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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088  13 WFVFFKDQLLLKKgytDKGEIkySVPVSIEPPLTPEAgsNIHEVFPPNGKQVRAFALEQPVAETDEWVMIGLRASYDYIS 92
Cdd:COG2816   33 VLVVDGGRLLLLE---DGGEL--LLPAGEAADLGPPA--EAVFLGLDDGRPVFAVDLPAELELPEGAEFVDLRELGGLLD 105

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088  93 PDEYRSAGKAFQILYWDEHSHFCPVCGTAMEH-QTPIMKKCPNCGNEMYPPVSTAIIVLIRKGDEILLVHARNFRGTFYG 171
Cdd:COG2816  106 PRDAGLAARAVALLNWHRTHRFCGRCGAPTVVaAAGWARRCPACGAEHYPRTDPAVIVLVTDGDRILLARQARWPPGRYS 185

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088 172 LVAGFLEAGETLEECVEREVFEETGLKVKNITYFSNQPWPYPSGLMVGFIADYESGEIKLQEDELTAAAFYSKDNLPE-- 249
Cdd:COG2816  186 LLAGFVEPGETLEQAVRREVFEEVGVRVKNVRYVGSQPWPFPSSLMLGFTAEADSGEITVDGDEIEDARWFSRDELPAal 265

                        250       260
                 ....*....|....*....|.
gi 496329088 250 ----IPRKLSIARRLIDWWME 266
Cdd:COG2816  266 agllLPPPGSIARRLIEAWLA 286

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088  13 WFVFFKDQLLLKKgytDKGEIkySVPVSIEPPLTPEAgsNIHEVFPPNGKQVRAFALEQPVAETDEWVMIGLRASYDYIS 92
Cdd:COG2816   33 VLVVDGGRLLLLE---DGGEL--LLPAGEAADLGPPA--EAVFLGLDDGRPVFAVDLPAELELPEGAEFVDLRELGGLLD 105

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088  93 PDEYRSAGKAFQILYWDEHSHFCPVCGTAMEH-QTPIMKKCPNCGNEMYPPVSTAIIVLIRKGDEILLVHARNFRGTFYG 171
Cdd:COG2816  106 PRDAGLAARAVALLNWHRTHRFCGRCGAPTVVaAAGWARRCPACGAEHYPRTDPAVIVLVTDGDRILLARQARWPPGRYS 185

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088 172 LVAGFLEAGETLEECVEREVFEETGLKVKNITYFSNQPWPYPSGLMVGFIADYESGEIKLQEDELTAAAFYSKDNLPE-- 249
Cdd:COG2816  186 LLAGFVEPGETLEQAVRREVFEEVGVRVKNVRYVGSQPWPFPSSLMLGFTAEADSGEITVDGDEIEDARWFSRDELPAal 265

                        250       260
                 ....*....|....*....|.
gi 496329088 250 ----IPRKLSIARRLIDWWME 266
Cdd:COG2816  266 agllLPPPGSIARRLIEAWLA 286

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088 144 STAIIVLIRKG-DEILLVHARNFRGTFYGLVAGFLEAGETLEECVEREVFEETGLKVKNITYFSNQPWPYPSGLMVGFIA 222
Cdd:cd03429    1 DPAVIVLVTNGeDKILLARQPRWPPGRYSLLAGFVEPGETLEEAVRREVKEEVGLRVKNVRYVGSQPWPFPSSLMLGFTA 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 496329088 223 DYESGEIKLQEDELTAAAFYSKDNLPEI---PRKLSIARRLIDWWM 265
Cdd:cd03429   81 EADSGEITVDDDELEDARWFSRDELPEAlflPPPGSIARRLIRAWL 126

nudix-type nucleoside diphosphatase, YffH/AdpP family; Members of this family include proteins of about 200 amino acids, including the recently characterized nudix hydrolase YffH, shows to be highly active as a GDP-mannose pyrophosphatase. It also includes the C-terminal half of a 361-amino acid protein, TrgB from Rhodobacter sphaeroides, shown experimentally to help confer tellurite resistance. This model also hits a region near the C-terminus of a 1092-amino acid protein of C. elegans. [Unknown function, Enzymes of unknown specificity]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088  144 STAIIVLIRKGDEILLVhaRNFR-GTFYG--------LVAGFLEAGETLEECVEREVFEETGLKVKNITYFSnQPWPYPS 214
Cdd:TIGR00052  46 AAAVLLYDPKKDTVVLI--EQFRiAAYVNgeepwlleLSAGMVEKGESPEDVARREAIEEAGYQVKNLRKLL-SFYMSPG 122

                          90
                  ....*....|....*
gi 496329088  215 G---LMVGFIADYES 226
Cdd:TIGR00052 123 GvteLIHLFIAEVDD 137

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088  13 WFVFFKDQLLLKKgytDKGEIkySVPVSIEPPLTPEAgsNIHEVFPPNGKQVRAFALEQPVAETDEWVMIGLRASYDYIS 92
Cdd:COG2816   33 VLVVDGGRLLLLE---DGGEL--LLPAGEAADLGPPA--EAVFLGLDDGRPVFAVDLPAELELPEGAEFVDLRELGGLLD 105

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088  93 PDEYRSAGKAFQILYWDEHSHFCPVCGTAMEH-QTPIMKKCPNCGNEMYPPVSTAIIVLIRKGDEILLVHARNFRGTFYG 171
Cdd:COG2816  106 PRDAGLAARAVALLNWHRTHRFCGRCGAPTVVaAAGWARRCPACGAEHYPRTDPAVIVLVTDGDRILLARQARWPPGRYS 185

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088 172 LVAGFLEAGETLEECVEREVFEETGLKVKNITYFSNQPWPYPSGLMVGFIADYESGEIKLQEDELTAAAFYSKDNLPE-- 249
Cdd:COG2816  186 LLAGFVEPGETLEQAVRREVFEEVGVRVKNVRYVGSQPWPFPSSLMLGFTAEADSGEITVDGDEIEDARWFSRDELPAal 265

                        250       260
                 ....*....|....*....|.
gi 496329088 250 ----IPRKLSIARRLIDWWME 266
Cdd:COG2816  266 agllLPPPGSIARRLIEAWLA 286

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088 144 STAIIVLIRKG-DEILLVHARNFRGTFYGLVAGFLEAGETLEECVEREVFEETGLKVKNITYFSNQPWPYPSGLMVGFIA 222
Cdd:cd03429    1 DPAVIVLVTNGeDKILLARQPRWPPGRYSLLAGFVEPGETLEEAVRREVKEEVGLRVKNVRYVGSQPWPFPSSLMLGFTA 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 496329088 223 DYESGEIKLQEDELTAAAFYSKDNLPEI---PRKLSIARRLIDWWM 265
Cdd:cd03429   81 EADSGEITVDDDELEDARWFSRDELPEAlflPPPGSIARRLIRAWL 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 496329088 146 AIIVLIRKGDEILLVHaRNFRGTFyGLVAGFLEAGETLEECVEREVFEETGLKVKNITYFSNQPWP-----YPSG----- 215
Cdd:cd04677   15 AAVIILNEQGRILLQK-RTDTGDW-GLPGGAMELGESLEETARREVFEETGLTVEELELLGVYSGKdlyytYPNGdevyn 92

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 496329088 216 LMVGFIADYESGEIKLQEDELTAAAFYSKDNLPEI 250
Cdd:cd04677   93 VTAVYLVRDVSGELKVDDEESLELRFFSLDELPEN 127

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 496329088 143 VSTAIIVLIRKGDEILLVhARNF---RGTFyGLVAGFLEAGETLEECVEREVFEETGLKVKNITYFSNQPWPYP-SGLMV 218
Cdd:cd04681    5 VAAAVGVIIRNEGEILFV-RRAKepgKGKL-DLPGGFVDPGESAEEALRRELREELGLKIPKLRYLCSLPNTYLyKGITY 82

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 496329088 219 G-----FIADY-ESGEIKLQEDELTAAAFYSKDNLPEIPRKLSIARRLIDWWM 265
Cdd:cd04681   83 KtcdlfFTAELdEKPKLKKAEDEVAELEWLDLEEIEPEKLAFPSIRKAVERYI 135

NUDIX domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088  141 PPVSTAIIVLIRKGDEILLVHARNFRGT-FYGLVAGFLEAGETLEECVEREVFEETGLKVKNITYFSNQPWPYPSG---- 215
Cdd:pfam00293   1 KRRVAVGVVLLNEKGRVLLVRRSKKPFPgWWSLPGGKVEPGETPEEAARRELEEETGLEPELLELLGSLHYLAPFDgrfp 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 496329088  216 ----LMVGFIADYESGEIKLQEDELTAAAFYSKDNLPeIPRKLSIARRLIDW 263
Cdd:pfam00293  81 deheILYVFLAEVEGELEPDPDGEVEEVRWVPLEELL-LLKLAPGDRKLLPW 131

nudix hydrolase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088 137 NEMYPPV-STAIIVLIRKGDEILLVHARNFRG-TFYGLVAGFLEAGETLEECVEREVFEETGLKVKNITY-------FSN 207
Cdd:PLN02325   1 METGEPIpRVAVVVFLLKGNSVLLGRRRSSIGdSTFALPGGHLEFGESFEECAAREVKEETGLEIEKIELltvtnnvFLE 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 496329088 208 QPWP--YPSGLMVGFIADYESGEIKLQEDELTAAAFYSKDNLPE 249
Cdd:PLN02325  81 EPKPshYVTVFMRAVLADPSQVPQNLEPEKCYGWDWYEWDNLPE 124

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088 146 AIIVLIRKGDEILLVHARN--FRGTfYGLVAGFLEAGETLEECVEREVFEETGLKVKNITYFsnqpWPY------PSG-- 215
Cdd:cd04673    3 AVGAVVFRDGRVLLVRRGNppDAGL-WSFPGGKVELGETLEDAALRELREETGLEAEVVGLL----TVVdvierdEAGrv 77

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 496329088 216 ----LMVGFIADYESGEIKLqEDELTAAAFYSKD---NLPEIPRKLSIARRL 260
Cdd:cd04673   78 rfhyVILDFLAEWVSGEPVA-GDDALDARWFSLEeldGLPLTPGTRDVLERA 128

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 496329088 148 IVLIRKGDEILLVH--ARNFRGTFYGlVAGFLEAGETLEECVEREVFEETGLKVKNITY-----FSNQPWPYPSGLMVgF 220
Cdd:cd18886    4 LCFIIRDDEVLLLNrnKKPNMGKWNG-VGGKLEPGESPEECAIREVFEETGLELEDLQLrgivtFPSFDGGEDWLMYV-F 81

                         90       100       110
                 ....*....|....*....|....*....|...
gi 496329088 221 IADYESGEIK--LQEDELtaaAFYSKDNLPEIP 251
Cdd:cd18886   82 LAEAFSGELVesDREGIL---AWVPIDWLLNLP 111

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 496329088 141 PPVSTAIIVLiRKGDEILLVHARN--FRGTfYGLVAGFLEAGETLEECVEREVFEETGLKVKNITYFS 206
Cdd:cd04678    1 PRVGVGVIVL-NDDGKVLLGRRKGshGAGT-WALPGGHLEFGESFEECAAREVLEETGLEIRNVRFLT 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        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 496329088 146 AIIVLIRKGDEILLVHARNFRGTFY----GLVAGFLEAGETLEECVEREVFEETGLKVKNITYFSNQPWPYPSGLMVGF 220
Cdd:cd18882    4 AIAILYDDRGKVLLQLRDDKPGIPYpgywGLFGGHLEPGETPEEAIRRELEEEIGYEPGEFRFFLLYTEDDGEDRIRHV 82

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 496329088 149 VLIRKGDEILLVHARNFRGTFYGLVAGFLEAGETLEECVEREVFEETGLKVK 200
Cdd:cd04670    8 LVINENNEVLVVQEKYGGPGGWKLPGGLVDPGEDIGEAAVREVFEETGIDTE 59

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 496329088 142 PVSTAIIVLIRKGDEILLVHARNFRGTfYGLVAGFLEAGETLEECVEREVFEETGLKVKNITY-------FSNQPWPYPS 214
Cdd:cd18874    1 PEPTVGALIFNPDGKVLLVRSHKWNDL-YGIPGGKVEWGETLEEALKREVKEETGLDITDIRFilvqesiNSEEFHKPAH 79

                         90       100
                 ....*....|....*....|
gi 496329088 215 GLMVGFIADYESGEIKLQED 234
Cdd:cd18874   80 FVFVDYLARTDSSEVVLNEE 99

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 496329088 146 AIIVLIRKGDEILLVHARN--FRGTFYGLVAGFLEAGETLEECVEREVFEETGLKVK-------------------NITY 204
Cdd:cd04683    2 DVHLLLVRGDEVLLLRRANtgYDDGWWHLPAGHVEAGETVRAAAVREAKEELGVEIDpedlrlvhtmhrrsdggreRIDF 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 496329088 205 FsnqpwpypsglmvgFIADYESGEIKLQE----DELtaaAFYSKDNLPE 249
Cdd:cd04683   82 F--------------FRATRWSGEPRNREpdkcAEL---RWFPLDALPE 113

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088 149 VLIRKGDEILLVHARNFRGTFYGlvaGFLEAGETLEECVEREVFEETGLKVKNITYFSNQpwpypsglMVG------FIA 222
Cdd:cd04667    5 VICRRGDRILLVARRGGRWLLPG---GKIEPGESPLEAAIRELKEETGLAALSLLYLFEH--------EGPhklhhvFLA 73

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 496329088 223 DYESGEIKLQEDELTAAAFYSKDNLPeiPRKLSIARRLI 261
Cdd:cd04667   74 EAPDGGRPRPGNEIARCRWVSADQLR--DLNLSRATRLI 110

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
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 496329088 147 IIVLIRKGDEI--LLVHARNFRgtFYGLVAGFLEAGETLEECVEREVFEETGLKVKNI 202
Cdd:cd03428    7 AIIYRRDNGEIefLLLQHSYGG--HWDFPKGHVEPGESELETALRETKEETGLTVDDL 62

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088 147 IIVLIRKGDEILLVHARNFRGtfYGLVAGFLEAGETLEECVEREVFEETGLKVKNITYFS----NQPWPYPSGlMVgFIA 222
Cdd:cd04665    3 VVVIARYKGKWLFTRHKERRG--WEFPGGKREPGETIEEAARRELYEETGAVIFELKPLGqysvHGKGQEFFG-AV-YYA 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 496329088 223 DYESGEIKLQE---------DELTAAAFYSKDNLPEIPRKL 254
Cdd:cd04665   79 EVKSFEPILPYfetaevrlfDELPEFSLTYPDIQPHLLEKL 119

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088 145 TAIIVLIRKGDEILLvhARNFRGTFYGLVAGF---LEAGETLEECVEREVFEETGLKVKNIT-------YFSNQPWPyps 214
Cdd:cd03427    3 TTLVFVLRGDDRVLL--GLKKRGFGAGKWNGFggkVEPGETIEEAAVRELEEEAGLTATELEkvgrlkfEFPDDPEA--- 77

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 496329088 215 glMVG--FIADYESGEIklQEDELTAAAFYSKDNLP 248
Cdd:cd03427   78 --MDVhvFRADSWTGEP--QETEEMRPQWFDLDDIP 109

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 496329088 143 VSTAIIVLiRKGDEILLVHARNFRGTFYglVAGFLEAGETLEECVEREVFEETGLKVKNITYFSNQPW----------PY 212
Cdd:cd03674    3 TASAFVVN-PDRGKVLLVHHRKLGRWLQ--PGGHVEPDEDPLEAALREAREETGLDVELLSPLSPDPLdidvhpipanPG 79

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 496329088 213 PSG---LMVGFIADYESGEIKLQEDELTAAAFYSKDNLPEiPRKLSIARRLI 261
Cdd:cd03674   80 EPAhlhLDVRYLAVADGDEALRKSDESSDVRWFPLDELEE-LSMDPNLRKLL 130

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 496329088 143 VSTAIIvliRKGDEILLvhARnfRGtfYGLV-AGF-------LEAGETLEECVEREVFEETGLKVKNITYFSNQPWPYPS 214
Cdd:cd03425    3 VVAAII---VDDGRVLI--AQ--RP--EGKHlAGLwefpggkVEPGETPEQALVRELREELGIEVEVGEPLGTVEHDYPD 73

                         90       100
                 ....*....|....*....|.
gi 496329088 215 G--LMVGFIADYESGEIKLQE 233
Cdd:cd03425   74 FhvRLHVYLCTLWSGEPQLLE 94

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
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 496329088 155 DEILLVhaRNFR-GTFYG--------LVAGFLEAGETLEECVEREVFEETGLKVKNITY 204
Cdd:cd24155   56 DEVVLI--EQFRiGALARdespwlleIVAGMIDAGETPEDVARREAEEEAGLTLDALEP 112

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 496329088 136 GNE--MYPPVStaiIVLIRKGDEILLVHARNFRgtFYGLVAGFLEAGETLEECVEREVFEETGLKVKN---ITYFSNQPW 210
Cdd:cd04676   11 GNEllFTPSVA---AVILNEDGRILLQRKGGLG--LWSLPAGAIEPGEHPAEAVIREVREETGLLVKPtrlLGVFGGKEF 85

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 496329088 211 --PYPSG-----LMVGFIADYESGEIKLQEDELTAAAFYSKDNLPEI 250
Cdd:cd04676   86 ryTYPNGdqveyTVIAFKCVVTGGTLNAIDGETSELRYFSRTQMPTL 132

bifunctional NMN adenylyltransferase/ADP-ribose pyrophosphatase and similar proteins; Bacterial NadM-Nudix is a bifunctional enzyme containing a nicotinamide mononucleotide (NMN) adenylyltransferase (NMNAT) and an ADP-ribose pyrophosphatase (ADPRase) domain. NMNAT was initially identified as an NAD+ synthase that catalyzes the reversible conversion of NMN to NAD+ in the final step of both the de novo biosynthesis and salvage pathways in most organisms across all three kingdoms of life ADPRase is a member of the NUDIX family proteins, catalyzes the metal-induced and concerted general acid-base hydrolysis of ADP ribose (ADPR) into AMP and ribose-5'-phosphate (R5P). Additional members in this cd include bacterial transcriptional regulator, NrtR, which represses the transcription of NAD biosynthetic genes in vitro and adenosine diphosphate ribose (ADPR), as well as NadQ, a NUDIX-like ATP-responsive regulator of NAD biosynthesis. Members of the NUDIX hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belong to this superfamily requires a divalent cation, such as Mg2+ or Mn2+ for their activity and contain a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, U=I, L or V) which functions as 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 _ "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 496329088 143 VSTAIIVLIRKGDEILLVHARN--FRGTfYGLVAGFLEAGETLEECVEREVFEETGLKV 199
Cdd:cd18873    5 VDCVIFGFDDGELKVLLIKRKNepFKGG-WALPGGFVREDETLEDAARRELREETGLKD 62

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 496329088 147 IIV--LIRKGDEILLVHaRNF--RGTFYGLVAGFLEAGETLEECVEREVFEETGLKVKNITYFSNQPWPYPSGLMVGFIA 222
Cdd:cd04511    3 IVVgcLPEWEGKVLLCR-RAIepRKGYWTLPAGFMELGETTEQGAARETREEAGARVEIGSLYAVYSLPHISQVYIIFRA 81

                         90       100
                 ....*....|....*....|....*....
gi 496329088 223 DYESGEIKLQEdELTAAAFYSKDnlpEIP 251
Cdd:cd04511   82 RLLSPDFSPGP-ESLEVRLFDEE---EIP 106

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 496329088 151 IRKGDEILLV-HARNFRGTFYGLVAGFLEAGETLEECVEREVFEETGLKVK---------NITYFSNQPWPYPSglmvgF 220
Cdd:cd04679    9 ILDDGRLLLVlRLRAPEAGHWGLPGGKVDWLETVEDAVRREILEELGLEIEltrllcvvdQIDAADGEHWVAPV-----Y 83

                         90       100       110
                 ....*....|....*....|....*....|
gi 496329088 221 IADYESGEIKLQEDE-LTAAAFYSKDNLPE 249
Cdd:cd04679   84 LAEIFSGEPRLMEPEkHGGIGWFALDALPQ 113

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 496329088 146 AIIVLIRKGDEILLVharnFRGTFYG-----LVAGFLEAGETLEECVEREVFEETGLK 198
Cdd:cd04663    3 VCAYVTRGRNRELLV----FEHPDFPeaglqVPKGTVEPGESPEEAALRELAEETGLT 56