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 1321613058  13 IISNSKkqILIMQL-NNSDHSWHFPGGRLNIDDESVEGLRREVKEETGLDIFDIKPIHTQIF---TEERKYGVFFTAKTT 88
Cdd:cd04699     9 IFDNGR--VLLLRRsRAGAGEWELPGGRLEPGESPEEALKREVKEETGLDVSVGELLDTWTFeldPDKGVFIVTYLCRLV 86

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1321613058  89 EpQDIKISFEHRDFRWINKEELDNINFWQPF 119
Cdd:cd04699    87 G-GEVTLSDEHEEYEWVTPEELAELELPEGY 116

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 1321613058  13 IISNSKkqILIMQL-NNSDHSWHFPGGRLNIDDESVEGLRREVKEETGLDIFDIKPIHTQIF---TEERKYGVFFTAKTT 88
Cdd:cd04699     9 IFDNGR--VLLLRRsRAGAGEWELPGGRLEPGESPEEALKREVKEETGLDVSVGELLDTWTFeldPDKGVFIVTYLCRLV 86

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1321613058  89 EpQDIKISFEHRDFRWINKEELDNINFWQPF 119
Cdd:cd04699    87 G-GEVTLSDEHEEYEWVTPEELAELELPEGY 116

NUDIX domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1321613058  12 AIISNSKKQILIMQLNNSDHS--WHFPGGRLNIDDESVEGLRREVKEETGLDIFDIKPI--------HTQIFTEERKYGV 81
Cdd:pfam00293   8 VVLLNEKGRVLLVRRSKKPFPgwWSLPGGKVEPGETPEEAARRELEEETGLEPELLELLgslhylapFDGRFPDEHEILY 87

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1321613058  82 FFTAKTTEPQDIKISFEHRDFRWINKEELDNINFWQPFYK 121
Cdd:pfam00293  88 VFLAEVEGELEPDPDGEVEEVRWVPLEELLLLKLAPGDRK 127

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 1321613058  13 IISNSKkqILIMQL-NNSDHSWHFPGGRLNIDDESVEGLRREVKEETGLDIFDIKPIHTQIF---TEERKYGVFFTAKTT 88
Cdd:cd04699     9 IFDNGR--VLLLRRsRAGAGEWELPGGRLEPGESPEEALKREVKEETGLDVSVGELLDTWTFeldPDKGVFIVTYLCRLV 86

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1321613058  89 EpQDIKISFEHRDFRWINKEELDNINFWQPF 119
Cdd:cd04699    87 G-GEVTLSDEHEEYEWVTPEELAELELPEGY 116

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1321613058  16 NSKKQILIMQLNNSDHsWHFPGGRLNIDDESVEGLRREVKEETGLDIFDIKP-----IHTQIFTEERKYGVFFTAKTTEP 90
Cdd:cd03428    14 NGEIEFLLLQHSYGGH-WDFPKGHVEPGESELETALRETKEETGLTVDDLPPgfretLTYSFKEGVEKTVVYFLAELTPD 92

                          90       100
                  ....*....|....*....|...
gi 1321613058  91 QDIKISFEHRDFRWINKEELDNI 113
Cdd:cd03428    93 VEVKLSEEHQDYKWLPYEEALQL 115

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 1321613058  12 AIISNSKKQILIMQLNNSDHSWHFPGGRLNIDDESVEGLRREVKEETGLDIFDIKPIHTQ--IFTEE---RKYGVF--FT 84
Cdd:cd18874     7 ALIFNPDGKVLLVRSHKWNDLYGIPGGKVEWGETLEEALKREVKEETGLDITDIRFILVQesINSEEfhkPAHFVFvdYL 86

                          90       100
                  ....*....|....*....|....*
gi 1321613058  85 AKtTEPQDIKISFEHRDFRWINKEE 109
Cdd:cd18874    87 AR-TDSSEVVLNEEAVEYLWVEPEE 110

NUDIX domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1321613058  12 AIISNSKKQILIMQLNNSDHS--WHFPGGRLNIDDESVEGLRREVKEETGLDIFDIKPI--------HTQIFTEERKYGV 81
Cdd:pfam00293   8 VVLLNEKGRVLLVRRSKKPFPgwWSLPGGKVEPGETPEEAARRELEEETGLEPELLELLgslhylapFDGRFPDEHEILY 87

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1321613058  82 FFTAKTTEPQDIKISFEHRDFRWINKEELDNINFWQPFYK 121
Cdd:pfam00293  88 VFLAEVEGELEPDPDGEVEEVRWVPLEELLLLKLAPGDRK 127

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 1321613058  12 AIISNSKKqILIMQLNNSDH---SWHFPGGRLNiDDESVE-GLRREVKEETGLDIFDIKPIHTQIFTEERKyGV---FFT 84
Cdd:cd03425     6 AIIVDDGR-VLIAQRPEGKHlagLWEFPGGKVE-PGETPEqALVRELREELGIEVEVGEPLGTVEHDYPDF-HVrlhVYL 82

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1321613058  85 AKTT--EPQdikiSFEHRDFRWINKEELDNINF 115
Cdd:cd03425    83 CTLWsgEPQ----LLEHQELRWVTPEELDDLDW 111

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 1321613058  13 IISNSKKQILiMQLNNSDHSWHFPGGRLNIDDESVEGLRREVKEETGLDIFDIKPIHTqIFTEE--RKY---------GV 81
Cdd:cd04677    18 IILNEQGRIL-LQKRTDTGDWGLPGGAMELGESLEETARREVFEETGLTVEELELLGV-YSGKDlyYTYpngdevynvTA 95

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1321613058  82 FFTAKTTEPQDIKISFEHRDFRWINKEEL-DNIN 114
Cdd:cd04677    96 VYLVRDVSGELKVDDEESLELRFFSLDELpENIN 129

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1321613058  12 AIISNSKKQILIMQLNNS--DHSWHFPGGRLNIDDESVEGLRREVKEETGLDIFDIK--PIHTQIFTEERKY--GVFFTA 85
Cdd:cd04678     7 VIVLNDDGKVLLGRRKGShgAGTWALPGGHLEFGESFEECAAREVLEETGLEIRNVRflTVTNDVFEEEGKHyvTIFVLA 86

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1321613058  86 K--------TTEPQDIKisfehrDFRWINKEEL 110
Cdd:cd04678    87 EvddgepeeNMEPDKCE------GWEWFSWDEL 113

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1321613058  12 AIISNSKKQILIMQLNNSDHSWHFPGGRLNIDDESVEGLRREVKEETGLDIFDIKPI------HTQIFTEER-------- 77
Cdd:cd03671     8 IVLFNRDGQVLVGRRIDVPGAWQFPQGGIDEGEDPEEAALRELYEETGLSPEDVEIIaetpdwLTYDLPEDLirkgwggk 87

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1321613058  78 ------KYGVFFTakTTEPQDIKISFEH----RDFRWINKEELDNIN--FWQPFYKELVE 125
Cdd:cd03671    88 yrgqkqKWFLFRF--TGDDSEINLDTHEhpefDAWRWVDLEELPDLVvpFKRDVYRQVLK 145

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1321613058  12 AIISNSKKQILIMQLNNSD-HSWHFPGGRLNIDDESVEGLRREVKEETGLD-----IFDIKPIHTQIFTEERKYGVfFTA 85
Cdd:cd04670     7 GLVINENNEVLVVQEKYGGpGGWKLPGGLVDPGEDIGEAAVREVFEETGIDtefvsILGFRHQHPGRFGKSDLYFV-CRL 85

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1321613058  86 KTTEPQDIKI-SFEHRDFRWINKEELDNINFWQPFYKELV 124
Cdd:cd04670    86 RPLSDEEIKIcPEEIAEAKWMPLEEYLKQPNVSQINKLVA 125

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1321613058  20 QILIMQLNNS---DHSWHFPGGRLNIDDESVEGLRREVKEETGLDIF--DIKPIHT---QIFTEERKYGVFFTAK--TTE 89
Cdd:cd04683    12 EVLLLRRANTgydDGWWHLPAGHVEAGETVRAAAVREAKEELGVEIDpeDLRLVHTmhrRSDGGRERIDFFFRATrwSGE 91

                          90       100
                  ....*....|....*....|.
gi 1321613058  90 PQdIKISFEHRDFRWINKEEL 110
Cdd:cd04683    92 PR-NREPDKCAELRWFPLDAL 111

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 1321613058  13 IISNSKKQILIMQLNNSDHSWH-FPGGRLNIDDESVEGLRREVKEETGLDIFDI--KPIhTQIFTEERKYGVFFTAKTTE 89
Cdd:cd18875     8 MIYDGEDRVLVLDRVKKDWGGYtFPGGHVEPGESFVDSVIREVKEETGLTIKNPelCGI-KQWINPDGERYIVFLYKTDH 86

                          90       100
                  ....*....|....*....|....*.
gi 1321613058  90 PQD-IKISFEHRDFrWINKEELDNIN 114
Cdd:cd18875    87 FSGeLLSSEEGELF-WIPIEELKKLP 111

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 1321613058  12 AIISNSKKQILIMQLNNSDHSWHFPGGRLNIDDESVEGLRREVKEETGLD------------IFDIKPIHT--QIFTEER 77
Cdd:cd18880     6 AIIIEDGKLLLVKHRDEGGIFYILPGGGQEHGETLPEALKRECLEETGLDvevgdllfvreyIGPNKPVHQveLFFLCTL 85

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 1321613058  78 KYGVFFTAKTTEPQDIKIsfehrdfRWINKEELDNINFwqpFYKELVEK 126
Cdd:cd18880    86 EGGELTLGSDPDLNQVGV-------EWIPLEELDSIRL---YPAILREL 124

8-oxo-DGDP phosphatase; 8-oxo-DGDP phosphatase (8DGDPP; EC 3.6.1.55), also known as NUDIX (nucleoside diphosphate-linked moiety X)) motif 18/Nudt18; 2-hydroxy-DADP phosphatase; 7,8-dihydro-8-oxoguanine phosphatase, hydrolyzes 8-oxo-7,8-dihydroguanine (8-oxo-Gua)-containing deoxyribo- and ribonucleoside diphosphates to the monophosphates. Members of the NUDIX hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of NUDIX hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance _ "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1321613058  12 AIISNSKKQILIMQLNNSD--HSWHFPGGRLNIDDESVEGLRREVKEETGLDI 62
Cdd:cd04671     5 AVIINEQGEVLMIQEAKRScrGKWYLPAGRVEPGESIVEAAKREVKEETGLKC 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 1321613058   8 IGEYAIISNSKKQILIMQlnnsdHS----WHFPGGRLNIDDESVEGLRREVKEETGLDIfDIKPIHTQIFTEERKYG--- 80
Cdd:cd04680     1 LGVRAIVLDDAGRVLLVR-----HTyvpgWYLPGGGVDKGETAEEAARRELREEAGVVL-TGPPRLFGVYFNRRVSPrdh 74

                          90
                  ....*....|....*
gi 1321613058  81 -VFFTAKTTEPQDIK 94
Cdd:cd04680    75 vALYRVREFEQTEPP 89

dihydroneopterin triphosphate pyrophosphatase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1321613058  20 QILIMQlnNSDHS--WHFPGGRLNIDDESVEGLRREVKEETGLDI-------FDI-KPIHTQIFTEER-KY--GVF---- 82
Cdd:PRK09438   20 GVLMLQ--RADDPdfWQSVTGSLEEGETPAQTAIREVKEETGIDVlaeqltlIDCqRSIEYEIFPHWRhRYapGVTrnte 97

                          90       100
                  ....*....|....*....|....*....
gi 1321613058  83 --FTAKTTEPQDIKISfEHRDFRWINKEE 109
Cdd:PRK09438   98 hwFCLALPHERPVVLT-EHLAYQWLDARE 125

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1321613058   8 IGEYAIISNSKKQILIMQLNNSDHsWHFPGGRLNIDDESVEGLRREVKEETGLDI 62
Cdd:cd18876     1 AAAGALFTDAAGRVLLVKPTYKDG-WELPGGVVEAGESPLQAARREVREELGLDV 54

8-oxo-dGTP diphosphatase MutT;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1321613058   1 MNHMKTKIGeyaIISNSKKQILIMQLNNSDH---SWHFPGGRLNIDDESVEGLRREVKEETGldifdIKPIHTQIF 73
Cdd:PRK10776    1 MKKLQIAVG---IIRNPNNEIFITRRAADAHmagKWEFPGGKIEAGETPEQALIRELQEEVG-----ITVQHATLF 68

translation initiation factor IF-2B alpha subunit; Eukaryotic translation initiation factor 2B subunit alpha (EIF2B1) is one of five subunits of eukaryotic translation initiation factor 2B (EIF2B), a GTP exchange factor for eukaryotic initiation factor 2 and an essential regulator for protein synthesis. Mutations in this gene and the genes encoding other EIF2B subunits have been associated with leukoencephalopathy with vanishing white matter. 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 1321613058  38 GRLNIDDESVEGLRREVKEETGLDIFDIKPI-HTQIFT-EERKYGV------F-FTAKTTEpqDIKISFEHRDFRWINKE 108
Cdd:cd18872    34 GSIESDDPPLAAAWREIREETGLTPEDVELLrQGKPFEfTDESLGRewtvhpFlFRLKDDR--AIKLDWEHTEWEWVDPT 111

                  ....
gi 1321613058 109 ELDN 112
Cdd:cd18872   112 DILD 115

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1321613058  45 ESVE-GLRREVKEETGLDIFDIKPIHTQIFTeerkygvF-------FTAKTTEPQDIKISFEHRDFRWINKEEL 110
Cdd:cd03429    39 ETLEeAVRREVKEEVGLRVKNVRYVGSQPWP-------FpsslmlgFTAEADSGEITVDDDELEDARWFSRDEL 105

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 1321613058  31 HSWHFPGGRLNIDDESVEGLRREVKEETGLDIFDIKPIHTQIFTEERKY---------GVFFTAKTTEPQD-IKISFEHR 100
Cdd:cd04686    26 GRYDLPGGSQEFGESLEDALKREFAEETGMTVTSYDNLGVYDFFVPWSDkelgdvhhiGVFYDVELLDNNIsELLQFEGQ 105

                          90       100
                  ....*....|....*....|..
gi 1321613058 101 D---FRWINKEELDNINfWQPF 119
Cdd:cd04686   106 DslgAVWIPLQDLTELN-SSPL 126

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 1321613058  12 AIISNSKKQILIMQLNNSD----HSWHFPGGRLNiDDESV-EGLRREVKEETGLDIF---DIKPI--HTQIFT------- 74
Cdd:cd04685     5 VLLLDPDGRVLLFRFHDPDdpgrSWWFTPGGGVE-PGESPeQAAVRELREETGLRLEpddLGGPVwrRRAVFDfsgetvr 83

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1321613058  75 -EERkygvFFTAKTTEPQdikISFEH---------RDFRWINKEEL 110
Cdd:cd04685    84 qDER----FFLVRVPAFE---VDTAGwtdleraviDGHRWWSLAEL 122

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 1321613058  12 AIISNSKKQILIMQLNNSDHsWHFPGGRLNIDDESVEGLRREVKEETGLDIFDIKPI---------HTQIFTEERKYGVF 82
Cdd:cd04676    22 AVILNEDGRILLQRKGGLGL-WSLPAGAIEPGEHPAEAVIREVREETGLLVKPTRLLgvfggkefrYTYPNGDQVEYTVI 100

                          90       100
                  ....*....|....*....|....*...
gi 1321613058  83 -FTAKTTEPQDIKISFEHRDFRWINKEE 109
Cdd:cd04676   101 aFKCVVTGGTLNAIDGETSELRYFSRTQ 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 1321613058  13 IISNSKKQILimqLNNSDHS-WHFPGGRLNIDDESVEGLRREVKEETGLDIFDIKPIHTQIFTEERKYgvFFTAKTTEPQ 91
Cdd:cd04667     5 VICRRGDRIL---LVARRGGrWLLPGGKIEPGESPLEAAIRELKEETGLAALSLLYLFEHEGPHKLHH--VFLAEAPDGG 79

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1321613058  92 DIKISFEHRDFRWINKEELDNINfWQPFYKELVEKAFER 130
Cdd:cd04667    80 RPRPGNEIARCRWVSADQLRDLN-LSRATRLIVRRYLRR 117

CDP-choline pyrophosphatase; CDP-choline pyrophosphatase catalyzes the hydrolysis of CDP-choline to produce CMP and phosphocholine. 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 1321613058  12 AIISNSKKQILIMQlNNSDHSWHFPGGRLNIDDESVEGLRREVKEETGldiFDIKPIHTQIFTEERK----------YGV 81
Cdd:cd18890     7 AVVFNDKEEILLVK-EKEDGKWTLPGGWADVGYTPTEVAAKEVEEETG---LEVSPKKLLAILDKRKhphppqptyvYKL 82

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1321613058  82 FFTAKTTEpQDIKISFEHRDFRWINKEELDNI 113
Cdd:cd18890    83 FILCEIEG-GELKPSFETGEVRFFSENELPEL 113

25 kDa subunit of cleavage factor Im; Precursor mRNA (pre-mRNA) cleavage factor I(m) (also called NUDIX (nucleoside diphosphate linked moiety X))-type motif 21) is a oligomer composed of a small 25 kDa subunit (CF I(m)25) and a variable larger subunit of either 59, 68 or 72 kDa and plays an important role in pre-mRNA 3'-end cleavage and the selection of poly(A) sites in a 3'-untranslated region (3'-UTR) of mRNA, producing mRNAs with variable 3' ends. The small subunit also interacts with RNA, poly(A) polymerase, and the nuclear poly(A)-binding protein and belongs to the NUDIX hydrolase superfamily. NUDIX hydrolases are 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.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 1321613058  21 ILIMQLNNSdhSWHFPGGRLNIDDESVEGLRREVKE 56
Cdd:cd18871    56 VLLLQLGNS--FFKLPGGRLRPGEDEVEGLKRKLTE 89

NUDIX family Ndx2; NUDIX family protein Ndx2 found in Thermus thermophilus has ADP-ribose pyrophosphatase (ADPRase) as well as flavin adenine dinucleotide (FAD) activity. 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        30
                  ....*....|....*....|....*....|.
gi 1321613058  30 DHSWHFPGGRLNIDDESVEGLRREVKEETGL 60
Cdd:cd24161    29 GWSWEIPAGGWPEGEDPEEAARRELREETGL 59

Nudix family hydrolase;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1321613058  12 AIISNSKKQILIMQlnNSDHS-----WHFPGGRLNiDDESVE-GLRREVKEETGLDI 62
Cdd:PRK08999   10 GVIRDADGRILLAR--RPEGKhqgglWEFPGGKVE-PGETVEqALARELQEELGIEV 63

nucleoside diphosphate-linked moiety X)) motif 16; U8 SnoRNA-decapping enzyme, also known as NUDIX (nucleoside diphosphate-linked moiety X)) motif 16/Nudt16, is encoded by the human NUDT16 gene and a RNA-binding and decapping enzyme that catalyzes the cleavage of the cap structure of snoRNAs and mRNAs in a metal-dependent manner. 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
                  ....*....|....*....|....*....|....*....|...
gi 1321613058  19 KQILIMQLNNsDHSWHFPGGRLNIDDESVEGLRREVKEETGLD 61
Cdd:cd18869    25 RATLLMQMRF-DGLLGFPGGFVDTGESLEEGLNRELREELGLA 66

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1321613058  13 IISNSKKQILIMQLNNS--DHSWHFPGGRLnIDDESV-EGLRREVKEETGLD--IFDIKPIHT-QIFTEERKYGVFFT-- 84
Cdd:cd03430    21 IIRNEDGEILLGKRNNRpaQGYWFVPGGRI-LKNETLdDAFKRIAREELGLEvtINAAEFLGVyEHFYDDNFSGEDFSth 99

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1321613058  85 ------------AKTTEPQDikisfEHRDFRWINKEELDN 112
Cdd:cd03430   100 yvvlayrlkldeGLLLLPDD-----QHDEYRWFTIDELLA 134

Uncharacterized conserved protein [Function unknown];

                          10        20
                  ....*....|....*....|....*..
gi 1321613058  36 PGGRLNiDDESVE-GLRREVKEETGLD 61
Cdd:COG4111     3 PGGFVR-EHESLEdAARRWLAEQTGLE 28

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 1321613058  12 AIISNSKKQILIMQLNN--SDHsWHFPGGRLNIDDESVEGLRREVKEETGLDI 62
Cdd:cd04679     7 AAILDDGRLLLVLRLRApeAGH-WGLPGGKVDWLETVEDAVRREILEELGLEI 58