Disease relevance of NGB

• Neuroglobin and cytoglobin overexpression protects human SH-SY5Y neuroblastoma cells against oxidative stress-induced cell death [1].
• Present evidence points to an important role of neuroglobin in neuronal oxygen homeostasis and hypoxia protection, though other functions are still conceivable [2].
• CO binding reactions initiated by rapid mixing are measured for four plant hexacoordinate hemoglobins, human neuroglobin and cytoglobin, and Synechocystis hemoglobin [3].
• Because both intracellular cystatin C and the amyloidogenic variant of cystatin C form dimers, Ngb may modulate the intracellular transport (or secretion) of cystatin C to protect against neuronal death under conditions of oxidative stress and/or it may have a role in the development of neurodegenerative diseases [4].
• Structurally homologous hexacoordinate hemoglobins (hxHbs) are also found in animals (neuroglobin and cytoglobin) and some cyanobacteria, where they are thought to play a role in free radical scavenging or ligand sensing [5].

High impact information on NGB

• The human neuroglobin gene (NGB), located on chromosome 14q24, has a unique exon-intron structure [6].
• We have also discovered a second, unique Myg isoform, distinct from neuroglobin, which is expressed exclusively in the neural tissue but whose transcript expression was unaffected by environmental hypoxia [7].
• Here we report that, like hemoglobin and myoglobin, neuroglobin expression can also be induced by hemin [8].
• These results provide evidence for regulation of neuroglobin expression by at least 2 signal transduction pathways [8].
• The histidine binding affinity is 100-fold lower than in neuroglobin [9].

Chemical compound and disease context of NGB

• A triple mutant (replacing three Cys residues) of human neuroglobin (151 amino acids) has been expressed in Escherichia coli, purified and crystallized in two crystal forms, the best of which diffracts to 1.95 A resolution using synchrotron radiation [10].
• While neuroglobin mRNA expression was significantly enhanced in cell culture after severe prolonged hypoxia (0-1% O2 for 24 h), we did not find any significant increases in neuroglobin mRNA levels in the rat brain after transient global ischemia [11].

Biological context of NGB

• The influence of neuroglobin and cytoglobin on cell death after oxidative stress in human neuroblastoma SH-SY5Y cells was evaluated [1].
• This finding suggests that neuroglobin and cytoglobin protect SH-SY5Y cells against oxidative stress-induced cell death [1].
• SH-SY5Y cells transfected with plasmid DNA containing the neuroglobin or cytoglobin sequence showed enhanced survival after exposure to 300muM H(2)O(2) for 24h as compared to untransfected controls [1].
• Kinetic and structural studies show that neuroglobin and cytoglobin belong to the class of hexa-coordinated globins with a biphasic ligand-binding kinetics [2].
• Here, we review what is currently known about neuroglobin and cytoglobin in terms of their function, tissue distribution and relatedness to the well-known hemoglobin and myoglobin [12].

Anatomical context of NGB

• Neuroglobin, which is predominantly expressed in nerve cells, is thought to protect neurons from hypoxic-ischemic injury [12].
• Ngb is held to facilitate O2 diffusion to the mitochondria and to protect neuronal cells from hypoxic-ischemic insults, may be an oxidative stress-responsive sensor protein for signal transduction, and may carry out enzymatic activities, such as NO/O2 scavenging [13].
• Neuroglobin is widely expressed in neurons, but not glia, in the vertebrate central and peripheral nervous systems [14].
• NGB protein immunoreactive cells were also widely distributed throughout normal adult rat brain, including cerebral cortex, hippocampus, thalamus, hypothalamus, pons, and cerebellum [15].
• Transcription of NGB mRNA was shown to be widely distributed throughout the adult rat brain, including cerebral cortex, hippocampus, thalamus, hypothalamus, olfactory bulb, and cerebellum [15].

Associations of NGB with chemical compounds

• NGB shows both alkaline and acid Bohr effects (pH-dependent O2 affinity) and temperature-dependent enthalpy of oxygenation [16].
• Structural characterization of the proximal and distal histidine environment of cytoglobin and neuroglobin [17].
• Picosecond time-resolved resonance Raman (ps-TR3) spectroscopy of transient five-coordinate heme species produced by the photolysis of carbon monoxide (CO) adducts of Cgb and Ngb showed Fe-His stretching (nu(Fe-His)) bands at 229 and 221 cm(-1), respectively [17].
• Moreover, flash photolysis experiments at high temperatures reveal that Ngb remains functional at 90 degrees C. Human Ngb may have a disulfide bond in the CD loop region; reduction of the disulfide bond increases the affinity of the iron atom for the distal (E7) histidine, and leads to a 3 degrees C increase in the T(m) for ferrous Ngb [18].
• There are three cysteine residues in human neuroglobin; those at positions CD7 and D5 are sufficiently close to form an internal disulfide bond [19].

Physical interactions of NGB

• Human neuroglobin interacts with flotillin-1, a lipid raft microdomain-associated protein [20].

Other interactions of NGB

• These structural characteristics of Cgb and Ngb are discussed in relation to their ligand binding and physiological properties [17].
• Both, neuroglobin and cytoglobin are structurally similar to myoglobin, although they contain distinct cavities that may be instrumental in ligand binding [2].
• The interaction of Ngb with flotillin-1 was confirmed by glutathione S-transferase pull-down experiments [20].
• p53-mediated apoptosis, neuroglobin overexpression, and globin deposits in a patient with hereditary ferritinopathy [21].
• By surface plasmon resonance, we found that ferric Ngb, which is generated spontaneously as a result of the rapid autoxidation, binds exclusively to the GDP-bound form of the alpha subunit of heterotrimeric G protein (Galphai) [22].

Analytical, diagnostic and therapeutic context of NGB

• Furthermore, it was demonstrated that NGB was extensively expressed in rat brain by using in situ hybridization and the immunohistochemical technique [15].
• Amino acid residues in the ligand binding pocket of human neuroglobin have been identified by site-directed mutagenesis and their properties investigated by resonance Raman and flash photolysis methods [23].
• Globin X displays the highest identity scores with neuroglobin (approximately 26% to 35%), although it is not a neuronal protein, as revealed by RT-PCR experiments on goldfish RNA from various tissues [24].
• Both the ferrous and ferric forms of wild-type neuroglobin are found to be hexacoordinated with axial ligation of the F8-His and E7-His [25].
• PURPOSE: In this preliminary study we sought to determine the effect of instituting nocturnal bladder emptying (NBE) in children with neurogenic (NGB) or nonneurogenic neurogenic bladder (NNGNGB) in whom urinary tract deterioration developed despite optimal daytime clean intermittent catheterization (CIC) and urotropic medications [26].

References