{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNCB5OR is a highly conserved, soluble flavohemoprotein characterized by an N‐terminal cytochrome b5–like domain and a C‐terminal cytochrome b5 reductase–like domain that localizes to the endoplasmic reticulum. Detailed biochemical and structural studies have demonstrated that this enzyme efficiently transfers electrons from NAD(P)H to substrates such as cytochrome c and methemoglobin, and its unique heme environment has been revealed by spectroscopic and crystallographic analyses. In addition, characterization of its promoter and expression in pancreatic islets underscores its critical role in maintaining beta‐cell health, since loss of NCB5OR leads to impaired glucose– and arginine–stimulated insulin secretion, beta–cell degranulation, and enhanced sensitivity to oxidant stress and diabetogenic agents."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNCB5OR also performs a pivotal role in lipid metabolism by supplying electrons required for Delta9 fatty acid desaturation. In vivo and in vitro studies have shown that deficiency of NCB5OR disrupts normal fatty acid processing in hepatocytes—resulting in lower triacylglycerol levels, accumulation of free fatty acids, and enhanced fatty acid oxidation that lead to oxidative stress and consequent lipoatrophy. Furthermore, experiments utilizing reconstituted enzyme systems have revealed that even minimal presence of the typical redox partner POR can be functionally substituted by cytochrome b5 activity in certain metabolic pathways, emphasizing its involvement in activating lipophilic xenobiotics."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its metabolic functions in the liver and pancreas, NCB5OR is critical for the maintenance of neural iron homeostasis and proper functioning of locomotor pathways. Conditional deletion of NCB5OR in the cerebellum and midbrain selectively disrupts cellular and mitochondrial iron regulation, resulting in aberrant iron uptake and altered locomotor behaviors, as well as modified feeding responses following metabolic challenges. These findings suggest that NCB5OR plays an essential role in integrating redox and metabolic signals within neural circuits that govern overall systemic homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hao Zhu, Kevin Larade, Timothy A Jackson, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Absence of a reductase, NCB5OR, causes insulin-deficient diabetes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0404044101"}], "href": "https://doi.org/10.1073/pnas.0404044101"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15247412"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15247412"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kevin Larade, H Franklin Bunn "}, {"type": "b", "children": [{"type": "t", "text": "Promoter characterization and transcriptional regulation of Ncb5or, a novel reductase necessary for pancreatic beta-cell maintenance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbaexp.2006.05.002"}], "href": "https://doi.org/10.1016/j.bbaexp.2006.05.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16814408"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16814408"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Kevin Larade, Zhi-gang Jiang, Andre Dejam, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The reductase NCB5OR is responsive to the redox status in beta-cells and is not involved in the ER stress response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20061859"}], "href": "https://doi.org/10.1042/BJ20061859"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17343567"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17343567"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Bin Deng, Sudharsan Parthasarathy, WenFang Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Study of the individual cytochrome b5 and cytochrome b5 reductase domains of Ncb5or reveals a unique heme pocket and a possible role of the CS domain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.120329"}], "href": "https://doi.org/10.1074/jbc.M110.120329"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20630863"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20630863"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Kevin Larade, Zhigang Jiang, Yongzhao Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of Ncb5or results in impaired fatty acid desaturation, lipoatrophy, and diabetes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M804645200"}], "href": "https://doi.org/10.1074/jbc.M804645200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18682384"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18682384"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yongzhao Zhang, Kevin Larade, Zhi-Gang Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The flavoheme reductase Ncb5or protects cells against endoplasmic reticulum stress-induced lipotoxicity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Lipid Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1194/jlr.M900146-JLR200"}], "href": "https://doi.org/10.1194/jlr.M900146-JLR200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19609006"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19609006"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Ming Xu, WenFang Wang, Jennifer R Frontera, et al. 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