Neuroglobins; The Ngb described in this subfamily is a hexacoordinated heme globin chiefly expressed in neurons of the brain and retina. In the human brain, it is highly expressed in the hypothalamus, amygdala, and in the pontine tegmental nuclei. It affords protection of brain neurons from ischemia and hypoxia. In rats, it plays a role in the neuroprotection of limb ischemic preconditioning (LIP). It plays roles as: a sensor of oxygen levels; a store or reservoir for oxygen; a facilitator for oxygen transport; a regulator of ROS; and a scavenger of nitric oxide. It also functions in the protection against apoptosis and in sleep regulation. This subgroup contains Ngb from mammalian and non-mammalian vertebrates, including fish, amphibians and reptiles; the functionally pentacoordinated acoelomorph Symsagittifera roscoffensis Ngb does not belong to this subgroup.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19923711   1 MERLESELIRQSWRAVSRSPLEHGTVLFSRLFALEPSLLPLFQYNGRQFSSPEDCLSSPEFLDHIRKVMLVIDAAVTNVE 80
Cdd:cd08920   1 LSRPQKELIRESWRSVSRSPLEHGTVLFSRLFELEPDLLPLFQYNGRQFSSPQDCLSSPEFLDHIRKVMLVIDAAVSHLE 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 19923711  81 DLSSLEEYLATLGRKHRAVGVRLSSFSTVGESLLYMLEKCLGPDFTPATRTAWSQLYGAVVQAMSRGW 148
Cdd:cd08920  81 DLSSLEEYLTSLGRKHRAVGVKLESFSTVGESLLYMLESSLGPAFTPDTREAWSTLYGAVVQAMSRGW 148

Neuroglobins; The Ngb described in this subfamily is a hexacoordinated heme globin chiefly expressed in neurons of the brain and retina. In the human brain, it is highly expressed in the hypothalamus, amygdala, and in the pontine tegmental nuclei. It affords protection of brain neurons from ischemia and hypoxia. In rats, it plays a role in the neuroprotection of limb ischemic preconditioning (LIP). It plays roles as: a sensor of oxygen levels; a store or reservoir for oxygen; a facilitator for oxygen transport; a regulator of ROS; and a scavenger of nitric oxide. It also functions in the protection against apoptosis and in sleep regulation. This subgroup contains Ngb from mammalian and non-mammalian vertebrates, including fish, amphibians and reptiles; the functionally pentacoordinated acoelomorph Symsagittifera roscoffensis Ngb does not belong to this subgroup.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19923711   1 MERLESELIRQSWRAVSRSPLEHGTVLFSRLFALEPSLLPLFQYNGRQFSSPEDCLSSPEFLDHIRKVMLVIDAAVTNVE 80
Cdd:cd08920   1 LSRPQKELIRESWRSVSRSPLEHGTVLFSRLFELEPDLLPLFQYNGRQFSSPQDCLSSPEFLDHIRKVMLVIDAAVSHLE 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 19923711  81 DLSSLEEYLATLGRKHRAVGVRLSSFSTVGESLLYMLEKCLGPDFTPATRTAWSQLYGAVVQAMSRGW 148
Cdd:cd08920  81 DLSSLEEYLTSLGRKHRAVGVKLESFSTVGESLLYMLESSLGPAFTPDTREAWSTLYGAVVQAMSRGW 148

Globin;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19923711    27 LFSRLFALEPSLLPLFqynGRQFSSPEDCLSSPEFLDHIRKVMLVIDAAVTNVEDLSSLEEYLATLGRKH-RAVGVRLSS 105
Cdd:pfam00042   3 ILARLFTAYPDTKAYF---PRFEKSADDLKGSPKFKAHGKKVLAALGEAVKHLDDLAALNAALKKLGARHkEKRGVDPAN 79

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 19923711   106 FSTVGESLLYMLEKcLGPDFTPATRTAWSQLYGAVVQAM 144
Cdd:pfam00042  80 FKLFGEALLVVLAE-HLGEFTPETKAAWDKALDVIAAAL 117

Neuroglobins; The Ngb described in this subfamily is a hexacoordinated heme globin chiefly expressed in neurons of the brain and retina. In the human brain, it is highly expressed in the hypothalamus, amygdala, and in the pontine tegmental nuclei. It affords protection of brain neurons from ischemia and hypoxia. In rats, it plays a role in the neuroprotection of limb ischemic preconditioning (LIP). It plays roles as: a sensor of oxygen levels; a store or reservoir for oxygen; a facilitator for oxygen transport; a regulator of ROS; and a scavenger of nitric oxide. It also functions in the protection against apoptosis and in sleep regulation. This subgroup contains Ngb from mammalian and non-mammalian vertebrates, including fish, amphibians and reptiles; the functionally pentacoordinated acoelomorph Symsagittifera roscoffensis Ngb does not belong to this subgroup.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19923711   1 MERLESELIRQSWRAVSRSPLEHGTVLFSRLFALEPSLLPLFQYNGRQFSSPEDCLSSPEFLDHIRKVMLVIDAAVTNVE 80
Cdd:cd08920   1 LSRPQKELIRESWRSVSRSPLEHGTVLFSRLFELEPDLLPLFQYNGRQFSSPQDCLSSPEFLDHIRKVMLVIDAAVSHLE 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 19923711  81 DLSSLEEYLATLGRKHRAVGVRLSSFSTVGESLLYMLEKCLGPDFTPATRTAWSQLYGAVVQAMSRGW 148
Cdd:cd08920  81 DLSSLEEYLTSLGRKHRAVGVKLESFSTVGESLLYMLESSLGPAFTPDTREAWSTLYGAVVQAMSRGW 148

Globin-like protein superfamily; This globin-like domain superfamily contains a wide variety of all-helical proteins that bind porphyrins, phycobilins, and other non-heme cofactors, and play various roles in all three kingdoms of life, including sensors or transporters of oxygen. It includes the M/myoglobin-like, S/sensor globin, and T/truncated globin (TrHb) families, and the phycobiliproteins (PBPs). The M family includes chimeric (FHbs/flavohemoglobins) and single-domain globins: FHbs, Ngbs/neuroglobins, Cygb/cytoglobins, GbE/avian eye specific globin E, GbX/globin X, amphibian GbY/globin Y, Mb/myoglobin, HbA/hemoglobin-alpha, HbB/hemoglobin-beta, SDgbs/single-domain globins related to FHbs, and Adgb/androglobin. The S family includes GCS/globin-coupled sensors, Pgbs/protoglobins, and SSDgbs/sensor single domain globins. The T family is classified into three main groups: TrHb1s (N), TrHb2s (O) and TrHb3s (P). The M- and S families exhibit the canonical secondary structure of hemoglobins, a 3-over-3 alpha-helical sandwich structure (3/3 Mb-fold), built by eight alpha-helical segments (named A through H). For M family Adgbs, this globin domain is permuted, such that C-H are followed by A-B. The T family globins adopt a 2-on-2 alpha-helical sandwich structure, resulting from extensive and complex modifications of the canonical 3-on-3 alpha-helical sandwich that are distributed throughout the whole protein molecule. PBPs bind the linear tetrapyrrole chromophore, phycobilin, a prosthetic group chemically and metabolically related to iron protoporphyrin IX/protoheme. Examples of other globin-like domains which bind non-heme cofactors include those of the Bacillus anthracis sporulation inhibitors pXO1-118 and pXO2-61 which bind fatty acid and halide in vitro, and the globin-like domain of Bacillus subtilis RsbRA which is presumed to channel sensory input to the C-terminal sulfate transporter/ anti-sigma factor antagonist (STAT) domain. RsbRA is a component of the sigma B-activating stressosome, and a regulator of the RNA polymerase sigma factor subunit sigma (B).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19923711  12 SWRAVSRSPLEHGTVLFSRLFAlEPSLLPLFQYNGRqfsspedclsspeFLDHIRKVMLVIDAAVTNVEDLSSLEEYLAT 91
Cdd:cd01067   1 AWGYLEENQEEIVDDFYDRLFA-LPSLSELFSPPGR-------------LAKCIRKQMHFLRYALYGLVDGDSIEEGLAG 66

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|...
gi 19923711  92 LGRKHRAVGVRLSSFSTVGESLLYMLEKCLGPDFTPATRTAWSQLYGAVVQAM 144
Cdd:cd01067  67 LGEAHKSLGVPISYFIAALNVMKDVLTELLGDKFTPAAGEAWTKIFDYIISSM 119

Hemoglobin-like flavoprotein [Energy production and conversion];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19923711   1 MERLESELIRQSWRAVSRSPLEHGTVLFSRLFALEPSLLPLF-QYNGRQfsspedclsspefldhIRKVMLVIDAAVTNV 79
Cdd:COG1017   1 LSPETIALVKASFPLVAPHGEEITARFYERLFELHPELRPLFnGDMGEQ----------------RKALAAALAAYARNL 64

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 19923711  80 EDLSSLEEYLATLGRKHRAVGVRLSSFSTVGESLLYMLEKCLGPDFTPATRTAWSQLYGAVVQAMSRG 147
Cdd:COG1017  65 DNLEALLPALERLGRKHVSYGVKPEHYPIVGEALLAALREVLGDAWTPEVAAAWAEAYGLLADVMIAA 132

Caenorhabditis elegans globin GLB-25, and related globins; The C. elegans genome contains 33 genes encoding globins that are all transcribed. These are very diverse in gene and protein structure and are localized in a variety of cells. The C. elegans globin GLB-25 (locus tag T06A1.3), like the majority of them, was expressed in neuronal cells in the head and tail portions of the body and in the nerve cord.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19923711   9 IRQSWRAVSRSPLEHGTVLFSRLFALEPSLLPLFQYNGRQFSSPEDCLSSPEFLDHIRKVMLVIDAAVTNVEDLSSLEEY 88
Cdd:cd14766   1 LKKSWKGIARKIDETGKTMFLRMLTENPELKELFPKLKNLEDEEDELRSSEILENHAARVMDTLDEAISNIENVDYVIDL 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 19923711  89 LATLGRKHRAV-GVRLSSFSTVGESLLYMLEKCLGPDFTPATRTAWSQLYGAVVQAM 144
Cdd:cd14766  81 LHKVGKMHAKKpGFRPEMFWKIEEPFLEAVSETLGDRYTDNMENIYRKTIKFILQTL 137

Globin_X (GbX); Zebrafish globin X (GbX) is expressed at low levels in neurons of the central nervous system, and appears to be associated with the sensory system. GbX is likely to be attached to the cell membrane via S-palmitoylation and N-myristoylation. It's unlikely to have a true respiratory function as it is membrane-associated. It has been suggested that it may protect the lipids in the cell membrane from oxidation or act as a redox-sensing or signaling protein. Zebrafish GbX is hexacoordinate, and displays cooperative O2 binding.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19923711   5 ESELIRQSWRAVSRSPLEHGTVLFSRLFALEPSLLPLF-QYNGRQFsspEDCLSSPEFLDHIRKVMLVIDAAVTNVEDLS 83
Cdd:cd12137   5 QKQLIESSWSILQEDIAKVGVIMFVRLFETHPDCKDAFfPFRDVDL---EDLRHSKELRAHGLRVLSFVEKSLARLHQPD 81

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 19923711  84 SLEEYLATLGRKHRAVGVRLSSFSTVGESLLYMLEKCLGPDFTPATRTAWSQLYGAVVQAMSRG 147
Cdd:cd12137  82 KLEELLHELGRKHYRYNAKVKYVDLVGQQFIFAIEPVLKEQWTPELEEAWKTLFRYLTYVMKEG 145

Class 1 nonsymbiotic hemoglobins and related proteins; Class1 nsHbs include the dimeric hexacoordinate Trema tomentosa nsHb and the dimeric hexacoordinate nsHb from monocot barley. This subfamily also includes ParaHb, a dimeric pentacoordinate Hb from the root nodules of Parasponia andersonii, a non-legume capable of symbiotic nitrogen fixation. ParaHb is unusual in that it has different heme redox potentials for each subunit.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19923711   7 ELIRQSWRAVSRSPLEHGTVLFSRLFALEPSLLPLFQYngrQFSSPEDCLSSPEFLDHIRKV-MLVIDAAVTNVED--LS 83
Cdd:cd14784   7 ALVKKSWAVMKKDAAELGLKFFLKIFEIAPSAKQLFSF---LRDSTVPLEKNPKLKPHAMSVfVMTCEAAVQLRKAgkVT 83

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 19923711  84 SLEEYLATLGRKHRAVGVRLSSFSTVGESLLYMLEKCLGPDFTPATRTAWSQLYGAVVQAMSR 146
Cdd:cd14784  84 VRESKLKRLGATHVKYGVVDEHFEVVKFALLETIKEAVPDMWSPEMKSAWGEAYDQLVAAIKA 146

Hemoglobin beta, gamma, delta, epsilon, and related Hb subunits; Hb is the oxygen transport protein of erythrocytes. It is an allosterically modulated heterotetramer. Hemoglobin A (HbA) is the most common Hb in adult humans, and is formed from two alpha-chains and two beta-chains (alpha2beta2). An equilibrium exists between deoxygenated/unliganded/T(tense state) Hb having low oxygen affinity, and oxygenated /liganded/R(relaxed state) Hb having a high oxygen affinity. Various endogenous heterotropic effectors bind Hb to modulate its oxygen affinity and cooperative behavior, e.g. hydrogen ions, chloride ions, carbon dioxide and 2,3-bisphosphoglycerate. Hb is also an allosterically regulated nitrite reductase; the plasma nitrite anion may be activated by hemoglobin in areas of hypoxia to bring about vasodilation. Other Hb types are: HbA2 (alpha2delta2) which in normal individuals, is naturally expressed at a low level; Hb Portland-1 (zeta2gamma2), Hb Gower-1 (zeta2epsilon2), and Hb Gower-2 (alpha2epsilon2), which are Hbs present during the embryonic period; and fetal hemoglobin (HbF, alpha2gamma2), the primary hemoglobin throughout most of gestation. These Hbs types have differences in O2 affinity and in their interactions with allosteric effectors.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19923711  49 FSSPEDCLSSPEFLDHIRKVMLVIDAAVTNVEDLsslEEYLATLGRKH-RAVGVRLSSFSTVGESLLYMLEKCLGPDFTP 127
Cdd:cd08925  42 LSSAAAIAGNPKVAAHGKKVLGALGEAIKHLDDI---KATFADLSEKHsEKLHVDPENFKLLGDCLVVVLAAHFGKEFTP 118

                        90       100
                ....*....|....*....|.
gi 19923711 128 ATRTAWSQLYGAVVQAMSRGW 148
Cdd:cd08925 119 EVQAAWEKFFAVVVDALSKGY 139

Cytoglobin and related globins; Cygb is a hexacoordinated heme-containing protein, able to bind O2, NO and carbon monoxide. It has both nitric oxide dioxygenase and lipid peroxidase activities, and potentially participates in the maintenance of normal phenotype by implementing a homeostatic effect, to counteract stress conditions imposed on a cell. Cygb is implicated in multiple human pathologies: it is up-regulated in fibrosis and neurodegenerative disorders, and down-regulated in multiple cancer types, and may have a tumor suppressor role. It is expressed ubiquitously across a broad range of vertebrate organs including liver, heart, brain, lung, retina, and gut. In the human brain, it was detected at high levels in the habenula, hypothalamus, thalamus, hippocampus and pontine tegmental nuclei, detected at a low level in the cerebral cortex, and undetected in the cerebellar cortex.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19923711   5 ESELIRQSWRAVSRSPLEHGTVLFSRLFALEPSLLPLFQyngrQFSSPEDCLS---SPEFLDHIRKVMLVIDAAVTNVED 81
Cdd:cd08924   5 ERKVIQDTWARVYANCEDVGVAILVRFFVNFPSAKQYFS----QFKHMEDPLEmerSSQLRKHARRVMGALNTVVENLHD 80

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 19923711  82 LSSLEEYLATLGR----KHRAVGVRLSSFSTVgesLLYMLEKCLGPDFTPATRTAWSQLYGAVVQAMSR-----GW 148
Cdd:cd08924  81 PDKVSSVLALVGKahalKHKVEPVYFKILSGV---ILEVLAEEFAQDFTPEVQSAWSKLRGLIYSHVTAaykevGW 153

Globin domain of Alcaligenes eutrophus flavohemoglobin (FHP) and related proteins; Flavohemoglobins (flavoHbs) function primarily as nitric oxide dioxygenases (NODs, EC 1.14.12.17), converting NO and O2 to inert NO3- (nitrate). They have an N-terminal globin domain and a C-terminal ferredoxin reductase-like NAD- and FAD-binding domain, and use the reducing power of cellular NAD(P)H to drive regeneration of the ferrous heme. They protect from nitrosative stress (the broad range of cellular toxicities caused by NO), and modulate NO signaling pathways. NO scavenging by flavoHb maintains Medicago truncatula-Sinorhizobium meliloti symbiosis. Alcaligenes eutrophus FHP contains a phospholipid-binding site.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19923711  22 EHGTVL----FSRLFALEPSLLPLF----QYNGRQfsspEDCLSspefldhirkvMLVIdAAVTNVEDLSSLEEYLATLG 93
Cdd:cd14779  18 EHGVALtkhfYQRMFEHNPELKNVFnmghQESGKQ----QQALA-----------MAVL-AYAENIDDPEVLLPVLKLIA 81

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|.
gi 19923711  94 RKHRAVGVRLSSFSTVGESLLYMLEKCLGPDFTPATRTAWSQLYGAVVQAM 144
Cdd:cd14779  82 HKHVSLGIRAEQYPIVGEHLLASIKEVLGDAATDELISAWAAAYGQLADIL 132

Globin domain of flavohemoglobins (flavoHbs); uncharacterized subgroup; FlavoHbs function primarily as nitric oxide dioxygenases (NODs, EC 1.14.12.17), converting NO and O2 to inert NO3- (nitrate). They have an N-terminal globin domain and a C-terminal ferredoxin reductase-like NAD- and FAD-binding domain, and use the reducing power of cellular NAD(P)H to drive regeneration of the ferrous heme. They protect from nitrosative stress (the broad range of cellular toxicities caused by NO), and modulate NO signaling pathways.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19923711  22 EHGTVL----FSRLFALEPSLLPLF----QYNGRQfsspedclsspefldhIRKVMLVIDAAVTNVEDLSSLEEYLATLG 93
Cdd:cd14783  18 ENGETLtrhfYKRMFEHNPEVKPFFnpahQHSGSQ----------------QRALAAAICAYAANIDNLEVLGNAVELIA 81

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 19923711  94 RKHRAVGVRLSSFSTVGESLLYMLEKCLGPDFTPATRTAWSQLYG 138
Cdd:cd14783  82 QKHASLGIKPEHYPIVGSNLLASIREVLGDAATDDIIEAWSEAYG 126

Globin domain of fungal flavohemoglobin; FlavoHbs function primarily as nitric oxide dioxygenases (NODs, EC 1.14.12.17), converting NO and O2 to inert NO3- (nitrate). They have an N-terminal globin domain and a C-terminal ferredoxin reductase-like NAD- and FAD-binding domain, and use the reducing power of cellular NAD(P)H to drive regeneration of the ferrous heme. They protect from nitrosative stress (the broad range of cellular toxicities caused by NO), and modulate NO signaling pathways. NO scavenging by flavoHb attenuates the expression of the nitrosative stress response, affects the swarming behavior of Escherichia coli, and maintains squid-Vibrio fischeri and Medicago truncatula-Sinorhizobium meliloti symbioses. FlavoHb expression affects Aspergillus nidulans sexual development and mycotoxin production, and Dictyostelium discoideum development.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 19923711  78 NVEDLSSLEEYLATLGRKHRAVGVRLSSFSTVGESLLYMLEKCLGPDF-TPATRTAWSQLYG 138
Cdd:cd19754  66 NIDDLTPLSGFVEQIVSKHVGLQVKPEHYPIVGECLIETMKELLPEAVaTDEFIEAWTTAYG 127

Globin domain of flavohemoglobins (flavoHbs); uncharacterized subgroup; FlavoHbs function primarily as nitric oxide dioxygenases (NODs, EC 1.14.12.17), converting NO and O2 to inert NO3- (nitrate). They have an N-terminal globin domain and a C-terminal ferredoxin reductase-like NAD- and FAD-binding domain, and use the reducing power of cellular NAD(P)H to drive regeneration of the ferrous heme. They protect from nitrosative stress (the broad range of cellular toxicities caused by NO), and modulate NO signaling pathways.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 19923711  80 EDLSSLEEYLATLGRKHRAVGVRLSSFSTVGESLLYMLEKCLGPDFTPATRTAWSQLY 137
Cdd:cd14782  71 PDAPPPDSVLSRIAHKHASLGITPEQYTIVHRHLFAAIAEVLGAAVTPEVAAAWDEVY 128