Cytoglobin: biochemical, functional and clinical perspective of the newest member of the globin family

Abstract

Since the discovery of cytoglobin (Cygb) a decade ago, growing amounts of data have been gathered to characterise Cygb biochemistry, functioning and implication in human pathologies. Its molecular roles remain under investigation, but nitric oxide dioxygenase and lipid peroxidase activities have been demonstrated. Cygb expression increases in response to various stress conditions including hypoxia, oxidative stress and fibrotic stimulation. When exogenously overexpressed, Cygb revealed cytoprotection against these factors. Cygb was shown to be upregulated in fibrosis and neurodegenerative disorders and downregulated in multiple cancer types. CYGB was also found within the minimal region of a hereditary tylosis with oesophageal cancer syndrome, and its expression was reduced in tylotic samples. Recently, Cygb has been shown to inhibit cancer cell growth in vitro, thus confirming its suggested tumour suppressor role. This article aims to review the biochemical and functional aspects of Cygb, its involvement in various pathological conditions and potential clinical utility.

Conformational Dynamics Associated with Ligand Binding to Vertebrate Hexa-coordinate Hemoglobins

“…It was previously reported that Cygb associates with sodium oleate in a 1:1 ratio with a dissociation constant that ranges from 0.7 to 110 μM (Reeder et al, 2011). Fatty acids interactions with Cygb may be relevant for its physiological function since Cygb may have a role in fatty acid transport which could be related to its involvement in cancer (Oleksiewicz et al, 2011). In addition, the interaction of Cygb with fatty acids may be …”

“…Consequently, Cygb exhibits extended Nand C-termini, whereas Adgb only displays an extended N-terminus. The role of these extended termini in Cygb is not clear, but it has been proposed that they may be involved in association with lipids and/or protein-protein interactions (Oleksiewicz et al, 2011;Reeder et al, 2011). Conserved residues are represented by a star below the sequence, whereas residues that strongly share similar properties are represented by two dots and those exhibiting weak similarity are represented by one dot below the sequence.…”

“…However, the molecular mechanism of Cygb cytoprotection remains under investigation. Some studies point out diverse roles of Cygb, including oxygen storage, oxygen sensing, as decomposition of reactive oxygen species (ROS), nitric dioxygenase activity, and lipid transport (Fago et al, 2004c;Halligan et al, 2007;Mammen et al, 2004;Oleksiewicz et al, 2011;Pesce et al, 2002;Reeder et al, 2011). …”

“…Moreover, Cygb has been shown to inhibit cancer cell growth in vitro, which indicates its tumor suppressor role (Shivapurkar et al, 2008). Numerous physiological roles including oxygen storage, oxygen sensing, nitric dioxygenase activity, protection against oxidative stress, and collagen synthesis were proposed (Oleksiewicz et al, 2011). Recently, it was shown that Cygb binds sodium oleate with an increased affinity (K d = 0.7 µM) and the formation of lipid-Cygb complexes promotes penta-coordinated heme iron, suggesting a possible Cygb role in lipid signaling (Reeder et al, 2011).…”

“…The localization of Cygb in connective tissue cells may explain its expression in several organs including brain, retina, lung, liver and heart at varying concentration levels, but the concentration of the protein is relatively low (usually in the micromolar range) (Oleksiewicz et al, 2011). At the subcellular level, Cygb can be found in both the cytoplasm and the nucleus upon over-expression of the protein, indicating that…”