Homocysteine and Redox Signaling

Zou, Cheng; Banerjee, Ruma

doi:10.1089/ars.2005.7.547

Cited by 137 publications

(112 citation statements)

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“…In the first case, oxidative stress is generated during oxidation of free thiol group of Hcys, when Hcys binds via disulphide bridge with plasma proteins -mainly albumin, or with another low-molecular plasma thiols or with second Hcys molecule. Oxidation of Hcys may induce in further oxidation of proteins, lipids and nucleic acids (Zou and Banerjee 2005). Accumulation of oxidized biomolecules alters functions of many cellular pathways.…”

Section: Introductionmentioning

confidence: 99%

May modifications of human plasma proteins stimulated by homocysteine and its thiolactone induce changes of hemostatic function of plasma in vitro?

Olas¹,

Kołodziejczyk²,

Malinowska³

2010

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Abstract. Homocysteine (Hcys) may be implicated in different diseases, especially in cardiovascular illnesses. The most reactive form of Hcys is its cyclic thioester -homocysteine thiolactone (HTL), which is formed in plasma and represents up to 0.29% of plasma total Hcys. Recently, it has been observed that Hcys and HTL may modify plasma proteins, including albumin, hemoglobin or fibrinogen, but the role of this process is not yet well known. The aim of our study in vitro was to investigate the modifications of human plasma total proteins after incubation with the reduced form of Hcys in concentrations 10-100 µmol/l, and HTL in concentrations 1-0.1 µmol/l, which correspond to levels found in human plasma during hyperhomocysteinemia in vivo. The aim of our study was also to explain the effects of Hcys and HTL on coagulation activity of human plasma. We showed that in model system in vitro Hcys and HTL change the level of thiol, amino and carbonyl groups in plasma total proteins. Moreover, our studies reported that not only Hcys (10-100 µmol/l), but also HTL (at lower concentrations than Hcys) modulates the coagulation properties of human plasma.

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Section: Introductionmentioning

confidence: 99%

May modifications of human plasma proteins stimulated by homocysteine and its thiolactone induce changes of hemostatic function of plasma in vitro?

Olas¹,

Kołodziejczyk²,

Malinowska³

2010

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“…(1) The first step in the pathway is catalyzed by cystathionine β-synthase and involves the condensation of homocysteine and serine to cystathionine (3). Human CGL has a subunit molecular mass of 44.5 kDa, purifies as a homotetramer (4), and belongs to the γ-family of PLP enzymes (5).…”

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confidence: 99%

Kinetic Properties of Polymorphic Variants and Pathogenic Mutants in Human Cystathionine γ-Lyase

2008

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Human cystathionine-γ-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 M s 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.The mammalian transsulfuration pathway represents one of two major metabolic routes for the removal of homocysteine, which at elevated levels, is an independent risk factor for cardiovascular diseases and other complex disorders (1,2). Cystathionine γ-lyase (CGL 1 ), the second enzyme in the transsulfuration pathway, catalyzes the conversion of † This work was supported in part by a grant from the National Institutes of Health (HL58984 to R.B.) and by an American Heart Association Postdoctoral Fellowship to W.Z.

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“…SAH hydrolase converts SAH to homocysteine in a reversible reaction, the kinetics of which favor condensation of homocysteine and adenosine. Clearance of homocysteine by methionine synthase therefore maintains a favorable SAM:SAH ratio, an index of cellular methylation potential (10 ).…”

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confidence: 99%