The micronutrient B12 (cobalamin, Cbl) plays an essential role in homocysteine metabolism in most if not all cells in the body. Hyperhomocysteinemia is a major independent risk factor for cardiovascular disease and is also associated with other devastating conditions such as neural tube defects and Alzheimer's disease. The determinants of hyperhomocysteinemia are multifactorial and include both genetic and acquired conditions. Cobalamin transport, processing and coenzyme formation by cardiovascular cells and tissues is a neglected area of research. The long-term objectives of this proposal are to gain an understanding of 1) Cbl transport processes in cultured human aortic endothelial cells and smooth muscle cells, 2) Cbl processing within these cells, and 3) the conversion of Cbl vitamers to methylcobalamin and adenosylcobalamin, coenzymes for cytosolic methionine synthase and mitochondrial methylmalonyI-CoA mutase, respectively. This study is driven by the hypotheses that 1) the vascular endotheliurn plays an essential role in maintaining Cbl homeostasis throughout the body; 2) it does so by a//owing the Cbl-binding protein transcobalarnin to transcytose from the/urinal/(apical/) space to the ablurninal (basolateral) space with Cbl as its cargo; 3) endothelial ceil injury, as occurs in atherogenesis and atherosclerosis, may cause localized disruption of Cbl homeostasis; and 4) Cbl deficiency itself/f is a cause of vascular ceil dysfunction due to a breakdown of the hornocysteine rernethylation machinery, which leads to hyperhornocysteinernia.
The Specific Aims of this proposal are: 1) to establish the mechanisms of Cbl transport and transcytosis in cultured human aortic endothelial and smooth muscle cells; 2) to determine how Cbl is processed in cultured vascular cells and the role that glutathionyl-Cbl plays in this processing; and 3) to elucidate the mechanisms of Cbl coenzyme formation in cultured human aortic endothelial and smooth muscle cells.
|Gherasim, Carmen; Hannibal, Luciana; Rajagopalan, Deepa et al. (2013) The C-terminal domain of CblD interacts with CblC and influences intracellular cobalamin partitioning. Biochimie 95:1023-32|
|Hannibal, Luciana; DiBello, Patricia M; Jacobsen, Donald W (2013) Proteomics of vitamin B12 processing. Clin Chem Lab Med 51:477-88|
|Moreira, Edward S; Brasch, Nicola E; Yun, June (2011) Vitamin B12 protects against superoxide-induced cell injury in human aortic endothelial cells. Free Radic Biol Med 51:876-83|
|Hannibal, Luciana; DiBello, Patricia M; Yu, Michelle et al. (2011) The MMACHC proteome: hallmarks of functional cobalamin deficiency in humans. Mol Genet Metab 103:226-39|
|Quadros, Edward V; Lai, Shao-Chiang; Nakayama, Yasumi et al. (2010) Positive newborn screen for methylmalonic aciduria identifies the first mutation in TCblR/CD320, the gene for cellular uptake of transcobalamin-bound vitamin B(12). Hum Mutat 31:924-9|
|Hannibal, Luciana; Smith, Clyde A; Jacobsen, Donald W (2010) The X-ray crystal structure of glutathionylcobalamin revealed. Inorg Chem 49:9921-7|
|Chen, Xiaocong; Sebastian, Becky M; Tang, Hui et al. (2009) Taurine supplementation prevents ethanol-induced decrease in serum adiponectin and reduces hepatic steatosis in rats. Hepatology 49:1554-62|
|Hannibal, Luciana; Smith, Clyde A; Smith, Jessica A et al. (2009) High resolution crystal structure of the methylcobalamin analogues ethylcobalamin and butylcobalamin by X-ray synchrotron diffraction. Inorg Chem 48:6615-22|
|Kim, Jihoe; Hannibal, Luciana; Gherasim, Carmen et al. (2009) A human vitamin B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins. J Biol Chem 284:33418-24|
|Hannibal, Luciana; Kim, Jihoe; Brasch, Nicola E et al. (2009) Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product. Mol Genet Metab 97:260-6|
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