8-oxo-dGTP pyrophosphatase MutT and related house-cleaning NTP pyrophosphohydrolases, NUDIX family [Defense mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 311905588  45 AIGIVPLDKEGNTYLVGQHRFPIDEYSWEIPEGGCPHDEDILDCAKRELLEETGLRAEKWTQISKIhTSNSVCNETGFIF 124
Cdd:COG0494   15 AVVVVLLDDDGRVLLVRRYRYGVGPGLWEFPGGKIEPGESPEEAALRELREETGLTAEDLELLGEL-PSPGYTDEKVHVF 93

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 311905588 125 LAEELTQGEAE--PEETEDLVVRKVSLEEAFQMVMKDEITDSL 165
Cdd:COG0494   94 LARGLGPGEEVglDDEDEFIEVRWVPLDEALALVTAGEIAKTL 136

adenosine nucleotide hydrolase NudE; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 311905588  45 AIGIVPLDKEGNTYLVGQHRFPIDEYSWEIPEGGCPHDEDILDCAKRELLEETGLRAEKWTQISKIHTSNSVCNETGFIF 124
Cdd:PRK11762  49 AVMIVPILDDDTLLLIREYAAGTERYELGFPKGLIDPGETPLEAANRELKEEVGFGARQLTFLKELSLAPSYFSSKMNIV 128

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 311905588 125 LAEELTQGEAEPEETEDLVVRKVSLEEAFQMVMKDEITDSLSIAGILktrLLRKY 179
Cdd:PRK11762 129 LAEDLYPERLEGDEPEPLEVVRWPLADLDELLARPDFSEARSVAALF---LAREW 180

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        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 311905588  45 AIGIVPLDKEGNTYLVGQHRFPIDEYSWEIPEGGCPHDEDILDCAKRELLEETGLRAEKWTQISKIHTSNSVCNETGFIF 124
Cdd:cd03424    4 AVAVLAITDDGKVVLVRQYRHPVGRVLLELPAGKIDPGEDPEEAARRELEEETGYTAGDLELLGSFYPSPGFSDERIHLF 83

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 311905588 125 LAEELTQGEA-EPEETEDLVVRKVSLEEAFQMVMKDEITDSLSIAGIL 171
Cdd:cd03424   84 LAEDLTPVSEqALDEDEFIEVVLVPLEEALEMIEDGEITDAKTLAALL 131

Bdellovibrio Bacteriovorus nucleoside diphosphate sugar hydrolase, and similar proteins; Bdellovibrio bacteriovorus nucleoside diphosphate sugar (NDPS) hydrolase Bd3179 has been shown to similarities to the Escherichia coli adenosine diphosphate ribose (ADPR) hydrolase and the guanosine diphosphate mannose (GDPM) hydrolase. It may have a role when Bdellovibrio degrades and metabolizes host cell. ADP-ribose pyrophosphatase (ADPRase) catalyzes the hydrolysis of ADP-ribose and a variety of additional ADP-sugar conjugates to AMP and ribose-5-phosphate. In humans, there are four distinct ADPRase activities, three putative cytosolic enzymes (ADPRase-I, -II, and -Mn) and a single mitochondrial enzyme (ADPRase-m). Human ADPRase-II is also referred to as NUDT5. It lacks the N-terminal target sequence unique to mitochondrial ADPRase. The different cytosolic types are distinguished by their specificities for substrate and specific requirement for metal ions. NUDT5 forms a homodimer. It also contains a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V) which functions as a metal binding site/catalytic site. In addition to the NUDIX motif, there are additional conserved amino acid residues, distal from the signature sequence, that correlate with substrate specificity. UDP-glucose pyrophosphatase (UGPPase) (EC 3.6.1.45; also known as nucleoside diphosphate-linked moiety X)) motif 14; Nudt14) hydrolyzes the pyrophosphate of the nucleoside diphosphate sugar to generate glucose-1-P and UMP. In mammals, UDP-glucose is the glucosyl donor for the synthesis of the storage polysaccharide glycogen. UGPPase, as a regulator of UDP-glucose, could play a regulatory role, but it has been shown to prefer ADP-ribose over UDP-glucose. Like other members of the NUDIX hydrolase superfamily, it requires a divalent cation, such as Mg2+, for its activity. It also contains a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V) which functions as a metal binding site/catalytic site.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 311905588   6 KKLDSQTVYENPWIEVQHHEVINPSGGKGIYGQVNFKNlAIGIVPLDKEGNTYLVGQHRFPIDEYSWEIPEGGCPHDEDI 85
Cdd:cd24159    5 KTLSSRVVYKGGFLKVHRDQVRLPDGSTSTREYITHPG-AVAVVPLLDDGRVVMERQYRYPLKRVFLEFPAGKIDPGEDT 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 311905588  86 LDCAKRELLEETGLRAEKWTQISKIHTSNSVCNETGFIFLAEELTQGEAEPEETEDLVVRKVSLEEAFQMVMKDEITDSL 165
Cdd:cd24159   84 LETAKRELLEETGYEAQEWAFLTTIHPAIGYSNEHIEIYLARGLTHVEQKLDDGEFLEVVEVSLAELLEMVLSGEITDVK 163

                 ....*.
gi 311905588 166 SIAGIL 171
Cdd:cd24159  164 TIIGLF 169

GDP-mannose hydrolase (GDPMK), and similar proteins; GDP-mannose hydrolase (GDPMK) is a NUDIX enzyme that uses GDP-mannose as the preferred substrate. It is distinct from Nudix ADP-ribose hydrolases. GDPMK and ADP-ribose pyrophosphatase seem to use similar catalytic mechanism. However, GDPMK hydrolysis does not rely on a single glutamate as the catalytic base; rather, it is dependent on residues that coordinate the magnesium ions and residues that position the substrate properly for catalysis. 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 311905588  45 AIGIVPLDKEGNT-YLVGQHRFPI-----DEYSWEIPeGGCPHDEDILDCAKRELLEETGLRAEKWTQISKIHTSNSVCN 118
Cdd:cd24157    6 AAAVLLYDPKRKTvVLVRQFRAPAylgggDGWLIEAC-AGLLDGDDPEDCIRREAEEETGYRLGDLEKVFTAYSSPGIVT 84

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 311905588 119 ETGFIFLAE-----ELTQGEAEPEETEDLVVRKVSLEEAFQMVMKDEITDSLSIAGILKTRL 175
Cdd:cd24157   85 ERIHLFIAEyssadRVGAGGGLAEEGEDIEVLELPLDEALAMIETGEIRDAKTIILLQYLRL 146

ADP-ribose pyrophosphatase YjhB, NUDIX family [Nucleotide transport and metabolism];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 311905588  43 NLAIGIVPLDKEGNtYLVGQHRFPIDEYSWEIPEGGCPHDEDILDCAKRELLEETGLRAEKWTQIsKIHTSNSVCNETGF 122
Cdd:COG1051    6 KVAVDAVIFRKDGR-VLLVRRADEPGKGLWALPGGKVEPGETPEEAALRELREETGLEVEVLELL-GVFDHPDRGHVVSV 83

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 311905588 123 IFLAeELTQGEAEPEEtEDLVVRKVSLEEAFQMVMKDEITDSL 165
Cdd:COG1051   84 AFLA-EVLSGEPRADD-EIDEARWFPLDELPELAFTPADHEIL 124

Adp-ribose pyrophosphatase (ADPRase) found in Thermus thermophilus, and similar proteins; ADP-ribose pyrophosphatase (ADPRase) such as found in extreme thermophile Thermus thermophilus (TtADPRase) catalyzes the hydrolysis of ADPR to AMP and ribose 5'-phosphate in the presence of Mg2+ and Zn2+ ions. 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        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 311905588  45 AIGIVPLdKEGNTYLVGQHRFPIDEYSWEIPEGGCPHDEDILDCAKRELLEETGLRAEkWTQISKIHTSNSVCNETGFIF 124
Cdd:cd24160   23 AVAVLAL-REGRMLFVRQMRPAVGAATLEIPAGLIDPGETPEEAARRELAEETGLSGD-LTYLTRFYVSPGFCDEKLHVF 100

                         90       100
                 ....*....|....*....|
gi 311905588 125 LAEELTQGEAEPEETEDLVV 144
Cdd:cd24160  101 LAENLREVEAHPDEDEAIEV 120

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 311905588  45 AIGIVPLD-KEGNTYLVGQHRFPI---DEYSW--EIPEGGCPHDEDILDCAKRELLEETGLRAEKWTQISKIHTSNSVCN 118
Cdd:cd24155   45 AVAVLPYDpVRDEVVLIEQFRIGAlarDESPWllEIVAGMIDAGETPEDVARREAEEEAGLTLDALEPIASYYPSPGGST 124

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 311905588 119 ETGFIFLAE----ELTQGEAEPEETEDLVVRKVSLEEAFQMVMKDEITDSLSIAGIL 171
Cdd:cd24155  125 ERVHLYLGLvdlsDLGGIHGLAEEGEDIRVHVVPFDEAMALLDDGEIDNAPLIIALQ 181

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 311905588  44 LAIGIVPLDKEGNtYLVGQHRFPIDEYSWEIPEGGCPHDEDILDCAKRELLEETGLRAE--KWTQISKIHTSNSVCNETG 121
Cdd:cd02883    1 VAVGAVVFDDEGR-VLLVRRSDGPGPGGWELPGGGVEPGETPEEAAVREVREETGLDVEvlRLLGVYEFPDPDEGRHVVV 79

                         90       100
                 ....*....|....*....|....
gi 311905588 122 FIFLAE--ELTQGEAEPEETEDLV 143
Cdd:cd02883   80 LVFLARvvGGEPPPLDDEEISEVR 103

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 311905588  42 KNLAIGIVPLDKEGNT--YLVGQHRFPideYSWEIPEGGCPHDEDILDCAKRELLEETGLRAE 102
Cdd:cd03428    1 KEKSAGAIIYRRDNGEieFLLLQHSYG---GHWDFPKGHVEPGESELETALRETKEETGLTVD 60

RNA pyrophosphohydrolase; Reviewed

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 311905588  47 GIVPLDKEGNTyLVGQhRFPiDEYSWEIPEGGCPHDEDILDCAKRELLEETGLRAE 102
Cdd:PRK00714  12 GIILLNRQGQV-FWGR-RIG-QGHSWQFPQGGIDPGETPEQAMYRELYEEVGLRPE 64

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 311905588  46 IGIVPLDKEGNTyLVGQhRFPIDeYSWEIPEGGCPHDEDILDCAKRELLEETGLRAEKWTQISKI 110
Cdd:cd03671    6 VGIVLFNRDGQV-LVGR-RIDVP-GAWQFPQGGIDEGEDPEEAALRELYEETGLSPEDVEIIAET 67

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 311905588  77 GGC-PHDEDILDCAKRELLEETGLRAEKWTQISKIHTSNSVCNETGFIFLAEelTQGEAEPEETEDLVVRKVSLEEAFQM 155
Cdd:cd04697   61 GGVvGAGESYEENARRELEEELGIDGVPLRPLFTFYYEDDRSRVWGALFECV--YDGPLKLQPEEVAEVDWMSEDEILQA 138

                         90
                 ....*....|.
gi 311905588 156 VMKDEIT-DSL 165
Cdd:cd04697  139 ARGEEFTpDGR 149

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

                         10        20        30
                 ....*....|....*....|....*....|....
gi 311905588  68 DEYSWEIPEGGCPHDEDILDCAKRELLEETGLRA 101
Cdd:cd04662   31 DEGAWSIPKGEVEPGEDPLAAARREFEEETGFPA 64

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 311905588  72 WEIPEGGCPHDEDILDCAKRELLEETGLRAE--KWTQISKIHTSNSVcnETGFIFLAEELTQGEAEPE-ETE 140
Cdd:cd04665   24 WEFPGGKREPGETIEEAARRELYEETGAVIFelKPLGQYSVHGKGQE--FFGAVYYAEVKSFEPILPYfETA 93

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 311905588  82 DEDILDCAKRELLEETGLRAEKWTQISKIHTSNSVCNETG--FIFLAEELTqGEAEPEETE 140
Cdd:cd18886   37 GESPEECAIREVFEETGLELEDLQLRGIVTFPSFDGGEDWlmYVFLAEAFS-GELVESDRE 96

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 311905588  68 DEYSWEIPEGGCPHDEDILDCAKRELLEETGLR--AEKWTQISKIHTSNSVCNE-TGFIFLAEELtQGE---AEPEETED 141
Cdd:cd04683   24 DDGWWHLPAGHVEAGETVRAAAVREAKEELGVEidPEDLRLVHTMHRRSDGGRErIDFFFRATRW-SGEprnREPDKCAE 102

                 .
gi 311905588 142 L 142
Cdd:cd04683  103 L 103

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

                         10        20        30
                 ....*....|....*....|....*....|....
gi 311905588  72 WEIPEGGCPHDEDILDCAKRELLEETGLRAEKWT 105
Cdd:cd04681   33 LDLPGGFVDPGESAEEALRRELREELGLKIPKLR 66

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 311905588  45 AIGIVpLDKEGNTYLvgQHRfpIDEYSWEIPEGGCPHDEDILDCAKRELLEETGLRAEK 103
Cdd:cd04677   15 AAVII-LNEQGRILL--QKR--TDTGDWGLPGGAMELGESLEETARREVFEETGLTVEE 68

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

                         10        20
                 ....*....|....*....|....*....
gi 311905588  72 WEIPEGGCPHDEDILDCAKRELLEETGLR 100
Cdd:cd04682   30 WDLPGGGREGDETPFACVLRELREELGLA 58

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
                 ....*....|....*....|....*....|.
gi 311905588  72 WEIPEGGCPHDEDILDCAKRELLEETGLRAE 102
Cdd:cd18880   27 YILPGGGQEHGETLPEALKRECLEETGLDVE 57

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

                         10        20
                 ....*....|....*....|.
gi 311905588  82 DEDILDCAKRELLEETGLRAE 102
Cdd:cd03675   36 GESLLEAAIRETLEETGWEVE 56

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 311905588  56 NTYLVGQHRFPIDEYSWEIPEGGCPHDEDILDCAKRELLEETGLRAEKWTQIS----KIHTSNSvcnETGFIFLAEELTq 131
Cdd:cd04691   12 GKVLLVKRAYGPGKGRWTLPGGFVEEGETLDEAIVREVLEETGIDAKPVGIIGvrsgVIRDGKS---DNYVVFLLEYVG- 87

                         90       100
                 ....*....|....*....|.
gi 311905588 132 GEAEPEETEDLVVRKVSLEEA 152
Cdd:cd04691   88 GEPKPDERENSEAGFLTLEEA 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        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 311905588  47 GIVPLDKEGNTYLVGQHRfPIDEYsWEIPEGGCPHDEDILDCAKRELLEETGLRAEKwTQISKIhtSNSVCNETGFIFLA 126
Cdd:cd04669    3 AVLVIYDDDKLLLIRRTK-PGEEY-YVFPGGGIEPGETPEEAALREAVEELGLDVAV-TLITLI--LRVLNDGTQHYFLA 77

                 .
gi 311905588 127 E 127
Cdd:cd04669   78 R 78

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 311905588  72 WEIPEGGCPHDEDILDCAKRELLEETGLRAEKWTQISKI-HTSNS----VCNETGFiFLAEELTQGEAEPEETEDLVVRK 146
Cdd:cd03673   29 WSLPKGKLEPGETPEEAAVREVEEETGLRVRLGRPLGTTrYTYTRkgkgILKKVHY-WLMRALGGEFLPQPEEEIDEVRW 107

                         90
                 ....*....|
gi 311905588 147 VSLEEAFQMV 156
Cdd:cd03673  108 LPPDEARRLL 117