BACKGROUND: Cystathionine β-synthase (CBS)-deficient homocystinuria (HCU) is an inherited disorder of sulfur amino acid metabolism with varying severity and organ complications, and a limited knowledge about underlying pathophysiological processes. Here we aimed at getting an in-depth insight into disease mechanisms using a transgenic mouse model of HCU (I278T). METHODS: We assessed metabolic, proteomic and sphingolipidomic changes, and mitochondrial function in tissues and body fluids of I278T mice and WT controls. Furthermore, we evaluated the efficacy of methionine-restricted diet (MRD) in I278T mice. RESULTS: In WT mice, we observed a distinct tissue/body fluid compartmentalization of metabolites with up to six-orders of magnitude differences in concentrations among various organs. The I278T mice exhibited the anticipated metabolic imbalance with signs of an increased production of hydrogen sulfide and disturbed persulfidation of free aminothiols. HCU resulted in a significant dysregulation of liver proteome affecting biological oxidations, conjugation of compounds, and metabolism of amino acids, vitamins, cofactors and lipids. Liver sphingolipidomics indicated upregulation of the pro-proliferative sphingosine-1-phosphate signaling pathway. Liver mitochondrial function of HCU mice did not seem to be impaired compared to controls. MRD in I278T mice improved metabolic balance in all tissues and substantially reduced dysregulation of liver proteome. CONCLUSION: The study highlights distinct tissue compartmentalization of sulfur-related metabolites in normal mice, extensive metabolome, proteome and sphingolipidome disruptions in I278T mice, and the efficacy of MRD to alleviate some of the HCU-related biochemical abnormalities.

BIOCEV 1st Faculty of Medicine Charles University 252 50 Vestec Czech Republic

Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA

Department of Environmental Medicine and Molecular Toxicology Tohoku University Graduate School of Medicine Sendai 980 8575 Japan

Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory National Institute of Oncology Budapest 1122 Hungary

Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory National Institute of Oncology Budapest 1122 Hungary; Department of Anatomy and Histology HUN REN UVMB Laboratory of Redox Biology Research Group University of Veterinary Medicine 1078 Budapest Hungary; Chemistry Institute University of Debrecen 4012 Debrecen Hungary

Department of Nutrition Institute of Basic Medical Sciences University of Oslo Oslo Norway

Department of Nutrition Institute of Basic Medical Sciences University of Oslo Oslo Norway; Department of Pediatrics and Inherited Metabolic Disorders Charles University 1st Faculty of Medicine Prague 12808 Czech Republic

Department of Pediatrics and Inherited Metabolic Disorders Charles University 1st Faculty of Medicine Prague 12808 Czech Republic; Department of Pediatrics and Inherited Metabolic Disorders General University Hospital Prague Prague 12808 Czech Republic

Department of Pharmacology University of Fribourg Faculty of Science and Medicine Fribourg 1700 Switzerland

See more in PubMed

Mudd S.H., Finkelstein J.D., Irreverre F., Laster L. Homocystinuria: an enzymatic defect. Science. 1964;143:1443–1445. PubMed

Mudd S.H., Skovby F., Levy H.L., Pettigrew K.D., Wilcken B., Pyeritz R.E., Andria G., Boers G.H.J., Bromberg I.L., Cerone R., Fowler B., Grobe H., Schmidt H., Schweitzer L. The natural history of homocystinuria due to cystathionine b-synthase deficiency. Am. J. Hum. Genet. 1985;37:1–31. PubMed PMC

Kozich V., Sokolova J., Morris A.A.M., Pavlikova M., Gleich F., Kolker S., Krijt J., Dionisi-Vici C., Baumgartner M.R., Blom H.J., Huemer M., consortium E.H. Cystathionine beta-synthase deficiency in the E-HOD registry-part I: pyridoxine responsiveness as a determinant of biochemical and clinical phenotype at diagnosis. J. Inherit. Metab. Dis. 2021;44:677–692. PubMed PMC

Zuhra K., Augsburger F., Majtan T., Szabo C. Cystathionine-beta-Synthase: molecular regulation and pharmacological inhibition. Biomolecules. 2020;10:697. PubMed PMC

Kraus J.P., Janosik M., Kozich V., Mandell R., Shih V., Sperandeo M.P., Sebastio G., de Franchis R., Andria G., Kluijtmans L.A.J., Blom H., Boers G.H.J., Gordon R.B., Kamoun P., Tsai M.Y., Kruger W.D., Koch H.G., Ohura T., Gaustadnes M. Cystathionine b-synthase mutations in homocystinuria. Hum.Mutation. 1999;13:362–375. PubMed

Finkelstein J.D. Methionine metabolism in mammals. J. Nutr. Biochem. 1990;1:228–237. PubMed

Kožich V., Morris A.A.M., Blom H.J. In: Inborn Metabolic Diseases: Diagnosis and Treatment. Saudubray J.-M., Baumgartner M.R., García-Cazorla Á., Walter J., editors. Springer Berlin Heidelberg; Berlin, Heidelberg: 2022. Disorders of sulfur amino acid MetabolismSulfur amino acid metabolism; pp. 407–422.

Majtan T., Kozich V., Kruger W.D. Recent therapeutic approaches to cystathionine beta-synthase-deficient homocystinuria. Br. J. Pharmacol. 2023;180:264–278. PubMed PMC

Morris A.A., Kozich V., Santra S., Andria G., Ben-Omran T.I., Chakrapani A.B., Crushell E., Henderson M.J., Hochuli M., Huemer M., Janssen M.C., Maillot F., Mayne P.D., McNulty J., Morrison T.M., Ogier H., O'Sullivan S., Pavlikova M., de Almeida I.T., Terry A., Yap S., Blom H.J., Chapman K.A. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J. Inherit. Metab. Dis. 2017;40:49–74. PubMed PMC

Kruger W.D. How to fix a broken protein: restoring function to mutant human cystathionine beta-synthase. Hum. Genet. 2022;141:1299–1308. PubMed PMC

Morrison T., Bosch F., Landolt M.A., Kozich V., Huemer M., Morris A.A.M. Homocystinuria patient and caregiver survey: experiences of diagnosis and patient satisfaction. Orphanet J. Rare Dis. 2021;16:124. PubMed PMC

Skvorak K., Mitchell V., Teadt L., Franklin K.A., Lee H.O., Kruse N., Huitt-Roehl C., Hang J., Du F., Galanie S., Guan S., Aijaz H., Zhang N., Rajkovic G., Kruger W.D., Ismaili M.H.A., Huisman G., McCluskie K., Silverman A.P. An orally administered enzyme therapeutic for homocystinuria that suppresses homocysteine by metabolizing methionine in the gastrointestinal tract. Mol. Genet. Metabol. 2023;139 PubMed

Perreault M., Means J., Gerson E., James M., Cotton S., Bergeron C.G., Simon M., Carlin D.A., Schmidt N., Moore T.C., Blasbalg J., Sondheimer N., Ndugga-Kabuye K., Denney W.S., Isabella V.M., Lubkowicz D., Brennan A., Hava D.L. The live biotherapeutic SYNB1353 decreases plasma methionine via directed degradation in animal models and healthy volunteers. Cell Host Microbe. 2024;32:382–395. PubMed

Kruger W.D. Cystathionine beta-synthase deficiency: of mice and men. Mol. Genet. Metabol. 2017;121:199–205. PubMed PMC

Watanabe M., Osada J., Aratani Y., Kluckman K., Reddick R., Malinow M.R., Maeda N. Mice deficient in cystathionine b-synthase: Animal models for mild and severe homocyst(e)inemia. Proceedings of the National Academy of Sciences USA. 1995;92:1585–1589. PubMed PMC

Maclean K.N., Sikora J., Kozich V., Jiang H., Greiner L.S., Kraus E., Krijt J., Overdier K.H., Collard R., Brodsky G.L., Meltesen L., Crnic L.S., Allen R.H., Stabler S.P., Elleder M., Rozen R., Patterson D., Kraus J.P. A novel transgenic mouse model of CBS-deficient homocystinuria does not incur hepatic steatosis or fibrosis and exhibits a hypercoagulative phenotype that is ameliorated by betaine treatment. Mol. Genet. Metabol. 2010;101:153–162. PubMed PMC

Majtan T., Hulkova H., Park I., Krijt J., Kozich V., Bublil E.M., Kraus J.P. Enzyme replacement prevents neonatal death, liver damage, and osteoporosis in murine homocystinuria. Faseb. J. 2017;31:5495–5506. PubMed PMC

Wang L., Chen X., Tang B., Hua X., Klein-Szanto A., Kruger W.D. Expression of mutant human cystathionine beta-synthase rescues neonatal lethality but not homocystinuria in a mouse model. Hum. Mol. Genet. 2005;14:2201–2208. PubMed PMC

Gupta S., Kuhnisch J., Mustafa A., Lhotak S., Schlachterman A., Slifker M.J., Klein-Szanto A., High K.A., Austin R.C., Kruger W.D. Mouse models of cystathionine beta-synthase deficiency reveal significant threshold effects of hyperhomocysteinemia. Faseb. J. 2009;23:883–893. PubMed PMC

Dayal S., Chauhan A.K., Jensen M., Leo L., Lynch C.M., Faraci F.M., Kruger W.D., Lentz S.R. Paradoxical absence of a prothrombotic phenotype in a mouse model of severe hyperhomocysteinemia. Blood. 2012;119:3176–3183. PubMed PMC

Gupta S., Melnyk S.B., Kruger W.D. Cystathionine beta-synthase-deficient mice thrive on a low-methionine diet. Faseb. J. 2014;28:781–790. PubMed PMC

Majtan T., Jones W., Jr., Krijt J., Park I., Kruger W.D., Kozich V., Bassnett S., Bublil E.M., Kraus J.P. Enzyme replacement therapy ameliorates multiple symptoms of murine homocystinuria. Mol. Ther. 2018;26:834–844. PubMed PMC

Majtan T., Park I., Cox A., Branchford B.R., di Paola J., Bublil E.M., Kraus J.P. Behavior, body composition, and vascular phenotype of homocystinuric mice on methionine-restricted diet or enzyme replacement therapy. Faseb. J. 2019;33:12477–12486. PubMed PMC

Lee H.O., Salami C.O., Sondhi D., Kaminsky S.M., Crystal R.G., Kruger W.D. Long-term functional correction of cystathionine beta-synthase deficiency in mice by adeno-associated viral gene therapy. J. Inherit. Metab. Dis. 2021;44:1382–1392. PubMed PMC

Kozich V., Krijt J., Sokolova J., Melenovska P., Jesina P., Vozdek R., Majtan T., Kraus J.P. Thioethers as markers of hydrogen sulfide production in homocystinurias. Biochimie. 2016;126:14–20. PubMed

Kozich V., Ditroi T., Sokolova J., Krizkova M., Krijt J., Jesina P., Nagy P. Metabolism of sulfur compounds in homocystinurias. Br. J. Pharmacol. 2019;176:594–606. PubMed PMC

Kožich V., Schwahn B., Sokolová J., Křížková M., Ditroi T., Krijt J., Khalil Y., Křížek T., Vaculíková-Fantlová T., Stibůrková B., Mills P., Clayton P., Barvíková K., Blessing H., Sykut-Cegielska J., Dionisi-Vici C., Gasperini S., Garcia Cazorla A., Haack T., Honzík T., Ješina P., Kuster A., Laugwitz L., Martinelli D., Porta F., Santer R., Schwarz G., Nagy P. Human ultrarare genetic disorders of sulfur metabolism demonstrate redundancies in H2S homeostasis. Redox Biol. 2022;58 PubMed PMC

Krijt J., Duta A., Kozich V. Determination of S-Adenosylmethionine and S-Adenosylhomocysteine by LC-MS/MS and evaluation of their stability in mice tissues. J. Chromatogr., B: Anal. Technol. Biomed. Life Sci. 2009;877:2061–2066. PubMed PMC

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

Ditroi T., Nagy A., Martinelli D., Rosta A., Kozich V., Nagy P. Comprehensive analysis of how experimental parameters affect H(2)S measurements by the monobromobimane method. Free Radic. Biol. Med. 2019;136:146–158. PubMed

Akaike T., Ida T., Wei F.Y., Nishida M., Kumagai Y., Alam M.M., Ihara H., Sawa T., Matsunaga T., Kasamatsu S., Nishimura A., Morita M., Tomizawa K., Nishimura A., Watanabe S., Inaba K., Shima H., Tanuma N., Jung M., Fujii S., Watanabe Y., Ohmuraya M., Nagy P., Feelisch M., Fukuto J.M., Motohashi H. Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics. Nat. Commun. 2017;8:1177. PubMed PMC

Bugajev V., Halova I., Demkova L., Cernohouzova S., Vavrova P., Mrkacek M., Utekal P., Draberova L., Kuchar L., Schuster B., Draber P. ORMDL2 deficiency potentiates the ORMDL3-dependent changes in mast cell signaling. Front. Immunol. 2020;11 PubMed PMC

Boudewyn L.C., Sikora J., Kuchar L., Ledvinova J., Grishchuk Y., Wang S.L., Dobrenis K., Walkley S.U. N-butyldeoxynojirimycin delays motor deficits, cerebellar microgliosis, and Purkinje cell loss in a mouse model of mucolipidosis type IV. Neurobiol. Dis. 2017;105:257–270. PubMed PMC

Rustin P., Chretien D., Bourgeron T., Gerard B., Rotig A., Saudubray J.M., Munnich A. Biochemical and molecular investigations in respiratory chain deficiencies. Clin. Chim. Acta. 1994;228:35–51. PubMed

Srere P.A. Academic Press; 1969. [1] Citrate Synthase: [EC 4.1.3.7. Citrate Oxaloacetate-Lyase (CoA-Acetylating)], Methods in Enzymology; pp. 3–11.

Mosca F., Fattorini D., Bompadre S., Littarru G.P. Assay of coenzyme Q(10) in plasma by a single dilution step. Anal. Biochem. 2002;305:49–54. PubMed

Krizova J., Hulkova M., Capek V., Mlejnek P., Silhavy J., Tesarova M., Zeman J., Hansikova H. Microarray and qPCR analysis of mitochondrial metabolism activation during prenatal and early postnatal development in rats and humans with emphasis on CoQ(10) biosynthesis. Biology. 2021;10 PubMed PMC

Lowry O.H., Rosebrough N.J., Farr A.L., Randall R.J. Protein measurement with the folin phenol reagent. J. Biol. Chem. 1951;193:265–275. PubMed

Petrosino M., Zuhra K., Kopec J., Hutchin A., Szabo C., Majtan T. H2S biogenesis by cystathionine beta-synthase: mechanism of inhibition by aminooxyacetic acid and unexpected role of serine. Cell. Mol. Life Sci. 2022;79:438. PubMed PMC

Majtan T., Krijt J., Sokolova J., Krizkova M., Ralat M.A., Kent J., Gregory J.F., 3rd, Kozich V., Kraus J.P. Biogenesis of hydrogen sulfide and thioethers by cystathionine beta-synthase. Antioxidants Redox Signal. 2018;28:311–323. PubMed

Chiku T., Padovani D., Zhu W., Singh S., Vitvitsky V., Banerjee R. H2S biogenesis by human cystathionine gamma-lyase leads to the novel sulfur metabolites lanthionine and homolanthionine and is responsive to the grade of hyperhomocysteinemia. J. Biol. Chem. 2009;284:11601–11612. PubMed PMC

Pajares M.A., Perez-Sala D. Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism? Cell. Mol. Life Sci. 2006;63:2792–2803. PubMed PMC

Lu S.C. Regulation of hepatic glutathione synthesis: current concepts and controversies. Faseb. J. 1999;13:1169–1183. PubMed

Stipanuk M.H., Dominy J.E., Jr., Lee J.I., Coloso R.M. Mammalian cysteine metabolism: new insights into regulation of cysteine metabolism. J. Nutr. 2006;136:1652S–1659S. PubMed

Gaull G.E., Schaffner F. Electron microscopic changes in hepatocytes of patients with homocystinuria. Pediatr. Res. 1971;5:23–32.

Gupta S., Kruger W.D. Cystathionine beta-synthase deficiency causes fat loss in mice. PLoS One. 2011;6 PubMed PMC

Gaull G.E., Sturman J.A., Schaffner F. Homocystinuria due to cystathionine synthase deficiency: enzymatic and ultrastructural studies. J. Pediatr. 1974;84:381–390. PubMed

Park I., Hulkova H., Krijt J., Kozich V., Bublil E.M., Majtan T. Long-term uninterrupted enzyme replacement therapy prevents liver disease in murine model of severe homocystinuria. Hum. Mutat. 2020;41:1662–1670. PubMed

Maclean K.N., Sikora J., Kozich V., Jiang H., Greiner L.S., Kraus E., Krijt J., Crnic L.S., Allen R.H., Stabler S.P., Elleder M., Kraus J.P. Cystathionine beta-synthase null homocystinuric mice fail to exhibit altered hemostasis or lowering of plasma homocysteine in response to betaine treatment. Mol. Genet. Metabol. 2010;101:163–171. PubMed PMC

Gupta S., Lee H.O., Wang L., Kruger W.D. Examination of two different proteasome inhibitors in reactivating mutant human cystathionine beta-synthase in mice. PLoS One. 2023;18 PubMed PMC

Kabil O., Vitvitsky V., Xie P., Banerjee R. The quantitative significance of the transsulfuration enzymes for H2S production in murine tissues. Antioxidants Redox Signal. 2011;15:363–372. PubMed PMC

Bianco C.L., Akaike T., Ida T., Nagy P., Bogdandi V., Toscano J.P., Kumagai Y., Henderson C.F., Goddu R.N., Lin J., Fukuto J.M. The reaction of hydrogen sulfide with disulfides: formation of a stable trisulfide and implications for biological systems. Br. J. Pharmacol. 2019;176:671–683. PubMed PMC

Bogdandi V., Ida T., Sutton T.R., Bianco C., Ditroi T., Koster G., Henthorn H.A., Minnion M., Toscano J.P., van der Vliet A., Pluth M.D., Feelisch M., Fukuto J.M., Akaike T., Nagy P. Speciation of reactive sulfur species and their reactions with alkylating agents: do we have any clue about what is present inside the cell? Br. J. Pharmacol. 2019;176:646–670. PubMed PMC

Takata T., Jung M., Matsunaga T., Ida T., Morita M., Motohashi H., Shen X., Kevil C.G., Fukuto J.M., Akaike T. Methods in sulfide and persulfide research. Nitric Oxide. 2021;116:47–64. PubMed PMC

Zainol Abidin Q.H., Ida T., Morita M., Matsunaga T., Nishimura A., Jung M., Hassan N., Takata T., Ishii I., Kruger W., Wang R., Motohashi H., Tsutsui M., Akaike T. Synthesis of sulfides and persulfides is not impeded by disruption of three canonical enzymes in sulfur metabolism. Antioxidants. 2023;12 PubMed PMC

Jiang H., Stabler S.P., Allen R.H., Abman S.H., Maclean K.N. Altered hepatic sulfur metabolism in cystathionine beta-synthase-deficient homocystinuria: regulatory role of taurine on competing cysteine oxidation pathways. Faseb. J. 2014;28:4044–4054. PubMed PMC

Stipanuk M.H., Ueki I., Dominy J.E., Jr., Simmons C.R., Hirschberger L.L. Cysteine dioxygenase: a robust system for regulation of cellular cysteine levels. Amino Acids. 2009;37:55–63. PubMed PMC

Poloni S., Leistner-Segal S., Bandeira I.C., D'Almeida V., de Souza C.F., Spritzer P.M., Castro K., Tonon T., Nalin T., Imbard A., Blom H.J., Schwartz I.V. Body composition in patients with classical homocystinuria: body mass relates to homocysteine and choline metabolism. Gene. 2014;546:443–447. PubMed

Zhang X., Li S., Zhou Y., Su W., Ruan X., Wang B., Zheng F., Warner M., Gustafsson J.A., Guan Y. Ablation of cytochrome P450 omega-hydroxylase 4A14 gene attenuates hepatic steatosis and fibrosis. Proc. Natl. Acad. Sci. U.S.A. 2017;114:3181–3185. PubMed PMC

Muller D.N., Schmidt C., Barbosa-Sicard E., Wellner M., Gross V., Hercule H., Markovic M., Honeck H., Luft F.C., Schunck W.H. Mouse Cyp4a isoforms: enzymatic properties, gender- and strain-specific expression, and role in renal 20-hydroxyeicosatetraenoic acid formation. Biochem. J. 2007;403:109–118. PubMed PMC

Lamsa V., Levonen A.L., Leinonen H., Yla-Herttuala S., Yamamoto M., Hakkola J. Cytochrome P450 2A5 constitutive expression and induction by heavy metals is dependent on redox-sensitive transcription factor Nrf2 in liver. Chem. Res. Toxicol. 2010;23:977–985. PubMed

Luo G., Zeldin D.C., Blaisdell J.A., Hodgson E., Goldstein J.A. Cloning and expression of murine CYP2Cs and their ability to metabolize arachidonic acid. Arch. Biochem. Biophys. 1998;357:45–57. PubMed

Edin M.L., Hamedani B.G., Gruzdev A., Graves J.P., Lih F.B., Arbes S.J., 3rd, Singh R., Orjuela Leon A.C., Bradbury J.A., DeGraff L.M., Hoopes S.L., Arand M., Zeldin D.C. Epoxide hydrolase 1 (EPHX1) hydrolyzes epoxyeicosanoids and impairs cardiac recovery after ischemia. J. Biol. Chem. 2018;293:3281–3292. PubMed PMC

Gautheron J., Jeru I. The multifaceted role of epoxide hydrolases in human Health and disease. Int. J. Mol. Sci. 2020;22 PubMed PMC

Yang G., Ge S., Singh R., Basu S., Shatzer K., Zen M., Liu J., Tu Y., Zhang C., Wei J., Shi J., Zhu L., Liu Z., Wang Y., Gao S., Hu M. Glucuronidation: driving factors and their impact on glucuronide disposition. Drug Metab. Rev. 2017;49:105–138. PubMed PMC

Hubatsch I., Ridderstrom M., Mannervik B. Human glutathione transferase A4-4: an alpha class enzyme with high catalytic efficiency in the conjugation of 4-hydroxynonenal and other genotoxic products of lipid peroxidation. Biochem. J. 1998;330(Pt 1):175–179. PubMed PMC

Ferguson G., Bridge W. Glutamate cysteine ligase and the age-related decline in cellular glutathione: the therapeutic potential of gamma-glutamylcysteine. Arch. Biochem. Biophys. 2016;593:12–23. PubMed

Lomelino C.L., Andring J.T., McKenna R., Kilberg M.S. Asparagine synthetase: function, structure, and role in disease. J. Biol. Chem. 2017;292:19952–19958. PubMed PMC

Kress J.K.C., Jessen C., Hufnagel A., Schmitz W., Xavier da Silva T.N., Ferreira Dos Santos A., Mosteo L., Goding C.R., Friedmann Angeli J.P., Meierjohann S. The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2. Cell Rep. 2023;42 PubMed

Zhang Y., Li J., Dong X., Meng D., Zhi X., Yuan L., Yao L. PSAT1 regulated oxidation-reduction balance affects the growth and prognosis of epithelial ovarian cancer. OncoTargets Ther. 2020;13:5443–5453. PubMed PMC

Tajan M., Hennequart M., Cheung E.C., Zani F., Hock A.K., Legrave N., Maddocks O.D.K., Ridgway R.A., Athineos D., Suarez-Bonnet A., Ludwig R.L., Novellasdemunt L., Angelis N., Li V.S.W., Vlachogiannis G., Valeri N., Mainolfi N., Suri V., Friedman A., Manfredi M., Blyth K., Sansom O.J., Vousden K.H. Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy. Nat. Commun. 2021;12:366. PubMed PMC

Park I., Johnson L.K., Cox A., Branchford B.R., Paola J.D., Bublil E.M., Majtan T. Hypermethioninemia leads to fatal bleeding and increased mortality in a transgenic I278T mouse model of homocystinuria. Biomedicines. 2020;8 PubMed PMC

Sikora M., Lewandowska I., Marczak L., Bretes E., Jakubowski H. Cystathionine beta-synthase deficiency: different changes in proteomes of thrombosis-resistant Cbs(-/-) mice and thrombosis-prone CBS(-/-) humans. Sci. Rep. 2020;10 PubMed PMC