Catalysis of thiol oxidation by cobalamins and cobinamides: reaction products and kinetics

Jacobsen, Donald W.; Troxell, Lawrence S.; Brown, Kenneth L.

doi:10.1021/bi00304a021

Cited by 48 publications

(43 citation statements)

References 48 publications

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“…A variety of reactive oxygen species can be produced upon Hcy oxidation, including superoxide (O 2 – ·) and hydrogen peroxide (H 2 O 2 ) [39,40]. Increasing evidence suggests that reactive oxygen species play an important role in the pathophysiology of glomerular dysfunction, interstitial fibrosis and glomerulosclerosis [5,41].…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Regulates Homocysteine-Mediated Glomerulosclerosis

et al. 2010

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Background/Aims: In this study we tested the hypothesis that H₂S regulates collagen deposition, matrix metalloproteinases (MMP) and inflammatory molecules during hyperhomocysteinemia (HHcy) resulting in attenuation of glomerulosclerosis and improved renal function. Materials and Methods: A genetic model of HHcy, cystathionine β-synthase heterozygous (CBS+/–) and wild-type (WT) 2-kidney (2K) mice were used in this study and supplemented with or without NaHS (30 µmol/l, H₂S donor) in drinking water for 8 weeks. To expedite the renal damage associated with HHcy, uninephrectomized (1K) mice of similar groups were also used. Results: Results demonstrated that NAD(P)H oxidase (p47^phoxsubunit) and blood pressure were upregulated in WT 1K, CBS+/– 2K and CBS+/– 1K mice with downregulation of H₂S production and reduced glomerular filtration rate. These changes were normalized with H₂S supplementation. Both pro- and active MMP-2 and -9 and collagen protein expressions and glomerular depositions were also upregulated in WT 1K, CBS+/– 2K and CBS+/– 1K mice. Increased expressions of inflammatory molecules, intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1, as well as increased macrophage infiltration, were detected in WT 1K, CBS+/– 2K and CBS+/– 1K mice. These changes were ameliorated with H₂S supplementation. Conclusion: Together, these results suggest that increased oxidative stress and decreased H₂S in HHcy causes matrix remodeling and inflammation resulting in glomerulosclerosis and reduced renal function.

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Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Regulates Homocysteine-Mediated Glomerulosclerosis

et al. 2010

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“…However, the role that homocysteine plays in atherothrombogenicity and progression of cardiovascular disease is not clear. Most thiols autooxidize in the presence of transition metal catalysts and molecular oxygen (10,31,32), and this process leads to the formation of reactive oxygen species such as hydrogen peroxide and superoxide anion radical. It is generally assumed that homocysteine, being a thiol compound, undergoes similar autooxidative chemistry (11).…”

Section: Discussionmentioning

confidence: 99%

Relative Roles of Albumin and Ceruloplasmin in the Formation of Homocystine, Homocysteine-Cysteine-mixed Disulfide, and Cystine in Circulation

Sengupta¹,

Wehbe²,

Majors³

et al. 2001

Journal of Biological Chemistry

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122

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Disulfide forms of homocysteine account for >98% of total homocysteine in plasma from healthy individuals. We recently reported that homocysteine reacts with albumin-Cys 34 -S-S-cysteine to form homocysteine-cysteine mixed disulfide and albumin-Cys 34 thiolate anion. The latter then reacts with homocystine or homocysteinecysteine mixed disulfide to form albumin-bound homocysteine (Sengupta, S., Chen, H., Togawa, T., DiBello, P. M., Majors, A. K., Bü dy, B., Ketterer, M. E., and Jacobsen, D. W. (2001) J. Biol. Chem. 276, 30111-30117). We now extend these studies to show that human albumin, but not ceruloplasmin, mediates the conversion of homocysteine to its low molecular weight disulfide forms (homocystine and homocysteine-cysteine mixed disulfide) by thiol/disulfide exchange reactions. Only a small fraction of homocystine is formed by an oxidative process in which copper bound to albumin, but not ceruloplasmin, mediates the reaction. When copper is removed from albumin by chelation, the overall conversion of homocysteine to its disulfide forms is reduced by only 20%. Ceruloplasmin was an ineffective catalyst of homocysteine oxidation, and immunoprecipitation of ceruloplasmin from human plasma did not inhibit the capacity of plasma to mediate the conversion of homocysteine to its disulfide forms. In contrast, ceruloplasmin was a highly efficient catalyst for the oxidation of cysteine and cysteinylglycine to cystine and bis(-Scysteinylglycine), respectively. However, when thiols (cysteine and homocysteine) that are disulfide-bonded to albumin-Cys 34 are removed by treatment with dithiothreitol to form albumin-Cys 34 -SH (mercaptalbumin), the conversion of homocysteine to its disulfide forms is completely blocked. In conclusion, albumin mediates the formation of disulfide forms of homocysteine by thiol/ disulfide exchange, whereas ceruloplasmin converts cysteine to cystine by copper-dependent autooxidation.

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“…16,17 Examination of the forms of homocysteine in circulation support the concept of thiol oxidation in vivo. Greater than 98% of tHcy in normal (5 to 12 mol/L) and mildly hyperhomocysteinemic (Ͼ12 to 25 mol/L) plasma is oxidized, consisting of the disulfide dimer homocystine (5% to 10%), the mixed disulfide with cysteine and other thiols (5% to 10%), and mixed disulfides with protein (Ն80%).…”

Section: See P 1199mentioning

confidence: 99%