough sulfur in our diet? Nutr Metab (Lond) 4: 24. PubMed PMC

Olson KR (2018). H2S and polysulfide metabolism: conventional and unconventional pathways. Biochem Pharmacol 149: 77–90. PubMed

Olson KR, Deleon ER, Liu F (2014). Controversies and conundrums in hydrogen sulfide biology. Nitric Oxide 41: 11–26. PubMed

Pan LL, Qin M, Liu XH, Zhu YZ (2017). The role of hydrogen sulfide on cardiovascular homeostasis: an overview with update on immunomodulation. Front Pharmacol 8: 686. PubMed PMC

Paul BD, Snyder SH (2018). Gasotransmitter hydrogen sulfide signaling in neuronal health and disease. Biochem Pharmacol 149: 101–109. PubMed PMC

Pol A, Renkema GH, Tangerman A, Winkel EG, Engelke UF, de Brouwer APM et al (2018). Mutations in SELENBP1, encoding a novel human methanethiol oxidase, cause extraoral halitosis. Nat Genet 50: 120–129. PubMed PMC

Shen X, Peter EA, Bir S, Wang R, Kevil CG (2012). Analytical measurement of discrete hydrogen sulfide pools in biological specimens. Free Radic Biol Med 52: 2276–2283. PubMed PMC

Szabo C (2016). Gasotransmitters in cancer: from pathophysiology to experimental therapy. Nat Rev Drug Discov 15: 185–203. PubMed PMC

Szabo C (2018). A timeline of hydrogen sulfide (H2S) research: from environmental toxin to biological mediator. Biochem Pharmacol 149: 5–19. PubMed PMC

Wallace JL, Motta JP, Buret AG (2018). Hydrogen sulfide: an agent of stability at the microbiome‐mucosa interface. Am J Physiol Gastrointest Liver Physiol 314: G143–G149. PubMed PMC

Wallace JL, Wang R (2015). Hydrogen sulfide‐based therapeutics: exploiting a unique but ubiquitous gasotransmitter. Nat Rev Drug Discov 14: 329–345. PubMed

Wintner EA, Deckwerth TL, Langston W, Bengtsson A, Leviten D, Hill P et al. (2010). A monobromobimane‐based assay to measure the pharmacokinetic profile of reactive sulphide species in blood. Br J Pharmacol 160: 941–957. PubMed PMC

Yang CT, Chen L, Xu S, Day JJ, Li X, Xian M (2017). Recent development of hydrogen sulfide releasing/stimulating reagents and their potential applications in cancer and glycometabolic disorders. Front Pharmacol 8: 664. PubMed PMC

Zschocke J (2016). SSIEM classification of inborn errors of metabolism In: Blau N, Duran M, Blaskovics ME, Gibson KM. (eds). Physician's Guide to the Diagnosis, Treatment, and Follow‐up of Inherited Metabolic Diseases. Springer: Berlin‐Heidelberg.

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