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 2664666850  19 VDVAVGVLINkDGAFLLTSRPPGKVYAGYWEFPGGKLEAGETVEQALRRELQEEIGVTIGSAAIWKVSMVDYPHGLVRLH 98
Cdd:cd03425     1 IEVVAAIIVD-DGRVLIAQRPEGKHLAGLWEFPGGKVEPGETPEQALVRELREELGIEVEVGEPLGTVEHDYPDFHVRLH 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 2664666850  99 FCKVRDWVGEMHMREGQQFGWhslpvscapVLAGTLPVLEWLAA 142
Cdd:cd03425    80 VYLCTLWSGEPQLLEHQELRW---------VTPEELDDLDWLPA 114

mutator mutT protein; All proteins in this family for which functions are known are involved in repairing oxidative damage to dGTP (they are 8-oxo-dGTPases). This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). Lowering the threshold picks up members of MutT superfamily well. [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2664666850  21 VAVGVLINKDGAFLLTSRPPGKVYAGYWEFPGGKLEAGETVEQALRRELQEEIGVTIGSAAIWKVSMVDYPHGLVRLHFC 100
Cdd:TIGR00586   6 IAVGIIRNENGEIIITRRADGHMFAKLLEFPGGKEEGGETPEQAVVRELEEEIGIPQHFSEFEKLEYEFYPRHITLWFWL 85

                          90       100
                  ....*....|....*....|..
gi 2664666850 101 KVRdWVGEMHMREGQQFGWHSL 122
Cdd:TIGR00586  86 LER-WEGGPPGKEGQPEEWWVL 106

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 2664666850  19 VDVAVGVLINkDGAFLLTSRPPGKVYAGYWEFPGGKLEAGETVEQALRRELQEEIGVTIGSAAIWKVSMVDYPHGLVRLH 98
Cdd:cd03425     1 IEVVAAIIVD-DGRVLIAQRPEGKHLAGLWEFPGGKVEPGETPEQALVRELREELGIEVEVGEPLGTVEHDYPDFHVRLH 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 2664666850  99 FCKVRDWVGEMHMREGQQFGWhslpvscapVLAGTLPVLEWLAA 142
Cdd:cd03425    80 VYLCTLWSGEPQLLEHQELRW---------VTPEELDDLDWLPA 114

pyrimidine (deoxy)nucleoside triphosphate diphosphatase;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2664666850  18 VVDVaVGVLINKDGAFLLTSRPPGKVYAGYWEFPGGKLEAGETVEQALRRELQEEIGVTIGSAAIWKVSMVDYPHGLVRL 97
Cdd:PRK10546    3 MIDV-VAAIIERDGKILLAQRPAHSDQAGLWEFAGGKVEPGESQPQALIRELREELGIEATVGEYVASHQREVSGRRIHL 81

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 2664666850  98 HFCKVRDWVGEMHMREGQQFGWhslpvsCAPVLAGTLP 135
Cdd:PRK10546   82 HAWHVPDFHGELQAHEHQALVW------CTPEEALRYP 113

mutator mutT protein; All proteins in this family for which functions are known are involved in repairing oxidative damage to dGTP (they are 8-oxo-dGTPases). This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). Lowering the threshold picks up members of MutT superfamily well. [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2664666850  21 VAVGVLINKDGAFLLTSRPPGKVYAGYWEFPGGKLEAGETVEQALRRELQEEIGVTIGSAAIWKVSMVDYPHGLVRLHFC 100
Cdd:TIGR00586   6 IAVGIIRNENGEIIITRRADGHMFAKLLEFPGGKEEGGETPEQAVVRELEEEIGIPQHFSEFEKLEYEFYPRHITLWFWL 85

                          90       100
                  ....*....|....*....|..
gi 2664666850 101 KVRdWVGEMHMREGQQFGWHSL 122
Cdd:TIGR00586  86 LER-WEGGPPGKEGQPEEWWVL 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 2664666850  19 VDVAVGVLINKDGAFLLTSRP--PGKVYAGYWEFPGGKLEAGETVEQALRRELQEEIGVTIGSAAIWKVSMVDYPHGLVR 96
Cdd:cd18882     1 HEVAIAILYDDRGKVLLQLRDdkPGIPYPGYWGLFGGHLEPGETPEEAIRRELEEEIGYEPGEFRFFLLYTEDDGEDRIR 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 2664666850  97 -LHFCKVRDWVGEMHMREGQQFGWHSLP-VSCAPVLAGTLPVLEWLAAEQ 144
Cdd:cd18882    81 hVFHAPLDVDLSDLVLNEGQALRLFSPEeILQGPLYSNLAGILRPLLAIH 130

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 2664666850  21 VAVGVLINKDGAFLLTSRPPGKvYAGYWEFPGGKLEAGETVEQALRRELQEEIGVTIGSAAIWKVSMVDYP--HGLVRLH 98
Cdd:cd02883     2 AVGAVVFDDEGRVLLVRRSDGP-GPGGWELPGGGVEPGETPEEAAVREVREETGLDVEVLRLLGVYEFPDPdeGRHVVVL 80

                          90       100
                  ....*....|....*....|....*.
gi 2664666850  99 FCKVRDWVGEMHMR---EGQQFGWHS 121
Cdd:cd02883    81 VFLARVVGGEPPPLddeEISEVRWVP 106

NUDIX domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2664666850  21 VAVGVLI-NKDGAFLLTSRPpGKVYAGYWEFPGGKLEAGETVEQALRRELQEEIGVT------IGSAAIWKVSMVDYPHG 93
Cdd:pfam00293   4 VAVGVVLlNEKGRVLLVRRS-KKPFPGWWSLPGGKVEPGETPEEAARRELEEETGLEpellelLGSLHYLAPFDGRFPDE 82

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2664666850  94 LVRLHFCkVRDWVGEMHMR---EGQQFGWHSLP-VSCAPVLAGTLPVLEWL 140
Cdd:pfam00293  83 HEILYVF-LAEVEGELEPDpdgEVEEVRWVPLEeLLLLKLAPGDRKLLPWL 132

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 2664666850  22 AVGVLINKDGAFLLTSRP--PGKvyaGYWEFPGGKLEAGETVEQALRRELQEEIGVTI 77
Cdd:cd04681     8 AVGVIIRNEGEILFVRRAkePGK---GKLDLPGGFVDPGESAEEALRRELREELGLKI 62

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
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 2664666850  21 VAVGVLINKDGAFLLTSRPPGKvyAGYWEFPGGKLEAGETVEQALRRELQEEIGVTI 77
Cdd:cd04699     3 VSVKGVIFDNGRVLLLRRSRAG--AGEWELPGGRLEPGESPEEALKREVKEETGLDV 57

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 2664666850  15 NRPVVDV-AVGVLINKDGAFLLTSRPPGkvyaGYWEFPGGKLEAGETVEQALRRELQEEIGVTIGSAAIWKV-----SMV 88
Cdd:cd04677     7 HRPLILVgAAVIILNEQGRILLQKRTDT----GDWGLPGGAMELGESLEETARREVFEETGLTVEELELLGVysgkdLYY 82

                          90       100
                  ....*....|....*....|....*....
gi 2664666850  89 DYPHG----LVRLHFcKVRDWVGEMHMRE 113
Cdd:cd04677    83 TYPNGdevyNVTAVY-LVRDVSGELKVDD 110

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 2664666850  21 VAVGVLINKDGAFLLTSR-PPGKVYAGYWEF-PGGKLEAGETVEQALRRELQEEIGVTI 77
Cdd:cd04693    31 VVHVWIFNSDGEILIQQRsPDKKGFPGMWEAsTGGSVLAGETSLEAAIRELKEELGIDL 89

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 2664666850  25 VLINKDGA-FLLTSRPPGKVYAGYWEFPGGKLEAGETVEQALRRELQEEIGVTIGSAA----IWKVSMVDYPHGLVRL-- 97
Cdd:cd04685     6 LLLDPDGRvLLFRFHDPDDPGRSWWFTPGGGVEPGESPEQAAVRELREETGLRLEPDDlggpVWRRRAVFDFSGETVRqd 85

                  ....*..
gi 2664666850  98 -HFCKVR 103
Cdd:cd04685    86 eRFFLVR 92

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
                  ....*....|....*....|....*....|..
gi 2664666850  45 AGYWEFPGGKLEAGETVEQALRRELQEEIGVT 76
Cdd:cd03427    26 AGKWNGFGGKVEPGETIEEAAVRELEEEAGLT 57

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 2664666850  23 VGVLINKDGAFLLtSRPPGKvyaGYWEFPGGKLEAGETVEQALRRELQEEIGVTI 77
Cdd:cd04688     5 VAAIIIRDGKVLL-ARGEDD---DYYRLPGGRVEFGETSEDALVREFKEELGVEV 55

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
                  ....*....|....*....|....*....|....
gi 2664666850  44 YAGYWEFPGGKLEAGETVEQALRRELQEEIGVTI 77
Cdd:cd04686    24 YQGRYDLPGGSQEFGESLEDALKREFAEETGMTV 57

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
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2664666850  21 VAVGVLINKDGAFLLTS-RPPGKVYagyWEFPGGKLEAGETVEQALRRELQEEIGVTI 77
Cdd:cd18880     2 IRAKAIIIEDGKLLLVKhRDEGGIF---YILPGGGQEHGETLPEALKRECLEETGLDV 56

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2664666850  21 VAVGVLINKDGAFLLTSR---PPgkvyAGYWEFPGGKLEAGETVEQALRRELQEEIGVTIGS 79
Cdd:cd04679     3 VGCGAAILDDGRLLLVLRlraPE----AGHWGLPGGKVDWLETVEDAVRREILEELGLEIEL 60

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 2664666850  25 VLINKDGAFLLTSRPPGKvyagyWEFPGGKLEAGETVEQALRRELQEEIGVTIGSAAI 82
Cdd:cd04667     5 VICRRGDRILLVARRGGR-----WLLPGGKIEPGESPLEAAIRELKEETGLAALSLLY 57

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 2664666850  24 GVLINKDGAFLLTSRppgkVYAGYWEFPGGKLEAGETVEQALRRELQEEIGVTIGSAAIwkvsmvdyphgLVRLHFCK-- 101
Cdd:cd04680     5 AIVLDDAGRVLLVRH----TYVPGWYLPGGGVDKGETAEEAARRELREEAGVVLTGPPR-----------LFGVYFNRrv 69

                          90       100
                  ....*....|....*....|
gi 2664666850 102 -VRDWVGEMHMREGQQFGWH 120
Cdd:cd04680    70 sPRDHVALYRVREFEQTEPP 89

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 2664666850  21 VAVGVLI-NKDGAFLLTSRPPgkvYAGYWEFPGGKLEAGETVEQALRRELQEEIGVTI 77
Cdd:cd18874     3 PTVGALIfNPDGKVLLVRSHK---WNDLYGIPGGKVEWGETLEEALKREVKEETGLDI 57

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 2664666850  21 VAVGVLINKDGAFLLTSR--PPGKvyaGYWEFPGGKLEAGETVEQALRRELQEEIG--VTIGSAaiwkVSMVDYPH-GLV 95
Cdd:cd04511     3 IVVGCLPEWEGKVLLCRRaiEPRK---GYWTLPAGFMELGETTEQGAARETREEAGarVEIGSL----YAVYSLPHiSQV 75

                  ....
gi 2664666850  96 RLHF 99
Cdd:cd04511    76 YIIF 79

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 2664666850  21 VAVGVLI-NKDGAFLLTSR--PPGKvyaGYWEFPGGKLEAGETVEQALRRELQEEIGVTI 77
Cdd:cd03430    16 VSIDLIIrNEDGEILLGKRnnRPAQ---GYWFVPGGRILKNETLDDAFKRIAREELGLEV 72

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
                  ....*....|....*....|....*....|....*....|....*....|....
gi 2664666850  29 KDGAFLLTSRPPGKV-----YAGYWEFPGGKLEAGETVEQALRRELQEEIGVTI 77
Cdd:cd04684    15 RPGAYAVIFNDEGKVllvqtPNGGYFLPGGGIEPGETPEEALHREVLEETGWEI 68

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 2664666850  25 VLINKDGAFLLTSRPpgKVYAGYWEFPGGKLEAGETVEQALRRELQEEIGVTI 77
Cdd:cd18875     8 MIYDGEDRVLVLDRV--KKDWGGYTFPGGHVEPGESFVDSVIREVKEETGLTI 58

NADH pyrophosphatase NudC, Nudix superfamily [Nucleotide transport and metabolism];

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 2664666850  17 PVVDVAVGVLINKDGAFLLT--SRPPGKVY---AGYwefpggkLEAGETVEQALRRELQEEIGVTIGS 79
Cdd:COG2816   155 PRTDPAVIVLVTDGDRILLArqARWPPGRYsllAGF-------VEPGETLEQAVRREVFEEVGVRVKN 215

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 2664666850  29 KDGAFLLTSRPPGK-VYAGYWEFP-GGKLEAGETVEQALRRELQEEIGVTI 77
Cdd:cd04692    37 EEGRLLLQKRSANKdDFPGLWDISaAGHIDAGETYEEAAVRELEEELGLTV 87

nucleoside triphosphatase YtkD; The functional assignment to the proteins of this family is contentious, with papers disagreeing in both interpretation and enzyme assay results. This protein belongs to the nudix family and shares some sequence identity with E. coli MutT but appears not to be functionally interchangeable with it. [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30
                  ....*....|....*....|....*....|.
gi 2664666850  49 EFPGGKLEAGETVEQALRRELQEEIGVTIGS 79
Cdd:TIGR02705  48 EFPGGKVEPGETSKEAAIREVMEETGAIVKE 78

coenzyme A pyrophosphatase and similar proteins; Coenzyme A pyrophosphatase (CoAse; EC 3.6.1.1), also called nucleoside diphosphate-linked moiety X)) motif 7, is a member of the NUDIX hydrolase superfamily, functions to catalyze the elimination of oxidized inactive CoA, which can inhibit CoA-utilizing enzymes. The need of CoAses mainly arises under conditions of oxidative stress. CoAse has a conserved NUDIX fold and requires a single divalent cation for catalysis. In addition to a signature NUDIX motif G[X5]E[X7]REUXEEXGU, where U is Ile, Leu, or Val, CoAse contains an additional motif upstream called the NuCoA motif (LLTXT(SA)X3RX3GX3FPGG) which is postulated to be involved in CoA recognition. CoA plays a central role in lipid metabolism. It is involved in the initial steps of fatty acid sythesis in the cytosol, in the oxidation of fatty acids and the citric acid cycle in the mitochondria, and in the oxidation of long-chain fatty acids in peroxisomes. CoA has the important role of activating fatty acids for further modification into key biological signalling molecules.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2664666850  22 AVGVLI---NKDGAFLLTSRPPG-KVYAGYWEFPGGKLEAG-ETVEQALRRELQEEIGVTIGSAAIW 83
Cdd:cd03426     4 AVLIPLvegDGELHVLLTKRASHlRSHPGQIAFPGGKREPGdESPVETALRETEEEIGLPPESVEVL 70

NUDIX domain family found in Deinococcus radiodurans, and similar proteins; Deinococcus radiodurans protein DR_0079 is one of 21 NUDIX hydrolases that it encodes, and it has been observed to have a marked preference for cytosine ribonucleoside 5'-diphosphate (CDP) and cytosine ribonucleoside 5'-triphosphate (CTP), and for their corresponding deoxyribose nucleotides, dCDP and dCTP, to a lesser degree. 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2664666850  26 LINKDGAFLLTSRPPGK-VYAGYWEFP-GGKLEAGETVEQALRRELQEEIGVTIgSAAIWKV 85
Cdd:cd24154     9 LINSQGQLWIPRRTADKrIFPLALDMSvGGHVSSGETYEQAFVRELQEELNLDL-DQLSYRV 69

Adp Ribose Pyrophosphatase; ADP-ribose pyrophosphatase (ADPRase) catalyzes the hydrolysis of ADP-ribose and a variety of additional ADP-sugar conjugates to AMP and ribose-5-phosphate. In humans, there are four distinct ADPRase activities, three putative cytosolic enzymes (ADPRase-I, -II, and -Mn) and a single mitochondrial enzyme (ADPRase-m). Human ADPRase-II is also referred to as NUDT5. It lacks the N-terminal target sequence unique to mitochondrial ADPRase. The different cytosolic types are distinguished by their specificities for substrate and specific requirement for metal ions. NUDT5 forms a homodimer. It also contains a highly conserved 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. UDP-glucose pyrophosphatase (UGPPase) (EC 3.6.1.45; also known as nucleoside diphosphate-linked moiety X)) motif 14; Nudt14) hydrolyzes the pyrophosphate of the nucleoside diphosphate sugar to generate glucose-1-P and UMP. In mammals, UDP-glucose is the glucosyl donor for the synthesis of the storage polysaccharide glycogen. UGPPase, as a regulator of UDP-glucose, could play a regulatory role, but it has been shown to prefer ADP-ribose over UDP-glucose. Like other members of the NUDIX hydrolase superfamily, it requires a divalent cation, such as Mg2+, for its activity. It also contains a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V) which functions as a metal binding site/catalytic site.

                          10        20        30
                  ....*....|....*....|....*....|.
gi 2664666850  48 WEFPGGKLEAGETVEQALRRELQEEIGVTIG 78
Cdd:cd24155    78 LEIVAGMIDAGETPEDVARREAEEEAGLTLD 108

adenosine nucleotide hydrolase NudE; Provisional

                          10        20
                  ....*....|....*....|....*
gi 2664666850  50 FPGGKLEAGETVEQALRRELQEEIG 74
Cdd:PRK11762   78 FPKGLIDPGETPLEAANRELKEEVG 102

bifunctional nicotinamide-nucleotide adenylyltransferase/Nudix hydroxylase;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2664666850   6 ADQDAPRssnrPVVDVAVGVLINKDGAFLLTSRP--PGKvyaGYWEFPGGKLEAGETVEQALRRELQEEIGVTIgSAAIW 83
Cdd:PRK05379  193 AWAAAPY----PPTFVTVDAVVVQSGHVLLVRRRaePGK---GLWALPGGFLEQDETLLDACLRELREETGLKL-PEPVL 264

                          90
                  ....*....|....
gi 2664666850  84 KVSMV-----DYPH 92
Cdd:PRK05379  265 RGSIRdqqvfDHPG 278

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 2664666850  22 AVGVLINKDGAFLLTSRPPGKVYAGYwEFPGGKLEAGETVEQALRRELQEEIGVT 76
Cdd:cd04663     3 VCAYVTRGRNRELLVFEHPDFPEAGL-QVPKGTVEPGESPEEAALRELAEETGLT 56

NUDIX domain family NudE found in Escherichia coli, and similar proteins; The adenosine nucleotide hydrolase NudE protein in Escherichia coli is a NUDIX hydrolase family member active against ADP ribose, NADH, AP2A and AP3A33, and is classified as a hydrolase (E.C. 3.6.1.-) based on gene annotations. It is an 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. 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
                  ....*....|....*....|....*
gi 2664666850  50 FPGGKLEAGETVEQALRRELQEEIG 74
Cdd:cd24156    33 FPKGLIDPGETPEEAANRELKEEIG 57