Altered hepatic sulfur metabolism in cystathionine β‐synthase‐deficient homocystinuria: regulatory role of taurine on competing cysteine oxidation pathways

Cystathionine β‐synthase‐deficient homocystinuria (HCU) is a serious life‐threatening inborn error of sulfur metabolism with poorly understood pathogenic mechanisms. We investigated the effect of HCU on hepatic cysteine oxidation in a transgenic mouse model of the disease. Cysteine dioxygenase (CDO) protein levels were 90% repressed without any change in mRNA levels. Cysteinesulfinic acid decarboxylase (CSAD) was induced at both the mRNA (8‐fold) and protein (15‐fold) levels. Cysteine supplementation normalized CDO protein levels without reversing the induction of CSAD. Regulatory changes in CDO and CSAD expression were proportional to homocysteine elevation, indicating a possible threshold effect. Hepatic and blood taurine levels in HCU animals were decreased by 21 and 35%, respectively, and normalized by cysteine supplementation. Expression of the cytoplasmic (GOT1) and mitochondrial (GOT2) isoforms of glutamic‐oxaloacetic transaminase were repressed in HCU animals by 86 and 30%, respectively. HCU induced regulatory changes in CSAD, CDO, and GOT1 expression were normalized by taurine supplementation, indicating that cysteine is not the only sulfur compound that regulates hepatic cysteine oxidation. Collectively, our results indicate that HCU induces significant alterations of sulfur metabolism with the potential to contribute to pathogenesis and that cysteine and taurine have the potential to serve as adjunctive treatments in this disease.—Jiang, H., Stabler, S. P., Allen, R. H., Abman, S. H., Maclean, K. N. Altered hepatic sulfur metabolism in cystathionine β‐synthase‐deficient homocystinuria: regulatory role of taurine on competing cysteine oxidation pathways. FASEB J. 28, 4044‐4054 (2014). www.fasebj.org

[1]  D. Moore,et al.  Cysteine sulfinic acid decarboxylase regulation: A role for farnesoid X receptor and small heterodimer partner in murine hepatic taurine metabolism , 2014, Hepatology research : the official journal of the Japan Society of Hepatology.

[2]  W. Kruger,et al.  Cystathionine β‐synthase‐deficient mice thrive on a low‐methionine diet , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  R. Lachmann,et al.  Dietary practices in pyridoxine non-responsive homocystinuria: a European survey. , 2013, Molecular genetics and metabolism.

[4]  D. Vanderveen,et al.  Genetics of Ectopia Lentis , 2013, Seminars in ophthalmology.

[5]  H. Blom,et al.  Treatment of Inherited Homocystinurias , 2012, Neuropediatrics.

[6]  Hua Jiang,et al.  Altered expression of apoA-I, apoA-IV and PON-1 activity in CBS deficient homocystinuria in the presence and absence of treatment: possible implications for cardiovascular outcomes. , 2012, Molecular genetics and metabolism.

[7]  R. Austin,et al.  Cystathionine Protects against Endoplasmic Reticulum Stress-induced Lipid Accumulation, Tissue Injury, and Apoptotic Cell Death* , 2012, The Journal of Biological Chemistry.

[8]  Hua Jiang,et al.  Long-term betaine therapy in a murine model of cystathionine beta-synthase deficient homocystinuria: decreased efficacy over time reveals a significant threshold effect between elevated homocysteine and thrombotic risk. , 2012, Molecular genetics and metabolism.

[9]  G. Brodsky,et al.  Constitutive induction of pro-inflammatory and chemotactic cytokines in cystathionine beta-synthase deficient homocystinuria. , 2011, Molecular genetics and metabolism.

[10]  L. Meltesen,et al.  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 , 2010, Molecular genetics and metabolism.

[11]  J. Kraus,et al.  Cystathionine beta-synthase null homocystinuric mice fail to exhibit altered hemostasis or lowering of plasma homocysteine in response to betaine treatment , 2010, Molecular genetics and metabolism.

[12]  M. Stipanuk,et al.  Dealing with methionine/homocysteine sulfur: cysteine metabolism to taurine and inorganic sulfur , 2011, Journal of Inherited Metabolic Disease.

[13]  M. Maroney.  Faculty Opinions recommendation of An insight into the mechanism of human cysteine dioxygenase. Key roles of the thioether-bonded tyrosine-cysteine cofactor. , 2007 .

[14]  P. Lee,et al.  A rationale for cystine supplementation in severe homocystinuria , 2007, Journal of Inherited Metabolic Disease.

[15]  Y. Kamei,et al.  Taurine (2-aminoethanesulfonic acid) deficiency creates a vicious circle promoting obesity. , 2006, Endocrinology.

[16]  G. Phillips,et al.  Structure and mechanism of mouse cysteine dioxygenase. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[17]  D. Maślińska,et al.  Taurine – chloramine is a potent antiinflammatory substance , 2006, Inflammation Research.

[18]  D. Maślińska,et al.  Taurine chloramine modifies adjuvant arthritis in rats , 2005, Inflammation Research.

[19]  M. Stipanuk,et al.  Regulation of cysteine dioxygenase and gamma-glutamylcysteine synthetase is associated with hepatic cysteine level. , 2004, The Journal of nutritional biochemistry.

[20]  A. Williams,et al.  Development of an in vitro model for cysteine dioxygenase expression in the brain , 2004, Cell Biology and Toxicology.

[21]  M. Gaustadnes,et al.  High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine β‐synthase (CBS) mutations , 2002, Human mutation.

[22]  M. Stipanuk,et al.  Effects of nonsulfur and sulfur amino acids on the regulation of hepatic enzymes of cysteine metabolism. , 1999, American journal of physiology. Endocrinology and metabolism.

[23]  M. Stipanuk,et al.  Mechanisms involved in the regulation of key enzymes of cysteine metabolism in rat liver in vivo. , 1999, American journal of physiology. Endocrinology and metabolism.

[24]  D. Jones,et al.  Cysteine sulfinic acid decarboxylase mRNA abundance decreases in rats fed a high-protein diet. , 1998, The Journal of nutrition.

[25]  M. D. Faiman,et al.  Regulation of taurine biosynthesis and its physiological significance in the brain. , 1998, Advances in experimental medicine and biology.

[26]  M. D. Faiman,et al.  Protein Phosphorylation and Taurine Biosynthesis In Vivo and In Vitro , 1997, The Journal of Neuroscience.

[27]  J. Bereta,et al.  Taurine chioramine , a product of activated neutrophils , inhibits in vitro the generation of nitric oxide and other macrophage inflammatory mediators , 2005 .

[28]  R. Allen,et al.  Elevation of serum cystathionine levels in patients with cobalamin and folate deficiency. , 1993, Blood.

[29]  R J Huxtable,et al.  Physiological actions of taurine. , 1992, Physiological reviews.

[30]  M. Panteghini.  Aspartate aminotransferase isoenzymes. , 1990, Clinical biochemistry.

[31]  S. Mudd.  Disorders of transsulfuration , 1989 .

[32]  J. Sturman.  Taurine in development. , 1988, The Journal of nutrition.

[33]  R. Kido,et al.  A direct determination of taurine in perchloric acid-deproteinized biological samples. , 1987, Analytical biochemistry.

[34]  M. Stipanuk,et al.  Response of the kitten to dietary taurine depletion: effects on renal reabsorption, bile acid conjugation and activities of enzymes involved in taurine synthesis. , 1986, Comparative biochemistry and physiology. B, Comparative biochemistry.

[35]  S. Weiss,et al.  Chlorination of taurine by human neutrophils. Evidence for hypochlorous acid generation. , 1982, The Journal of clinical investigation.

[36]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.