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 505448518   5 PRLGCGVAIVRDGQLLLVKRLRDPEAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLLCVVDQIDPLRQEHWVS 84
Cdd:cd04679    1 PRVGCGAAILDDGRLLLVLRLRAPEAGHWGLPGGKVDWLETVEDAVRREILEELGLEIELTRLLCVVDQIDAADGEHWVA 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 505448518  85 PVYLASAPAMPARNCEPHKHSDVAWFELDRLPQPLTQATRSAVRAL 130
Cdd:cd04679   81 PVYLAEIFSGEPRLMEPEKHGGIGWFALDALPQPLTVATRDALEAL 126

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 505448518   5 PRLGCGVAIVRDGQLLLVKRLRDPEAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLLCVVDQIDPLRQEHWVS 84
Cdd:cd04679    1 PRVGCGAAILDDGRLLLVLRLRAPEAGHWGLPGGKVDWLETVEDAVRREILEELGLEIELTRLLCVVDQIDAADGEHWVA 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 505448518  85 PVYLASAPAMPARNCEPHKHSDVAWFELDRLPQPLTQATRSAVRAL 130
Cdd:cd04679   81 PVYLAEIFSGEPRLMEPEKHGGIGWFALDALPQPLTVATRDALEAL 126

NUDIX domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 505448518   10 GVAIV---RDGQLLLVKRLRDPEAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLL----CVVDQIDPLRQEHW 82
Cdd:pfam00293   5 AVGVVllnEKGRVLLVRRSKKPFPGWWSLPGGKVEPGETPEEAARRELEEETGLEPELLELLgslhYLAPFDGRFPDEHE 84

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 505448518   83 VSPVYLASAPAMPARNCEPHkHSDVAWFELDRLPQP 118
Cdd:pfam00293  85 ILYVFLAEVEGELEPDPDGE-VEEVRWVPLEELLLL 119

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 505448518   10 GVAIVRD--GQLLLVKRLRDPE-AGCWGLPGGKVDWLEPVEQAMRREIHEELGLTlQGVSLL 68
Cdd:TIGR00586   7 AVGIIRNenGEIIITRRADGHMfAKLLEFPGGKEEGGETPEQAVVRELEEEIGIP-QHFSEF 67

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 505448518   5 PRLGCGVAIVRDGQLLLVKRLRDPEAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLLCVVDQIDPLRQEHWVS 84
Cdd:cd04679    1 PRVGCGAAILDDGRLLLVLRLRAPEAGHWGLPGGKVDWLETVEDAVRREILEELGLEIELTRLLCVVDQIDAADGEHWVA 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 505448518  85 PVYLASAPAMPARNCEPHKHSDVAWFELDRLPQPLTQATRSAVRAL 130
Cdd:cd04679   81 PVYLAEIFSGEPRLMEPEKHGGIGWFALDALPQPLTVATRDALEAL 126

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 505448518   7 LGCGVAIVRD-GQLLLVKRLRDPEAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLLCVVDQIDPLRQEHWVSP 85
Cdd:cd02883    1 VAVGAVVFDDeGRVLLVRRSDGPGPGGWELPGGGVEPGETPEEAAVREVREETGLDVEVLRLLGVYEFPDPDEGRHVVVL 80

                         90       100
                 ....*....|....*....|....*
gi 505448518  86 VYLASAPAMPARNCEPHKHSDVAWF 110
Cdd:cd02883   81 VFLARVVGGEPPPLDDEEISEVRWV 105

ADP-ribose pyrophosphatase; 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 505448518   6 RLGCGVAIVRDGQLLLVKRLRDPEAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLLCVVDQIDPLRQE----H 81
Cdd:cd04673    1 IVAVGAVVFRDGRVLLVRRGNPPDAGLWSFPGGKVELGETLEDAALRELREETGLEAEVVGLLTVVDVIERDEAGrvrfH 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 505448518  82 WVSPVYLASAPAMparncEPHKHSD---VAWFELDRLPQ-PLTQATRSAVRAL 130
Cdd:cd04673   81 YVILDFLAEWVSG-----EPVAGDDaldARWFSLEELDGlPLTPGTRDVLERA 128

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 505448518   8 GCGVAIVRD-GQLLLVKRlRDPeaGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLLCVV------------DQI 74
Cdd:cd04677   14 GAAVIILNEqGRILLQKR-TDT--GDWGLPGGAMELGESLEETARREVFEETGLTVEELELLGVYsgkdlyytypngDEV 90

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 505448518  75 dplrqeHWVSPVYLASAPAmPARNCEPHKHSDVAWFELDRLPQPLTQATR 124
Cdd:cd04677   91 ------YNVTAVYLVRDVS-GELKVDDEESLELRFFSLDELPENINPQHR 133

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 505448518  13 IVRDGQLLLVKRLRDPEAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLLCVVDQIDPLRQEHWVSPVYLASAP 92
Cdd:cd18886    7 IIRDDEVLLLNRNKKPNMGKWNGVGGKLEPGESPEECAIREVFEETGLELEDLQLRGIVTFPSFDGGEDWLMYVFLAEAF 86

                         90       100
                 ....*....|....*....|....*
gi 505448518  93 AMPARNCEPhkHSDVAWFELDRLPQ 117
Cdd:cd18886   87 SGELVESDR--EGILAWVPIDWLLN 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 505448518  10 GVAIVRDGQLLLVKRLRDPEAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLLC 69
Cdd:cd04681   10 GVIIRNEGEILFVRRAKEPGKGKLDLPGGFVDPGESAEEALRRELREELGLKIPKLRYLC 69

nudix hydrolase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 505448518   5 PRLGCGVAIVRDGQLLLVKRLRDPEAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLLCVVDQI--DPLRQEHW 82
Cdd:PLN02325   8 PRVAVVVFLLKGNSVLLGRRRSSIGDSTFALPGGHLEFGESFEECAAREVKEETGLEIEKIELLTVTNNVflEEPKPSHY 87

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 505448518  83 VSPVYLA--SAPAMPARNCEPHKHSDVAWFELDRLPQPL 119
Cdd:PLN02325  88 VTVFMRAvlADPSQVPQNLEPEKCYGWDWYEWDNLPEPL 126

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 505448518  12 AIVRDGQLLLVKRLRDPE-AGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLLCVVDQIDP-----LRqehwvsp 85
Cdd:cd03425    7 IIVDDGRVLIAQRPEGKHlAGLWEFPGGKVEPGETPEQALVRELREELGIEVEVGEPLGTVEHDYPdfhvrLH------- 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 505448518  86 VYLASAPAMPARNCEphkHSDVAWFELDRLPQ-PLTQATRSAVRAL 130
Cdd:cd03425   80 VYLCTLWSGEPQLLE---HQELRWVTPEELDDlDWLPADIPIVEAL 122

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 505448518  13 IVRDGQLLLVKRLRDpEAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLL-CVVDQIDPLRQEhwVSPVYLASA 91
Cdd:cd04699    9 IFDNGRVLLLRRSRA-GAGEWELPGGRLEPGESPEEALKREVKEETGLDVSVGELLdTWTFELDPDKGV--FIVTYLCRL 85

                         90       100
                 ....*....|....*....|....*...
gi 505448518  92 PamparNCEP---HKHSDVAWFELDRLP 116
Cdd:cd04699   86 V-----GGEVtlsDEHEEYEWVTPEELA 108

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 505448518  13 IVRDGQLLLVKRLRDPEAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLLCVVDQIDP 76
Cdd:cd04686    8 IIRNDKLLLIRKTRGPYQGRYDLPGGSQEFGESLEDALKREFAEETGMTVTSYDNLGVYDFFVP 71

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 505448518   7 LGCGVAIVRDGQLLLVKRLRDPEAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLLCVVDQIDPLRQEHWVSpV 86
Cdd:cd04691    2 LGVGGVVVKEGKVLLVKRAYGPGKGRWTLPGGFVEEGETLDEAIVREVLEETGIDAKPVGIIGVRSGVIRDGKSDNYV-V 80

                         90       100
                 ....*....|....*....|....*....
gi 505448518  87 YLASAPAmPARNCEPHKHSDVAWFELDRL 115
Cdd:cd04691   81 FLLEYVG-GEPKPDERENSEAGFLTLEEA 108

Nudix family hydrolase;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 505448518  10 GVAIVRDGQLLLVKRLRD-PEAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTlqgvsllcvVDQIDPLRQEHWVSP--- 85
Cdd:PRK08999  10 GVIRDADGRILLARRPEGkHQGGLWEFPGGKVEPGETVEQALARELQEELGIE---------VTAARPLITVRHDYPdkr 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 505448518  86 ----VYLASAPAMPARncePHKHSDVAWFELDRLPQ-PLTQATRSAVRAL 130
Cdd:PRK08999  81 vrldVRRVTAWQGEPH---GREGQPLAWVAPDELAVyPFPPANQPIVRAL 127

CDP-Choline Pyrophosphatase and similar proteins; Members include: CDP-Choline Pyrophosphatase, ADP-ribose pyrophosphatase, and UDP-X diphosphatase. CDP-choline pyrophosphatase catalyzes the hydrolysis of CDP-choline to produce CMP and phosphocholine. ADP-ribose pyrophosphatase catalyzes the hydrolysis of ADP-ribose to AMP and ribose-5-P. UDP-X diphosphatase hydrolyzes UDP-N-acetylmuramic acid and UDP-N-acetylmuramoyl-L-alanine. 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 505448518   5 PRLGCGVAIVRDGQLLLVKRLRDpeaGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQgVSLLCVVDqiDPLRQEHWVS 84
Cdd:cd04672    1 PKVDVRAAVFKDGKILLVREKSD---GRWTLPGGWADVGLSPAENAVKEVREESGYEVR-ARKLLAVF--DRNKGGHPPS 74

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 505448518  85 P------VYLASapAMPARNCEPHKHSDVAWFELDRLPqPLTQA 122
Cdd:cd04672   75 PfhvyklFFLCE--LIGGEAQTSIETSEVGFFALDDLP-PLSLG 115

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 505448518   6 RLGCGVAIV-RDGQLLLVKRLRDPEAgcWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLL 68
Cdd:cd03671    3 RPNVGIVLFnRDGQVLVGRRIDVPGA--WQFPQGGIDEGEDPEEAALRELYEETGLSPEDVEII 64

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 505448518   9 CGVAIVRD--GQLLLVKRLRdpeAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSllcvVDQIDPLR-QEHWVSP 85
Cdd:cd03674    4 ASAFVVNPdrGKVLLVHHRK---LGRWLQPGGHVEPDEDPLEAALREAREETGLDVELLS----PLSPDPLDiDVHPIPA 76

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 505448518  86 ------------VYLASAPAmPARNCEPHKHSDVAWFELDRLPQPLTQA 122
Cdd:cd03674   77 npgepahlhldvRYLAVADG-DEALRKSDESSDVRWFPLDELEELSMDP 124

ADP-ribose pyrophosphatase, UDP-glucose pyrophosphatase, and similar proteins; ADP-ribose pyrophosphatase (ADPRase) ( NUDIX (Nucleoside diphosphate-linked moiety X)) motif 5; Nudt5) 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        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 505448518  11 VAIVRDGQLLLVKRLRDP-EAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLL 68
Cdd:cd03424    8 LAITDDGKVVLVRQYRHPvGRVLLELPAGKIDPGEDPEEAARRELEEETGYTAGDLELL 66

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 505448518  17 GQLLLVKRLRDPEagcWGLPGGKVDWLEPVEQAMRREIHEELGLTlqgvsllcvVDQIDPL-RQEHWVSPV--------- 86
Cdd:cd03673   16 GEVLLIHRPRYDD---WSLPKGKLEPGETPEEAAVREVEEETGLR---------VRLGRPLgTTRYTYTRKgkgilkkvh 83

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 505448518  87 -YLASA---PAMPARNCEPhkhSDVAWFELDRLPQPLTQAT-RSAVRALVQ 132
Cdd:cd03673   84 yWLMRAlggEFLPQPEEEI---DEVRWLPPDEARRLLTYPSdREVLDAALE 131

ADP-ribose pyrophosphatase; 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 505448518   5 PRLGCGVAIVRDGQLLLVKRlRDpeaGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLLCVVDqidplRQEHWVS 84
Cdd:cd18889    1 PKIDTRAAIFKDDKILLVQE-KD---GRWSLPGGWVDVNQSIKENTIKEAKEEAGLDVEPKRIIAVLD-----RNKHNKP 71

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 505448518  85 PV--------YLasapamparnCEPHKH--------SDVAWFELDRLPQ 117
Cdd:cd18889   72 PYaygiykifVL----------CELLGGefqpnietIESGYFSLDELPP 110

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 505448518  10 GVAIV---RDGQLLLVKRLRDPEA--GCWGLPGGKVDWLEPVEQAMRREIHEELGLTL---QGVSLLCV 70
Cdd:cd04694    4 GVVVLiedSDDRVLLTRRAKHMRTfpGVWVPPGGHVELGESLLEAGLRELQEETGLEVsdiQSLSLLGL 72

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 505448518  11 VAIVRD--GQLLLVKRLRDpeaGCWGLPGGKVdwlEPVEQ---AMRREIHEELGLTLQGVSLLCVvDQIDPLRQEHWVSP 85
Cdd:cd18879   22 TAVVLRdaGRVLLVRRADN---GRWTPVTGIV---EPGEQpadAAVREVLEETGVDVEVERLASV-GASPPVTYPNGDQC 94

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 505448518  86 VYLASAPAMPARNCEPH----KHSDVAWFELDRLPQPLTQATR 124
Cdd:cd18879   95 QYLDLTFRCRPVGGEARvnddESLEVGWFPVDALPPMLPRFRR 137

8-oxo-dGTP diphosphatase MutT;

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 505448518  11 VAIVRD--GQLLLVKRLRDPE-AGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLL 68
Cdd:PRK10776   8 VGIIRNpnNEIFITRRAADAHmAGKWEFPGGKIEAGETPEQALIRELQEEVGITVQHATLF 68

UDP-X diphosphatase; UDP-X diphosphatase hydrolyzes UDP-N-acetylmuramic acid and UDP-N-acetylmuramoyl-L-alanine, the last step of the Mur pathway of peptidoglycan biosynthesis. 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 505448518  13 IVRDGQLLLVkrlRDPEAGCWGLPGG--KVDWlEPVEQAMRrEIHEELGLTLQGVSLLCVVDQidPLRQEHWVSPVYLAS 90
Cdd:cd18891    9 IQNENKVLLV---QDKHTKEWALPGGfaEVGL-SPKENILK-EVKEETGLHVEVERLLAVFDT--DLRQDIPQSFQYYKF 81

                         90       100       110
                 ....*....|....*....|....*....|....
gi 505448518  91 APAMPARNCEPHKH---SDVAWFELDRLPqPLTQ 121
Cdd:cd18891   82 IFACKILDGEFQENsetSDLQYFSLDQLP-NLSL 114

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 505448518  10 GVAIV---RDGQLLLvkrLRDPEAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLLCV 70
Cdd:cd04676   19 SVAAVilnEDGRILL---QRKGGLGLWSLPAGAIEPGEHPAEAVIREVREETGLLVKPTRLLGV 79

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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 505448518  13 IVRDGQLLLVKRLRDPEA--GCWGLPGGKVDWLEPVEQAMRREIHEELG--LTLQGVSLLCVVDQI 74
Cdd:cd04696    9 IENEGCYLLCKMADDRGVfpGQWALSGGGVEPGERIEEALRREIREELGeqLILSDITPWTFRDDI 74

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
                 ....*....|....*....|....*....|....*....|....*....|...
gi 505448518  13 IVRD--GQLLLVKRLRDPEAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQ 63
Cdd:cd03430   21 IIRNedGEILLGKRNNRPAQGYWFVPGGRILKNETLDDAFKRIAREELGLEVT 73

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 505448518  11 VAIVR--DGQLLLVKR--LRDPEAGCWGLP-GGKVDWLEPVEQAMRREIHEELGLTLQ 63
Cdd:cd04692   31 VWLVNpeEGRLLLQKRsaNKDDFPGLWDISaAGHIDAGETYEEAAVRELEEELGLTVS 88

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
                 ....*....|....*....|....*....|....*....|....*...
gi 505448518  13 IVRDGQLLLVKRLRDPEAGcwgLPGGKVDWLEPVEQAMRREIHEELGL 60
Cdd:cd18883    7 IISDEHLLLARVKGDDKTF---LPGGHIEIGESAEIALVRELREELGL 51

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.

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gi 505448518   4 QPRLGCGVAIVRD-GQLLLVKrlrdPEAGCWGLPGGKVDWLEPVEQAMRREIHEELGLTLQGVSLLCVVDQ 73
Cdd:cd04684   13 KDRPGAYAVIFNDeGKVLLVQ----TPNGGYFLPGGGIEPGETPEEALHREVLEETGWEIEIGEFLGNASR 79