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Postepy Higieny I Medycyny... Jan 2014γ-Cystathionase (CTH, EC: 4.4.1.1), an enzyme widely distributed in the world of prokaryotic and eukaryotic organisms, catalyzes the formation and transformations of... (Review)
Review
γ-Cystathionase (CTH, EC: 4.4.1.1), an enzyme widely distributed in the world of prokaryotic and eukaryotic organisms, catalyzes the formation and transformations of sulfane sulfur-containing compounds and plays a pivotal role in the L-cysteine desulfuration pathway. Human, tetrameric CTH is composed of two dimers and each monomer binds pyridoxal phosphate (PLP). The gene, located on the short arm of chromosome 1, consists of 13 exons and 12 introns. As a result of alternative splicing, three isoforms of human CTH arise. Analysis of genetic variations of the CTH encoding gene showed a large number of polymorphisms. A decrease of the expression of CTH entails a drop in the level of cysteine , glutathione (GSH), taurine and hydrogen sulfide (H2S) in the cells and, more importantly, leads to cystathioninuria. H2S, endogenously formed by CTH, affects the vasodilation and regulation of blood pressure. CTH knockout mice have decreased levels of H2S, hypertension, and reduced capacity for vascular endothelium relaxation. Overexpression of the gene encoding CTH in the cells leads to increased production of H2S. H2S plays a role in protection of neurons against oxidative stress, and stimulates an increase in γ-glutamylcysteine synthetase and thereby an increase in the level of GSH. Sulfurtransferases, including CTH, can locally prevent oxidative stress due to reversible oxidation of - SH groups in the presence of increased levels of reactive oxygen species, and reduction in the presence of GSH and/or reduced thioredoxin.
Topics: Animals; Cystathionine gamma-Lyase; Cysteine; Gene Expression; Glutathione; Humans; Hydrogen Sulfide; Hyperhomocysteinemia; Hypertension; Mice; Mice, Knockout; Oxidation-Reduction; Oxidative Stress; Polymorphism, Genetic; Reactive Oxygen Species
PubMed: 24491890
DOI: 10.5604/17322693.1085372 -
British Medical Journal Nov 1963
PubMed: 20789999
DOI: No ID Found -
Journal of Medical Genetics Dec 1967
Topics: Adult; Aged; Amino Acid Metabolism, Inborn Errors; Amino Acids; Chromatography; Female; Humans; Intellectual Disability; Male; Methionine; Middle Aged; Pedigree
PubMed: 6082903
DOI: 10.1136/jmg.4.4.260 -
British Medical Journal Dec 1963
Topics: Amino Acid Metabolism, Inborn Errors; Amino Acids; Cystathionine gamma-Lyase; Humans; Hyperhomocysteinemia; Mental Disorders; Neurologic Manifestations; Renal Aminoacidurias; Toxicology
PubMed: 14072653
DOI: 10.1136/bmj.2.5372.1587-a -
International Journal of Molecular... Jul 2019Elevated plasma homocysteine levels are considered as a risk factor for cardiovascular diseases as well as preeclampsia-a pregnancy disorder characterized by...
Elevated plasma homocysteine levels are considered as a risk factor for cardiovascular diseases as well as preeclampsia-a pregnancy disorder characterized by hypertension and proteinuria. We previously generated mice lacking cystathionine γ-lyase (Cth) as cystathioninuria models and found them to be with cystathioninemia/homocysteinemia. We investigated whether Cth-deficient () pregnant mice display any features of preeclampsia. females developed normally but showed mild hypertension (~10 mmHg systolic blood pressure elevation) in late pregnancy and mild proteinuria throughout development/pregnancy. dams had normal numbers of pups and exhibited normal maternal behavior except slightly lower breastfeeding activity. However, half of them could not raise their pups owing to defective lactation; they could produce/store the first milk in their mammary glands but not often provide milk to their pups after the first ejection. The serum oxytocin levels and oxytocin receptor expression in the mammary glands were comparable between wild-type and dams, but the contraction responses of mammary gland myoepithelial cells to oxytocin were significantly lower in dams. The contraction responses to oxytocin were lower in uteruses isolated from mice. Our results suggest that elevated homocysteine or other unknown factors in preeclampsia-like dams interfere with oxytocin that regulates milk ejection reflex.
Topics: Animals; Cystathionine gamma-Lyase; Disease Models, Animal; Female; Hyperhomocysteinemia; Lactation Disorders; Mice; Mice, Knockout; Pre-Eclampsia; Pregnancy
PubMed: 31319489
DOI: 10.3390/ijms20143507 -
The Journal of Clinical Investigation Jun 1967Cystathionine is more readily cleared from the plasma than other amino acids. This is because the amino acid has a very low tubular maximum (Tm), in the order of 1...
Cystathionine is more readily cleared from the plasma than other amino acids. This is because the amino acid has a very low tubular maximum (Tm), in the order of 1 mumole per minute per 1.73 square meters body surface area (BSA). No essential differences in the reabsorption of cystathionine were observed in four normal subjects, two patients with homozygous cystathioninuria, one patient with heterozygous cystathioninuria, and one patient with cystinuria. Apparent net tubular secretion of cystathionine was demonstrated in a child with homozygous cystathioninuria only after an intravenously administered load of lysine.
Topics: Adult; Amino Acid Metabolism, Inborn Errors; Amino Acids; Child, Preschool; Cystinuria; Glycine; Humans; Kidney; Lysine; Male; Methionine; Renal Tubular Transport, Inborn Errors
PubMed: 6026103
DOI: 10.1172/JCI105604 -
Neutral aminoaciduria in cystathionine β-synthase-deficient mice; an animal model of homocystinuria.American Journal of Physiology. Renal... Jun 2014The kidney is one of the major loci for the expression of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH). While CBS-deficient (Cbs(-/-)) mice display...
The kidney is one of the major loci for the expression of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH). While CBS-deficient (Cbs(-/-)) mice display homocysteinemia/methioninemia and severe growth retardation, and rarely survive beyond the first 4 wk, CTH-deficient (Cth(-/-)) mice show homocysteinemia/cystathioninemia but develop with no apparent abnormality. This study examined renal amino acid reabsorption in those mice. Although both 2-wk-old Cbs(-/-) and Cth(-/-) mice had normal renal architecture, their serum/urinary amino acid profiles largely differed from wild-type mice. The most striking feature was marked accumulation of Met and cystathionine in serum/urine/kidney samples of Cbs(-/-) and Cth(-/-) mice, respectively. Levels of some neutral amino acids (Val, Leu, Ile, and Tyr) that were not elevated in Cbs(-/-) serum were highly elevated in Cbs(-/-) urine, and urinary excretion of other neutral amino acids (except Met) was much higher than expected from their serum levels, demonstrating neutral aminoaciduria in Cbs(-/-) (not Cth(-/-)) mice. Because the bulk of neutral amino acids is absorbed via a B(0)AT1 transporter and Met has the highest substrate affinity for B(0)AT1 than other neutral amino acids, hypermethioninemia may cause hyperexcretion of neutral amino acids.
Topics: Amino Acids, Neutral; Animals; Comorbidity; Cystathionine; Cystathionine beta-Synthase; Cystathionine gamma-Lyase; Disease Models, Animal; Female; Homocystinuria; Hyperhomocysteinemia; Kidney Tubules, Proximal; Male; Methionine; Mice; Mice, Inbred C57BL; Mice, Knockout; Renal Aminoacidurias
PubMed: 24761004
DOI: 10.1152/ajprenal.00623.2013 -
Proceedings of the National Academy of... Apr 1966
Topics: Adolescent; Amino Acid Metabolism, Inborn Errors; Humans; Hydro-Lyases; In Vitro Techniques; Liver; Liver Extracts; Lyases; Male; Urine
PubMed: 5219695
DOI: 10.1073/pnas.55.4.865 -
Biochemistry Jun 2008Human cystathionine-gamma-lyase (CGL) is a pyridoxal-5'-phosphate (PLP)-dependent enzyme, which functions in the transsulfuration pathway that converts homocysteine to...
Human cystathionine-gamma-lyase (CGL) is a pyridoxal-5'-phosphate (PLP)-dependent enzyme, which functions in the transsulfuration pathway that converts homocysteine to cysteine. In addition, CGL is one of two major enzymes that can catalyze the formation of hydrogen sulfide, an important gaseous signaling molecule. Recently, several mutations in CGL have been described in patients with cystathioninuria, a rare but poorly understood genetic disease. Moreover, a common single nucleotide polymorphism in CGL, c.1364G>T that converts serine at position 403 to isoleucine, has been linked to elevated plasma homocysteine levels. In this study, we have characterized the pathogenic T67I and Q240E missense mutations and the polymorphic variants at amino acid residues 403 using kinetic and spectrophotometric methods. We report that the polymorphism does not influence the cofactor content of the enzyme or its steady-state kinetic properties. In contrast, the T67I mutant exhibits a 3.5-fold decrease in V max compared to that of wild-type CGL, while the Q240E mutant exhibits a 70-fold decrease in V max. The K Ms for cystathionine for both pathogenic mutants are comparable to that of wild type CGL. The PLP content of the T67I and Q240E mutants were about 4-fold and 80-fold lower than that of wild-type enzyme, respectively. Preincubation of the T67I mutant with PLP restored activity to wild-type levels while the same treatment resulted in only partial restoration of activity of the Q240E mutant. These results reveal that both mutations weaken the affinity for PLP and suggest that cystathionuric patients with these mutations should be responsive to pyridoxine therapy.
Topics: Crystallography, X-Ray; Cystathionine gamma-Lyase; Genetic Variation; Humans; Isoleucine; Kinetics; Models, Molecular; Molecular Conformation; Mutation; Polymorphism, Single Nucleotide; Pyridoxal Phosphate; Recombinant Proteins; Serine; Spectrophotometry; Templates, Genetic
PubMed: 18476726
DOI: 10.1021/bi800351a -
The Journal of Biological Chemistry Aug 2010Cysteine is considered a nonessential amino acid in mammals as it is synthesized from methionine via trans-sulfuration. However, premature infants or patients with...
Cysteine is considered a nonessential amino acid in mammals as it is synthesized from methionine via trans-sulfuration. However, premature infants or patients with hepatic failure may require dietary cysteine due to a lack of cystathionine gamma-lyase (CTH), a key trans-sulfuration enzyme. Here, we generated CTH-deficient (Cth(-/-)) mice as an animal model of cystathioninemia/cystathioninuria. Cth(-/-) mice developed normally in general but displayed hypercystathioninemia/hyperhomocysteinemia though not hypermethioninemia. When fed a low cyst(e)ine diet, Cth(-/-) mice showed acute skeletal muscle atrophy (myopathy) accompanied by enhanced gene expression of asparagine synthetase and reduced contents of glutathione in livers and skeletal muscles, and intracellular accumulation of LC3 and p62 in skeletal myofibers; they finally died of severe paralysis of the extremities. Cth(-/-) hepatocytes required cystine in a culture medium and showed greater sensitivity to oxidative stress. Cth(-/-) mice exhibited systemic vulnerability to oxidative injury, which became more prominent when they were fed the low cyst(e)ine diet. These results reveal novel roles of trans-sulfuration previously unrecognized in mice lacking another trans-sulfuration enzyme cystathionine beta-synthase (Cbs(-/-)). Because Cbs(-/-) mice display hyperhomocysteinemia and hypermethioninemia, our results raise questions against the homocysteine-based etiology of CBS deficiency and the current newborn screening for homocysteinemia using Guthrie's method, which detects hypermethioninemia.
Topics: Animals; Cystathionine gamma-Lyase; Cysteine; Disease Models, Animal; Homocystinuria; Hyperhomocysteinemia; Mice; Mice, Knockout; Muscular Diseases; Oxidative Stress; Protective Agents
PubMed: 20566639
DOI: 10.1074/jbc.M110.147439