NUDIX hydrolase superfamily; NUDIX hydrolase is a superfamily of enzymes found in all three kingdoms of life, and it catalyzes the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+ for their activity. Members of this family are recognized by a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site. Substrates of NUDIX hydrolase include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance and "house-cleaning" enzymes. Substrate specificity is used to define child families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required. This superfamily consists of at least nine families: IPP (isopentenyl diphosphate) isomerase, ADP ribose pyrophosphatase, mutT pyrophosphohydrolase, coenzyme-A pyrophosphatase, MTH1-7,8-dihydro-8-oxoguanine-triphosphatase, diadenosine tetraphosphate hydrolase, NADH pyrophosphatase, GDP-mannose hydrolase and the c-terminal portion of the mutY adenine glycosylase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640   7 IARAIIEEEGKILLCRGKGNKNYFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIGASENKFEIKGEETHEINLVFE 86
Cdd:cd18883     2 TARGVIISDEHLLLARVKGDDKTFLPGGHIEIGESAEIALVRELREELGLSCKVGRYLGAVENQWQDKEVIHVELNHLFE 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1278723640  87 VTLLSDSGRI---SQENHLEFAWLTREELSDVIVFPTSLKDAVLLHHAKGKPFW 137
Cdd:cd18883    82 VELQDLHTSDtpeSQEPHLEFYWIPYNDLELHNLQPMPLRNLLLNRKLSDGLFW 135

MutT homolog-1 and similar proteins; MutT homolog-1 (MTH1), also known as NUDIX (nucleoside diphosphate-linked moiety X)) motif 1/Nudt1, is a member of the NUDIX hydrolase superfamily. MTH1, the mammalian counterpart of MutT, hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP and 2-hydroxy-ATP, to monophosphates, thereby preventing the incorporation of such oxygen radicals during replication. This is an important step in the repair mechanism in genomic and mitochondrial DNA. Like other members of the NUDIX family, it requires a divalent cation, such as Mg2+ or Mn2+, for activity, and contain the NUDIX motif, a highly conserved 23-residue block (GX5EX7REUXEEXGU, where U = I, L or V), that functions as a metal binding and catalytic site. MTH1 is predominantly localized in the cytoplasm and mitochondria. Structurally, this enzyme adopts a similar fold to MutT despite low sequence similarity outside the conserved NUDIX motif. The most distinctive structural difference between MutT and MTH1 is the presence of a beta-hairpin, which is absent in MutT. This results in a much deeper and narrower substrate binding pocket. Mechanistically, MTH1 contains dual specificity for nucleotides that contain 2-OH-adenine bases and those that contain 8-oxo-guanine bases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640   7 IARAIIEEEGKILLCRGKGNKNYFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIGASENKFEIKGEETHEINLVFE 86
Cdd:cd18883     2 TARGVIISDEHLLLARVKGDDKTFLPGGHIEIGESAEIALVRELREELGLSCKVGRYLGAVENQWQDKEVIHVELNHLFE 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1278723640  87 VTLLSDSGRI---SQENHLEFAWLTREELSDVIVFPTSLKDAVLLHHAKGKPFW 137
Cdd:cd18883    82 VELQDLHTSDtpeSQEPHLEFYWIPYNDLELHNLQPMPLRNLLLNRKLSDGLFW 135

pyrimidine (deoxy)nucleoside triphosphate diphosphatase;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640   1 MNIIECIArAIIEEEGKILLCRGKGNKN----YFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIgASeNKFEIKGE 76
Cdd:PRK10546    1 MKMIDVVA-AIIERDGKILLAQRPAHSDqaglWEFAGGKVEPGESQPQALIRELREELGIEATVGEYV-AS-HQREVSGR 77

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1278723640  77 ETHeinlVFEVTLLSDSGRISQENHLEFAWLTREE 111
Cdd:PRK10546   78 RIH----LHAWHVPDFHGELQAHEHQALVWCTPEE 108

MutT homolog-1 and similar proteins; MutT homolog-1 (MTH1), also known as NUDIX (nucleoside diphosphate-linked moiety X)) motif 1/Nudt1, is a member of the NUDIX hydrolase superfamily. MTH1, the mammalian counterpart of MutT, hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP and 2-hydroxy-ATP, to monophosphates, thereby preventing the incorporation of such oxygen radicals during replication. This is an important step in the repair mechanism in genomic and mitochondrial DNA. Like other members of the NUDIX family, it requires a divalent cation, such as Mg2+ or Mn2+, for activity, and contain the NUDIX motif, a highly conserved 23-residue block (GX5EX7REUXEEXGU, where U = I, L or V), that functions as a metal binding and catalytic site. MTH1 is predominantly localized in the cytoplasm and mitochondria. Structurally, this enzyme adopts a similar fold to MutT despite low sequence similarity outside the conserved NUDIX motif. The most distinctive structural difference between MutT and MTH1 is the presence of a beta-hairpin, which is absent in MutT. This results in a much deeper and narrower substrate binding pocket. Mechanistically, MTH1 contains dual specificity for nucleotides that contain 2-OH-adenine bases and those that contain 8-oxo-guanine bases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640   7 IARAIIEEEGKILLCRGKGNKNYFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIGASENKFEIKGEETHEINLVFE 86
Cdd:cd18883     2 TARGVIISDEHLLLARVKGDDKTFLPGGHIEIGESAEIALVRELREELGLSCKVGRYLGAVENQWQDKEVIHVELNHLFE 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1278723640  87 VTLLSDSGRI---SQENHLEFAWLTREELSDVIVFPTSLKDAVLLHHAKGKPFW 137
Cdd:cd18883    82 VELQDLHTSDtpeSQEPHLEFYWIPYNDLELHNLQPMPLRNLLLNRKLSDGLFW 135

ADP-ribose pyrophosphatase and similar proteins; ADP-ribose pyrophosphatase (ADPRase; EC 3.6.1.13) catalyzes the hydrolysis of ADP-ribose to AMP and ribose-5-P. Like other members of the NUDIX hydrolase superfamily of enzymes, it is thought to require a divalent cation, such as Mg2+, for its activity. It also contains a 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V) which functions as a metal binding site/catalytic site. In addition to the NUDIX motif, there are additional conserved amino acid residues, distal from the signature sequence, that correlate with substrate specificity. In humans, there are four distinct ADPRase activities, three putative cytosolic (ADPRase-I, -II, and -Mn) and a single mitochondrial enzyme (ADPRase-m). ADPRase-m is also known as NUDT9. It can be distinugished from the cytosolic ADPRase by a N-terminal target sequence unique to mitochondrial ADPRase. NUDT9 functions as a monomer.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640   8 ARAIIEEEGKILLCRGKGNKN--YFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIGASEnkFEIKGEETHEINLVF 85
Cdd:cd18880     4 AKAIIIEDGKLLLVKHRDEGGifYILPGGGQEHGETLPEALKRECLEETGLDVEVGDLLFVRE--YIGPNKPVHQVELFF 81

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1278723640  86 EVTLlsDSGRISQE-----NHLEFAWLTREELSDVIVFPTSLKD 124
Cdd:cd18880    82 LCTL--EGGELTLGsdpdlNQVGVEWIPLEELDSIRLYPAILRE 123

MutT pyrophosphohydrolase; The MutT pyrophosphohydrolase is a prototypical NUDIX hydrolase that catalyzes the hydrolysis of nucleoside and deoxynucleoside triphosphates (NTPs and dNTPs) by substitution at a beta-phosphorus to yield a nucleotide monophosphate (NMP) and inorganic pyrophosphate (PPi). This enzyme requires two divalent cations for activity; one coordinates the phosphoryl groups of the NTP/dNTP substrate, and the other coordinates to the enzyme. It also contains the NUDIX motif, a highly conserved 23-residue block (GX5EX7REUXEEXGU, where U = I, L or V), that functions as metal binding and catalytic site. MutT pyrophosphohydrolase is important in preventing errors in DNA replication by hydrolyzing mutagenic nucleotides such as 8-oxo-dGTP (a product of oxidative damage), which can mispair with template adenine during DNA replication, to guanine nucleotides.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640  10 AIIEEEGKILLCR---GKGNKNYF-FPGGHIEDGESAPEALMREIKEELGEESKVKRFIGASENKFEIKgeethEINL-V 84
Cdd:cd03425     6 AIIVDDGRVLIAQrpeGKHLAGLWeFPGGKVEPGETPEQALVRELREELGIEVEVGEPLGTVEHDYPDF-----HVRLhV 80

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1278723640  85 FEVTLLsdSGRISQENHLEFAWLTREELSDV 115
Cdd:cd03425    81 YLCTLW--SGEPQLLEHQELRWVTPEELDDL 109

NUDIX hydrolase superfamily; NUDIX hydrolase is a superfamily of enzymes found in all three kingdoms of life, and it catalyzes the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+ for their activity. Members of this family are recognized by a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site. Substrates of NUDIX hydrolase include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance and "house-cleaning" enzymes. Substrate specificity is used to define child families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required. This superfamily consists of at least nine families: IPP (isopentenyl diphosphate) isomerase, ADP ribose pyrophosphatase, mutT pyrophosphohydrolase, coenzyme-A pyrophosphatase, MTH1-7,8-dihydro-8-oxoguanine-triphosphatase, diadenosine tetraphosphate hydrolase, NADH pyrophosphatase, GDP-mannose hydrolase and the c-terminal portion of the mutY adenine glycosylase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640  10 AIIEEEGKILLCR---GKGNKNYFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIGASEnkFEIKGEETHEINLVFE 86
Cdd:cd02883     6 VVFDDEGRVLLVRrsdGPGPGGWELPGGGVEPGETPEEAAVREVREETGLDVEVLRLLGVYE--FPDPDEGRHVVVLVFL 83

                          90       100
                  ....*....|....*....|...
gi 1278723640  87 VTLLSDSGRISQEN-HLEFAWLT 108
Cdd:cd02883    84 ARVVGGEPPPLDDEeISEVRWVP 106

uncharacterized NUDIX hydrolase subfamily; NUDIX hydrolase is a superfamily of enzymes found in all three kingdoms of life, and it catalyzes the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+ for their activity. Members of this family are recognized by a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site. Substrates of NUDIX hydrolase include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance and "house-cleaning" enzymes. Substrate specificity is used to define child families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required. This superfamily consists of at least nine families: IPP (isopentenyl diphosphate) isomerase, ADP ribose pyrophosphatase, mutT pyrophosphohydrolase, coenzyme-A pyrophosphatase, MTH1-7,8-dihydro-8-oxoguanine-triphosphatase, diadenosine tetraphosphate hydrolase, NADH pyrophosphatase, GDP-mannose hydrolase and the c-terminal portion of the mutY adenine glycosylase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640  10 AIIEEEGKILLCR-----GKGNKNyfFPGGHIEDGESAPEALMREIKEELGEESKVKRFIGASENKFEIKGEETHEINLV 84
Cdd:cd04681    11 VIIRNEGEILFVRrakepGKGKLD--LPGGFVDPGESAEEALRRELREELGLKIPKLRYLCSLPNTYLYKGITYKTCDLF 88

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1278723640  85 FEVTLLSDSGRISQENHL-EFAWLTREEL-SDVIVFPtSLKDAVLLH 129
Cdd:cd04681    89 FTAELDEKPKLKKAEDEVaELEWLDLEEIePEKLAFP-SIRKAVERY 134

GDP-mannose glycosyl hydrolase; GDP-mannose glycosyl hydrolase, also known as GDP-mannose mannosyl hydrolase/GDPMH, is a member of the NUDIX hydrolase superfamily. This class of enzymes is unique from other members of the superfamily in two aspects. First, it contains a modified NUDIX signature sequence. The slight changes to the conserved sequence motif, GX5EX7REUXEEXGU, where U = I, L or V), are believed to contribute to the removal of all magnesium binding sites but one, retaining only the metal site that coordinates the pyrophosphate of the substrate. Secondly, it is not a pyrophosphatase that substitutes at a phosphorus; instead, it hydrolyzes nucleotide sugars such as GDP-mannose to GDP and mannose, cleaving the phosphoglycosyl bond by substituting at a carbon position. GDP-mannose provides mannosyl components for cell wall synthesis and is required for the synthesis of other glycosyl donors (such as GDP-fucose and colitose) for the cell wall. The importance of GDP-sugar hydrolase activities is thus closely related to the regulation of cell wall biosynthesis. Enzymes in this family are believed to regulate the concentration of GDP-mannose and GDP-glucose in the bacterial cell wall.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640   6 CIARAIIEEEGKILLcrGKGN----KNYFF-PGGHIEDGESAPEALMREIKEELGEESKVK--RFIGASE-----NKFEi 73
Cdd:cd03430    17 SIDLIIRNEDGEILL--GKRNnrpaQGYWFvPGGRILKNETLDDAFKRIAREELGLEVTINaaEFLGVYEhfyddNFSG- 93

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1278723640  74 KGEETHEINLVFEVTLLSDSGRISQENHLEFAWLTREEL 112
Cdd:cd03430    94 EDFSTHYVVLAYRLKLDEGLLLLPDDQHDEYRWFTIDEL 132

MutT homolog-1 and similar proteins; MutT homolog-1 (MTH1), also known as NUDIX (nucleoside diphosphate-linked moiety X)) motif 1/Nudt1, is a member of the NUDIX hydrolase superfamily. MTH1, the mammalian counterpart of MutT, hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP and 2-hydroxy-ATP, to monophosphates, thereby preventing the incorporation of such oxygen radicals during replication. This is an important step in the repair mechanism in genomic and mitochondrial DNA. Like other members of the NUDIX family, it requires a divalent cation, such as Mg2+ or Mn2+, for activity, and contain the NUDIX motif, a highly conserved 23-residue block (GX5EX7REUXEEXGU, where U = I, L or V), that functions as a metal binding and catalytic site. MTH1 is predominantly localized in the cytoplasm and mitochondria. Structurally, this enzyme adopts a similar fold to MutT despite low sequence similarity outside the conserved NUDIX motif. The most distinctive structural difference between MutT and MTH1 is the presence of a beta-hairpin, which is absent in MutT. This results in a much deeper and narrower substrate binding pocket. Mechanistically, MTH1 contains dual specificity for nucleotides that contain 2-OH-adenine bases and those that contain 8-oxo-guanine bases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640   8 ARAIIEEEGKILLCR--GKGNKNYFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIGASEnkFEIKgEETHEINLVF 85
Cdd:cd04699     5 VKGVIFDNGRVLLLRrsRAGAGEWELPGGRLEPGESPEEALKREVKEETGLDVSVGELLDTWT--FELD-PDKGVFIVTY 81

                          90       100
                  ....*....|....*....|....*....
gi 1278723640  86 EVTLLSDSGRISQEnHLEFAWLTREELSD 114
Cdd:cd04699    82 LCRLVGGEVTLSDE-HEEYEWVTPEELAE 109

uncharacterized NUDIX hydrolase subfamily; NUDIX hydrolase is a superfamily of enzymes found in all three kingdoms of life, and it catalyzes the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+ for their activity. Members of this family are recognized by a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site. Substrates of NUDIX hydrolase include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance and "house-cleaning" enzymes. Substrate specificity is used to define child families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required. This superfamily consists of at least nine families: IPP (isopentenyl diphosphate) isomerase, ADP ribose pyrophosphatase, mutT pyrophosphohydrolase, coenzyme-A pyrophosphatase, MTH1-7,8-dihydro-8-oxoguanine-triphosphatase, diadenosine tetraphosphate hydrolase, NADH pyrophosphatase, GDP-mannose hydrolase and the c-terminal portion of the mutY adenine glycosylase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640  10 AIIEEEGKILLCRGKGNKNYFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIGA-SENKFEIK---GEETHEINLVF 85
Cdd:cd04677    18 IILNEQGRILLQKRTDTGDWGLPGGAMELGESLEETARREVFEETGLTVEELELLGVySGKDLYYTypnGDEVYNVTAVY 97

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1278723640  86 EVTLLSDSGRISQENHLEFAWLTREELSDVIV 117
Cdd:cd04677    98 LVRDVSGELKVDDEESLELRFFSLDELPENIN 129

uncharacterized NUDIX hydrolase subfamily; Contains a crystal structure of the NUDIX hydrolase from Enterococcus faecalis, which has an unknown function. NUDIX hydrolase is a superfamily of enzymes found in all three kingdoms of life, and it catalyzes the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+ for their activity. Members of this family are recognized by a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site. Substrates of NUDIX hydrolase include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance and "house-cleaning" enzymes. Substrate specificity is used to define child families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required. This superfamily consists of at least nine families: IPP (isopentenyl diphosphate) isomerase, ADP ribose pyrophosphatase, mutT pyrophosphohydrolase, coenzyme-A pyrophosphatase, MTH1-7,8-dihydro-8-oxoguanine-triphosphatase, diadenosine tetraphosphate hydrolase, NADH pyrophosphatase, GDP-mannose hydrolase and the c-terminal portion of the mutY adenine glycosylase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640   8 ARAIIE-EEGKILLCRgKGNKNYFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIG-ASENKFEIKGEE-THEINLV 84
Cdd:cd04684    18 AYAVIFnDEGKVLLVQ-TPNGGYFLPGGGIEPGETPEEALHREVLEETGWEIEIGEFLGnASRYFYSPDYDRyYLNIGYF 96

                          90       100       110
                  ....*....|....*....|....*....|
gi 1278723640  85 FEVTLLSDSGRISQENHlEFAWLTREELSD 114
Cdd:cd04684    97 YLAELVRKVSEPTEEDH-ELVWLPPEEAAD 125

uncharacterized NUDIX hydrolase subfamily; NUDIX hydrolase is a superfamily of enzymes found in all three kingdoms of life, and it catalyzes the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+ for their activity. Members of this family are recognized by a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site. Substrates of NUDIX hydrolase include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance and "house-cleaning" enzymes. Substrate specificity is used to define child families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required. This superfamily consists of at least nine families: IPP (isopentenyl diphosphate) isomerase, ADP ribose pyrophosphatase, mutT pyrophosphohydrolase, coenzyme-A pyrophosphatase, MTH1-7,8-dihydro-8-oxoguanine-triphosphatase, diadenosine tetraphosphate hydrolase, NADH pyrophosphatase, GDP-mannose hydrolase and the c-terminal portion of the mutY adenine glycosylase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640   7 IARAII-EEEGKILLCRGKGNKNYFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIG---ASEnkfeiKGEETHEIN 82
Cdd:cd18876     2 AAGALFtDAAGRVLLVKPTYKDGWELPGGVVEAGESPLQAARREVREELGLDVPVGRLLAvdwVPP-----AGGGDDAVL 76

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1278723640  83 LVFEVTLLSDS--GRIS-QENHL-EFAWLTREELSDV 115
Cdd:cd18876    77 FVFDGGVLTPEqaAAIRlQDEELsAYRFVTPEEAAEL 113

uncharacterized NUDIX hydrolase subfamily; NUDIX hydrolase is a superfamily of enzymes found in all three kingdoms of life, and it catalyzes the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+ for their activity. Members of this family are recognized by a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site. Substrates of NUDIX hydrolase include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance and "house-cleaning" enzymes. Substrate specificity is used to define child families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required. This superfamily consists of at least nine families: IPP (isopentenyl diphosphate) isomerase, ADP ribose pyrophosphatase, mutT pyrophosphohydrolase, coenzyme-A pyrophosphatase, MTH1-7,8-dihydro-8-oxoguanine-triphosphatase, diadenosine tetraphosphate hydrolase, NADH pyrophosphatase, GDP-mannose hydrolase and the c-terminal portion of the mutY adenine glycosylase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640   7 IARAIIEEEGKILLCRGKGNKNYFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIGASENK-FEIK---GEETHEIN 82
Cdd:cd04676    20 VAAVILNEDGRILLQRKGGLGLWSLPAGAIEPGEHPAEAVIREVREETGLLVKPTRLLGVFGGKeFRYTypnGDQVEYTV 99

                          90       100
                  ....*....|....*....|....*....
gi 1278723640  83 LVFEVTLLSDSGRISQENHLEFAWLTREE 111
Cdd:cd04676   100 IAFKCVVTGGTLNAIDGETSELRYFSRTQ 128

Nudix family hydrolase;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1278723640   1 MNIIECIARAIIEEEGKILLCRGKGNKNYF----FPGGHIEDGESAPEALMREIKEELG 55
Cdd:PRK08999    2 MKRIHVAAGVIRDADGRILLARRPEGKHQGglweFPGGKVEPGETVEQALARELQEELG 60

MutT homolog-1 and similar proteins; MutT homolog-1 (MTH1), also known as NUDIX (nucleoside diphosphate-linked moiety X)) motif 1/Nudt1, is a member of the NUDIX hydrolase superfamily. MTH1, the mammalian counterpart of MutT, hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP and 2-hydroxy-ATP, to monophosphates, thereby preventing the incorporation of such oxygen radicals during replication. This is an important step in the repair mechanism in genomic and mitochondrial DNA. Like other members of the NUDIX family, it requires a divalent cation, such as Mg2+ or Mn2+, for activity, and contain the NUDIX motif, a highly conserved 23-residue block (GX5EX7REUXEEXGU, where U = I, L or V), that functions as a metal binding and catalytic site. MTH1 is predominantly localized in the cytoplasm and mitochondria. Structurally, this enzyme adopts a similar fold to MutT despite low sequence similarity outside the conserved NUDIX motif. The most distinctive structural difference between MutT and MTH1 is the presence of a beta-hairpin, which is absent in MutT. This results in a much deeper and narrower substrate binding pocket. Mechanistically, MTH1 contains dual specificity for nucleotides that contain 2-OH-adenine bases and those that contain 8-oxo-guanine bases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640  10 AIIEEEGKILLCRGKGNKN---YFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIGASENKFEIKGEetHEINLVFE 86
Cdd:cd04679     7 AAILDDGRLLLVLRLRAPEaghWGLPGGKVDWLETVEDAVRREILEELGLEIELTRLLCVVDQIDAADGE--HWVAPVYL 84

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1278723640  87 VTLLSDSGRISQ-ENHLEFAWLTREELSDVIVFPTslKDAV 126
Cdd:cd04679    85 AEIFSGEPRLMEpEKHGGIGWFALDALPQPLTVAT--RDAL 123

MutT homolog 2; MutT Homolog 2 (MTH2; EC 3.6.1.9), also known as NUDIX (nucleoside diphosphate-linked moiety X)) motif 15/Nudt15, may catalyze the hydrolysis of nucleoside diphosphates, triphosphates including dGTP, dTTP, dCTP, their oxidized forms like 8-oxo-dGTP, and prodrug thiopurine derivatives 6-thio-dGTP and 6-thio-GTP. MTH2 may also play a role in DNA synthesis and cell cycle progression by stabilizing PCNA. Members of the NUDIX hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of NUDIX hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance _ "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640  11 IIEEEGKILLCRGKGNK---NYFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIGASENKFEIKGEetHEINLVFEV 87
Cdd:cd04678     9 VLNDDGKVLLGRRKGSHgagTWALPGGHLEFGESFEECAAREVLEETGLEIRNVRFLTVTNDVFEEEGK--HYVTIFVLA 86

                          90       100
                  ....*....|....*....|....*..
gi 1278723640  88 TLLSDSGRISQENHL--EFAWLTREEL 112
Cdd:cd04678    87 EVDDGEPEENMEPDKceGWEWFSWDEL 113

diadenosine hexaphosphate (Ap6A) hydrolase; Diadenosine hexaphosphate (Ap6A) hydrolase is a member of the NUDIX hydrolase superfamily. Ap6A hydrolase specifically hydrolyzes diadenosine polyphosphates, but not ATP or diadenosine triphosphate, and it generates ATP as the product. Ap6A, the most preferred substrate, hydrolyzes to produce two ATP molecules, which is a novel hydrolysis mode for Ap6A. These results indicate that Ap6A hydrolase is a diadenosine polyphosphate hydrolase. It requires the presence of a divalent cation, such as Mn2+, Mg2+, Zn2+, and Co2+, for activity. Members of the NUDIX hydrolase superfamily are recognized by a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640  13 EEEGKILLCRGKGNKNYFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIGASENKFEIKGEETHEINLVFEVTLLSD 92
Cdd:cd03673    13 GGGGEVLLIHRPRYDDWSLPKGKLEPGETPEEAAVREVEEETGLRVRLGRPLGTTRYTYTRKGKGILKKVHYWLMRALGG 92

                          90       100
                  ....*....|....*....|....*....
gi 1278723640  93 SGRISQENHLEFA-WLTREELSDVIVFPT 120
Cdd:cd03673    93 EFLPQPEEEIDEVrWLPPDEARRLLTYPS 121

NUDIX hydrolase subfamily; Nucleoside triphosphatase NudI catalyzes the hydrolysis of nucleoside triphosphates, with a preference for pyrimidine deoxynucleoside triphosphates (dUTP, dTTP and dCTP). It is a members of the NUDIX hydrolase superfamily which catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of NUDIX hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance _ "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1278723640  11 IIEEEGKILLCRGKGNKNYF-----FPGGHIEDGESAPEALMREIKEELGEE 57
Cdd:cd04696     8 LIENEGCYLLCKMADDRGVFpgqwaLSGGGVEPGERIEEALRREIREELGEQ 59

plant diadenosine tetraphosphate (Ap4A) hydrolase and similar proteins; Diadenosine tetraphosphate (Ap4A) hydrolase is a member of the NUDIX hydrolase superfamily. Members of this family are well represented in a variety of prokaryotic and eukaryotic organisms. Phylogenetic analysis reveals two distinct subgroups where plant enzymes fall into one group (represented by this subfamily) and fungi/animals/archaea enzymes fall into another. Bacterial enzymes are found in both subfamilies. Ap4A is a potential by-product of aminoacyl tRNA synthesis, and accumulation of Ap4A has been implicated in a range of biological events, such as DNA replication, cellular differentiation, heat shock, metabolic stress, and apoptosis. Ap4A hydrolase cleaves Ap4A asymmetrically into ATP and AMP. It is important in the invasive properties of bacteria and thus presents a potential target for the inhibition of such invasive bacteria. Besides the signature NUDIX motif (G[X5]E[X7]REUXEEXGU where U is Ile, Leu, or Val), Ap4A hydrolase is structurally similar to the other members of the NUDIX hydrolase superfamily with some degree of variations. Several regions in the sequences are poorly defined and substrate and metal binding sites are only predicted based on kinetic studies.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1278723640   6 CIARAIIEEEGKILLCRGKGNKNYF-FPGGHIEDGESAPEALMREIKEELGEESKVKRFIGASE 68
Cdd:cd03671     5 NVGIVLFNRDGQVLVGRRIDVPGAWqFPQGGIDEGEDPEEAALRELYEETGLSPEDVEIIAETP 68

Antisense Basic Fibroblast Growth Factor; Antisense Basic Fibroblast Growth Factor (ASFGF2; EC 3.6.1.-), also known as nucleoside diphosphate-linked moiety X)) motif 6/Nudt6, and similar proteins including peroxisomal coenzyme A diphosphatase/Nudt7 and mitochondrial coenzyme A diphosphatase/Nudt8. The Nudt6 gene overlaps and lies on the opposite strand from FGF2 gene, and is thought to be the FGF2 antisense gene. The two genes are independently transcribed, and their expression shows an inverse relationship, suggesting that this antisense transcript may regulate FGF2 expression. This gene has also been shown to have hormone-regulatory and antiproliferative actions in the pituitary that are independent of FGF2 expression. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. Members of the NUDIX hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of NUDIX hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance _ "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1278723640  11 IIEEEGKILLC--RGKGNKNYFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIG 65
Cdd:cd04670     9 VINENNEVLVVqeKYGGPGGWKLPGGLVDPGEDIGEAAVREVFEETGIDTEFVSILG 65

MutT homolog-1 (MTH1); MutT homolog-1 (MTH1; EC 3.6.1.- ), also called nucleoside diphosphate-linked moiety X)) motif 1 (Nudt1), is a member of the NUDIX hydrolase superfamily. MTH1, the mammalian counterpart of MutT, hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP and 2-hydroxy-ATP, to monophosphates, thereby preventing the incorporation of such oxygen radicals during replication. This is an important step in the repair mechanism in genomic and mitochondrial DNA. Like other members of the NUDIX family, it requires a divalent cation, such as Mg2+ or Mn2+, for activity, and contain the NUDIX motif, a highly conserved 23-residue block (GX5EX7REUXEEXGU, where U = I, L or V), that functions as a metal binding and catalytic site. MTH1 is predominantly localized in the cytoplasm and mitochondria. Structurally, this enzyme adopts a similar fold to MutT despite low sequence similarity outside the conserved NUDIX motif. The most distinctive structural difference between MutT and MTH1 is the presence of a beta-hairpin, which is absent in MutT. This results in a much deeper and narrower substrate binding pocket. Mechanistically, MTH1 contains dual specificity for nucleotides that contain 2-OH-adenine bases and those that contain 8-oxo-guanine bases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640  11 IIEEEGKILLC---RGKGNKNYFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIGasENKFEIKGEETHEINLVFEV 87
Cdd:cd03427     8 VLRGDDRVLLGlkkRGFGAGKWNGFGGKVEPGETIEEAAVRELEEEAGLTATELEKVG--RLKFEFPDDPEAMDVHVFRA 85

                  .
gi 1278723640  88 T 88
Cdd:cd03427    86 D 86

uncharacterized NUDIX hydrolase subfamily; NUDIX hydrolase is a superfamily of enzymes found in all three kingdoms of life, and it catalyzes the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+ for their activity. Members of this family are recognized by a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site. Substrates of NUDIX hydrolase include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance and "house-cleaning" enzymes. Substrate specificity is used to define child families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required. This superfamily consists of at least nine families: IPP (isopentenyl diphosphate) isomerase, ADP ribose pyrophosphatase, mutT pyrophosphohydrolase, coenzyme-A pyrophosphatase, MTH1-7,8-dihydro-8-oxoguanine-triphosphatase, diadenosine tetraphosphate hydrolase, NADH pyrophosphatase, GDP-mannose hydrolase and the c-terminal portion of the mutY adenine glycosylase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640  31 FPGGHIEDGESAPEALMREIKEELGEEskvkrfigASENKFEIKGEETHEINL---VFEVTLLSDsgrISQENHLE---F 104
Cdd:cd18882    34 LFGGHLEPGETPEEAIRRELEEEIGYE--------PGEFRFFLLYTEDDGEDRirhVFHAPLDVD---LSDLVLNEgqaL 102

                          90
                  ....*....|....*....
gi 1278723640 105 AWLTREELSDVIVFPTSLK 123
Cdd:cd18882   103 RLFSPEEILQGPLYSNLAG 121

RNA pyrophosphohydrolase; The initiation of mRNA degradation often requires deprotection of its 5' end. In eukaryotes, the 5'-methylguanosine (cap) structure is principally removed by the NUDIX family decapping enzyme Dcp2, yielding a 5'-monophosphorylated RNA that is a substrate for 5' exoribonucleases. In bacteria, the 5'-triphosphate group of primary transcripts is also converted to a 5' monophosphate by a NUDIX protein called RNA pyrophosphohydrolase (RppH), allowing access to both endo- and 5' exoribonucleases. NUDIX hydrolase is a superfamily of enzymes found in all three kingdoms of life, and it catalyzes the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+ for their activity. Members of this family are recognized by a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site. Substrates of NUDIX hydrolase include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance and "house-cleaning" enzymes. Substrate specificity is used to define child families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required. This superfamily consists of at least nine families: IPP (isopentenyl diphosphate) isomerase, ADP ribose pyrophosphatase, mutT pyrophosphohydrolase, coenzyme-A pyrophosphatase, MTH1-7,8-dihydro-8-oxoguanine-triphosphatase, diadenosine tetraphosphate hydrolase, NADH pyrophosphatase, GDP-mannose hydrolase and the c-terminal portion of the mutY adenine glycosylase.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1278723640  10 AIIEEEGKILLCRGKGNKNYFFPGGHIEDGESAPEALMREIKEELG 55
Cdd:cd04665     5 VIARYKGKWLFTRHKERRGWEFPGGKREPGETIEEAARRELYEETG 50

diadenosine tetraphosphate; Diadenosine tetraphosphate (Ap4A; EC 3.6.1.17), also called NUDIX (nucleoside diphosphate-linked moiety X)) motif 2/Nudt2, is a member of the NUDIX hydrolase superfamily. Ap4A hydrolases are well represented in a variety of prokaryotic and eukaryotic organisms. Phylogenetic analysis reveals two distinct subgroups where plant enzymes fall into one subfamily and fungi/animals/archaea enzymes, represented by this subfamily, fall into another. Bacterial enzymes are found in both subfamilies. Ap4A is a potential by-product of aminoacyl tRNA synthesis, and accumulation of Ap4A has been implicated in a range of biological events, such as DNA replication, cellular differentiation, heat shock, metabolic stress, and apoptosis. Ap4A hydrolase cleaves Ap4A asymmetrically into ATP and AMP. It is important in the invasive properties of bacteria and thus presents a potential target for inhibition of such invasive bacteria. Besides the signature NUDIX motif (G[X5]E[X7]REUXEEXGU, where U is Ile, Leu, or Val) that functions as a metal binding and catalytic site, and a required divalent cation, Ap4A hydrolase is structurally similar to the other members of the NUDIX hydrolase superfamily with some degree of variation. Several regions in the sequences are poorly defined and substrate and metal binding sites are only predicted based on kinetic studies.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640  13 EEEGKILLCRGKGNKNYFFPGGHIEDGESAPEALMREIKEELGeeSKVKRFIGASENKFEIKGEETHEINLVFEVTLLSD 92
Cdd:cd03428    14 NGEIEFLLLQHSYGGHWDFPKGHVEPGESELETALRETKEETG--LTVDDLPPGFRETLTYSFKEGVEKTVVYFLAELTP 91

                          90       100
                  ....*....|....*....|....*....
gi 1278723640  93 SGRIS-QENHLEFAWLTREELSDVIVFPT 120
Cdd:cd03428    92 DVEVKlSEEHQDYKWLPYEEALQLLTYEN 120

nudix hydrolase

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640  18 ILLCRGK---GNKNYFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIGASENKFEIKGEETHEINlVFEVTLLSDSG 94
Cdd:PLN02325   22 VLLGRRRssiGDSTFALPGGHLEFGESFEECAAREVKEETGLEIEKIELLTVTNNVFLEEPKPSHYVT-VFMRAVLADPS 100

                  ....
gi 1278723640  95 RISQ 98
Cdd:PLN02325  101 QVPQ 104

Mitochondrial ribosomal protein L46; Mitochondrial ribosomal protein L46 (MRP L46) is a component of the large subunit (39S) of the mammalian mitochondrial ribosome and a member of the NUDIX hydrolase superfamily. MRPs are thought to be involved in the maintenance of the mitochondrial DNA. In general, members of the NUDIX hydrolase superfamily require a divalent cation, such as Mg2+ or Mn2+, for activity and contain the NUDIX motif, a highly conserved 23-residue block (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. MRP L46 appears to contain a modified NUDIX motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640  19 LLCRGKGNKN-YFFPGGHIEDGESAPEALMREIKEELGEESKVkRFIG---------ASENKFEIKGEETHeinlvfevt 88
Cdd:cd04661    33 LLVKQKKGKGpWQFPQGDVEEGETLREAAERGLRELGGDNMNT-WFVGnapigvykyKYPKKTKEFGYKSF--------- 102

                          90       100
                  ....*....|....*....|....*...
gi 1278723640  89 LLSDSGRISQ-ENHLEFAWLTREELSDV 115
Cdd:cd04661   103 FLKGRFMPGQkKGVSDFAWLTKEELKEY 130

NADH pyrophosphatase; NADH pyrophosphatase, also known as NUDIX (nucleoside diphosphate linked moiety X)) motif 13/Nudt13, is thought to have NADH pyrophosphatase activity, be involved in NADH metabolic process and NADP catabolic process, catalyzing the cleavage of NADH into reduced nicotinamide mononucleotide (NMNH) and AMP, and located in mitochondrion. Like other members of the NUDIX family, it requires a divalent cation, such as Mg2+ or Mn2+, for activity. Members of this family are also recognized by the NUDIX motif, a highly conserved 23-residue block (GX5EX7REUXEEXGU, where U = I, L or V), that functions as a metal binding and catalytic site. A block of 8 conserved amino acids downstream of the NUDIX motif is thought to give NADH pyrophosphatase its specificity for NADH. NADH pyrophosphatase forms a dimer.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1278723640   6 CIARAIIEEEGKILLCRGKG--NKNYFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIG 65
Cdd:cd03429     3 AVIVLVTNGEDKILLARQPRwpPGRYSLLAGFVEPGETLEEAVRREVKEEVGLRVKNVRYVG 64

nucleoside diphosphate-linked moiety X)) motif 17; Nucleoside diphosphate-linked moiety X)) motif 17 (EC 3.6.1.-) encoded by the NUDT17 gene on chromosome 1q21.1 and encodes an enzyme thought to hydrolyse some nucleoside diphosphate derivatives. Members of the NUDIX hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of NUDIX hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance _ "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640  31 FPGGHIEDGESAPEALMREIKEELG---EESKVKRFIGASEN----KFEIKGEETHEINLVFEVTLLSDSG---RIS-QE 99
Cdd:cd04694    34 PPGGHVELGESLLEAGLRELQEETGlevSDIQSLSLLGLWESvyptLLSIGLPKRHHIVVYYLVKLSESHEnqeQLKlQE 113

                          90
                  ....*....|....*...
gi 1278723640 100 NHL-EFAWLTREELSDVI 116
Cdd:cd04694   114 DEVdAAVWLPKSLLAKLL 131

uncharacterized NUDIX hydrolase subfamily; NUDIX hydrolase is a superfamily of enzymes found in all three kingdoms of life, and it catalyzes the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+ for their activity. Members of this family are recognized by a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site. Substrates of NUDIX hydrolase include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance and "house-cleaning" enzymes. Substrate specificity is used to define child families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required. This superfamily consists of at least nine families: IPP (isopentenyl diphosphate) isomerase, ADP ribose pyrophosphatase, mutT pyrophosphohydrolase, coenzyme-A pyrophosphatase, MTH1-7,8-dihydro-8-oxoguanine-triphosphatase, diadenosine tetraphosphate hydrolase, NADH pyrophosphatase, GDP-mannose hydrolase and the c-terminal portion of the mutY adenine glycosylase.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1278723640   7 IARAIIEEEGKILLCR-------GKGNknyfFPGGHIEDGESAPEALMREIKEELG 55
Cdd:cd04511     4 VVGCLPEWEGKVLLCRraieprkGYWT----LPAGFMELGETTEQGAARETREEAG 55

uncharacterized NUDIX hydrolase subfamily; Contains a crystal structure of the NUDIX hydrolase from Nitrosomonas europaea, which has an unknown function. NUDIX hydrolase is a superfamily of enzymes found in all three kingdoms of life, and it catalyzes the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+ for their activity. Members of this family are recognized by a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site. Substrates of NUDIX hydrolase include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance and "house-cleaning" enzymes. Substrate specificity is used to define child families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required. This superfamily consists of at least nine families: IPP (isopentenyl diphosphate) isomerase, ADP ribose pyrophosphatase, mutT pyrophosphohydrolase, coenzyme-A pyrophosphatase, MTH1-7,8-dihydro-8-oxoguanine-triphosphatase, diadenosine tetraphosphate hydrolase, NADH pyrophosphatase, GDP-mannose hydrolase and the c-terminal portion of the mutY adenine glycosylase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1278723640  10 AIIEEEGKILLC--RGKGNKNYFFPGGHIEDGESAPEALMREIKEELGEESKVKRFIGASENKFEIKGEETHEINLVFEV 87
Cdd:cd03675     5 AVVERDGRFLLVeeETDGRLVLNQPAGHLEPGESLLEAAIRETLEETGWEVEPTALLGIYQWTAPDNGVTYLRFAFAGEL 84

                          90       100       110
                  ....*....|....*....|....*....|
gi 1278723640  88 TLLS-----DSGRISQenhlefAWLTREEL 112
Cdd:cd03675    85 LEHLpdqplDSGIIRA------HWLTLEEI 108

RNA pyrophosphohydrolase; Reviewed