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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096   1 MTDPPVEPPTVAPPGGFLPGADRSRPPGPSDLALPVTGAKLLTGVDGHPLR-----VADLPVDTDWVPLGTLDGVPAWGA 75
Cdd:COG2816     1 MSAPLAFAGSPLDRAAELRADPDWLAAWADPRVLVVDGGRLLLLEDGGELLlpageAADLGPPAEAVFLGLDDGRPVFAV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096  76 DLTTTANDLPG-RARGWASLAAEVPEPHATLASRALAVLTWRRTHRWCGACRAELTDRPGETARQCPDC-ALYVPmQLSA 153
Cdd:COG2816    81 DLPAELELPEGaEFVDLRELGGLLDPRDAGLAARAVALLNWHRTHRFCGRCGAPTVVAAAGWARRCPACgAEHYP-RTDP 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096 154 AVLVAITRPgppghvDELLLVQHATGPTGLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYFGSQPWAIsgPGVLL 233
Cdd:COG2816   160 AVIVLVTDG------DRILLARQARWPPGRYSLLAGFVEPGETLEQAVRREVFEEVGVRVKNVRYVGSQPWPF--PSSLM 231

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2195104096 234 AGFTARAAdsGTEPVVDGRELTRAQWFGLDELPAQ-----LPPAYSISRWLIDATV 284
Cdd:COG2816   232 LGFTAEAD--SGEITVDGDEIEDARWFSRDELPAAlagllLPPPGSIARRLIEAWL 285

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096   1 MTDPPVEPPTVAPPGGFLPGADRSRPPGPSDLALPVTGAKLLTGVDGHPLR-----VADLPVDTDWVPLGTLDGVPAWGA 75
Cdd:COG2816     1 MSAPLAFAGSPLDRAAELRADPDWLAAWADPRVLVVDGGRLLLLEDGGELLlpageAADLGPPAEAVFLGLDDGRPVFAV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096  76 DLTTTANDLPG-RARGWASLAAEVPEPHATLASRALAVLTWRRTHRWCGACRAELTDRPGETARQCPDC-ALYVPmQLSA 153
Cdd:COG2816    81 DLPAELELPEGaEFVDLRELGGLLDPRDAGLAARAVALLNWHRTHRFCGRCGAPTVVAAAGWARRCPACgAEHYP-RTDP 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096 154 AVLVAITRPgppghvDELLLVQHATGPTGLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYFGSQPWAIsgPGVLL 233
Cdd:COG2816   160 AVIVLVTDG------DRILLARQARWPPGRYSLLAGFVEPGETLEQAVRREVFEEVGVRVKNVRYVGSQPWPF--PSSLM 231

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2195104096 234 AGFTARAAdsGTEPVVDGRELTRAQWFGLDELPAQ-----LPPAYSISRWLIDATV 284
Cdd:COG2816   232 LGFTAEAD--SGEITVDGDEIEDARWFSRDELPAAlagllLPPPGSIARRLIEAWL 285

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 2195104096 152 SAAVLVAITRPGppghvDELLLVQHATGPTGLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYFGSQPWAIsgPGV 231
Cdd:cd03429     1 DPAVIVLVTNGE-----DKILLARQPRWPPGRYSLLAGFVEPGETLEEAVRREVKEEVGLRVKNVRYVGSQPWPF--PSS 73

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2195104096 232 LLAGFTARAAdsGTEPVVDGRELTRAQWFGLDELPA--QLPPAYSISRWLIDA 282
Cdd:cd03429    74 LMLGFTAEAD--SGEITVDDDELEDARWFSRDELPEalFLPPPGSIARRLIRA 124

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096   1 MTDPPVEPPTVAPPGGFLPGADRSRPPGPSDLALPVTGAKLLTGVDGHPLR-----VADLPVDTDWVPLGTLDGVPAWGA 75
Cdd:COG2816     1 MSAPLAFAGSPLDRAAELRADPDWLAAWADPRVLVVDGGRLLLLEDGGELLlpageAADLGPPAEAVFLGLDDGRPVFAV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096  76 DLTTTANDLPG-RARGWASLAAEVPEPHATLASRALAVLTWRRTHRWCGACRAELTDRPGETARQCPDC-ALYVPmQLSA 153
Cdd:COG2816    81 DLPAELELPEGaEFVDLRELGGLLDPRDAGLAARAVALLNWHRTHRFCGRCGAPTVVAAAGWARRCPACgAEHYP-RTDP 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096 154 AVLVAITRPgppghvDELLLVQHATGPTGLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYFGSQPWAIsgPGVLL 233
Cdd:COG2816   160 AVIVLVTDG------DRILLARQARWPPGRYSLLAGFVEPGETLEQAVRREVFEEVGVRVKNVRYVGSQPWPF--PSSLM 231

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2195104096 234 AGFTARAAdsGTEPVVDGRELTRAQWFGLDELPAQ-----LPPAYSISRWLIDATV 284
Cdd:COG2816   232 LGFTAEAD--SGEITVDGDEIEDARWFSRDELPAAlagllLPPPGSIARRLIEAWL 285

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 2195104096 152 SAAVLVAITRPGppghvDELLLVQHATGPTGLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYFGSQPWAIsgPGV 231
Cdd:cd03429     1 DPAVIVLVTNGE-----DKILLARQPRWPPGRYSLLAGFVEPGETLEEAVRREVKEEVGLRVKNVRYVGSQPWPF--PSS 73

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2195104096 232 LLAGFTARAAdsGTEPVVDGRELTRAQWFGLDELPA--QLPPAYSISRWLIDA 282
Cdd:cd03429    74 LMLGFTAEAD--SGEITVDDDELEDARWFSRDELPEalFLPPPGSIARRLIRA 124

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096 154 AVLVAITRPGppghvDELLLVQHATGP-TGLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYFGSQPWAISGPGVL 232
Cdd:COG1051     8 AVDAVIFRKD-----GRVLLVRRADEPgKGLWALPGGKVEPGETPEEAALRELREETGLEVEVLELLGVFDHPDRGHVVS 82

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 2195104096 233 LAgFTARAADSgtEPVVDgRELTRAQWFGLDELPA 267
Cdd:COG1051    83 VA-FLAEVLSG--EPRAD-DEIDEARWFPLDELPE 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2195104096 152 SAAVLVAITRPGppghvdELLLVQHATGPT-GLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYFGSQP 223
Cdd:cd04681     6 AAAVGVIIRNEG------EILFVRRAKEPGkGKLDLPGGFVDPGESAEEALRRELREELGLKIPKLRYLCSLP 72

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096 153 AAVLVAITRPGppghvdELLLVQHATGPT--GLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYFGSqPWAISGPG 230
Cdd:COG0494    15 AVVVVLLDDDG------RVLLVRRYRYGVgpGLWEFPGGKIEPGESPEEAALRELREETGLTAEDLELLGE-LPSPGYTD 87

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 2195104096 231 VLLAGFTARAADSGTEPVVDG-RELTRAQWFGLDELPAQL 269
Cdd:COG0494    88 EKVHVFLARGLGPGEEVGLDDeDEFIEVRWVPLDEALALV 127

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096 153 AAVLVAITRPGPPGHVdelLLVQHATGP-TGLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYFG--SQP------ 223
Cdd:cd18873     4 TVDCVIFGFDDGELKV---LLIKRKNEPfKGGWALPGGFVREDETLEDAARRELREETGLKDIYLEQLGtfGDPdrdprg 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 2195104096 224 WAISgpgvllAGFTArAADSGTEPVVDGRELTRAQWFGLDELPAQL 269
Cdd:cd18873    81 RVIS------VAYLA-LVPEEDLAPKAGDDAAEARWFPVDELLPPL 119

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 2195104096 168 VDELLLVQHATgpTGLWALVAGFVEAGETLEAAVHREVGEEVGLP--VDRLAyfgsqpWAISGPGVLLA----------G 235
Cdd:cd18879    29 AGRVLLVRRAD--NGRWTPVTGIVEPGEQPADAAVREVLEETGVDveVERLA------SVGASPPVTYPngdqcqyldlT 100

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 2195104096 236 FTARAAdSGTEPVVDGrELTRAQWFGLDELPAQLP 270
Cdd:cd18879   101 FRCRPV-GGEARVNDD-ESLEVGWFPVDALPPMLP 133

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
                  ....*....|....*....|....*....|....*....|....*
gi 2195104096 167 HVDELLLVQHATGPTGLWALVAGFVEAGETLEAAVHREVGEEVGL 211
Cdd:cd18884    18 HDGHIVLARNKAWPEGWYGLVTGFLEAGESPEEAVLREVKEELGL 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 2195104096 169 DELLLVQHATGptGLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYFGSQPWAI------SGPGV-----LLAGFT 237
Cdd:cd03674    14 GKVLLVHHRKL--GRWLQPGGHVEPDEDPLEAALREAREETGLDVELLSPLSPDPLDIdvhpipANPGEpahlhLDVRYL 91

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 2195104096 238 ARAadSGTEPVVDGRELTRAQWFGLDELP-AQLPPAY 273
Cdd:cd03674    92 AVA--DGDEALRKSDESSDVRWFPLDELEeLSMDPNL 126

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096 182 GLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYFG--SQPWAISGPGVLLAGFTARAADSGTEPVVDGRELTRAQW 259
Cdd:cd04678    28 GTWALPGGHLEFGESFEECAAREVLEETGLEIRNVRFLTvtNDVFEEEGKHYVTIFVLAEVDDGEPEENMEPDKCEGWEW 107

                          90
                  ....*....|.
gi 2195104096 260 FGLDELPAQLP 270
Cdd:cd04678   108 FSWDELPPLRP 118

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 2195104096 149 MQLSAAVLVAITRPGPPghvdELLLVQHATGptGLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRL 216
Cdd:cd03428     1 KEKSAGAIIYRRDNGEI----EFLLLQHSYG--GHWDFPKGHVEPGESELETALRETKEETGLTVDDL 62

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 2195104096 182 GLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYFGSQPWAISGPGVLLAGFTARAAdSGTEPVVDGRELtraQWFG 261
Cdd:cd03425    27 GLWEFPGGKVEPGETPEQALVRELREELGIEVEVGEPLGTVEHDYPDFHVRLHVYLCTLW-SGEPQLLEHQEL---RWVT 102

                          90
                  ....*....|..
gi 2195104096 262 LDELPA-QLPPA 272
Cdd:cd03425   103 PEELDDlDWLPA 114

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096 169 DELLLVQ------HATGPTG-LWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYFGS 221
Cdd:cd24155    56 DEVVLIEqfrigaLARDESPwLLEIVAGMIDAGETPEDVARREAEEEAGLTLDALEPIAS 115

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096 169 DELLLVQ-HATG-PTGLWALVAGFVEAGETLEAAVHREVGEEVGLPVD----RLAYFGSQPwaiSGPGVLLAGFTARAAD 242
Cdd:cd04683    11 DEVLLLRrANTGyDDGWWHLPAGHVEAGETVRAAAVREAKEELGVEIDpedlRLVHTMHRR---SDGGRERIDFFFRATR 87

                          90       100       110
                  ....*....|....*....|....*....|..
gi 2195104096 243 SGTEPVVdgRELTRA---QWFGLDELPAQLPP 271
Cdd:cd04683    88 WSGEPRN--REPDKCaelRWFPLDALPENTVP 117

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096 169 DELLLVQHATGPTGLWALVAGFVEAGETLEAAVHREVGEEVGL---PVDRLAyFGSQPWAISGPGVLLAGFTARAAdSGT 245
Cdd:cd04670    14 NEVLVVQEKYGGPGGWKLPGGLVDPGEDIGEAAVREVFEETGIdteFVSILG-FRHQHPGRFGKSDLYFVCRLRPL-SDE 91

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 2195104096 246 EPVVDGRELTRAQWFGLDELPAQlpPAYSISRWLI 280
Cdd:cd04670    92 EIKICPEEIAEAKWMPLEEYLKQ--PNVSQINKLV 124

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 2195104096 169 DELLLVQHATGP-TGLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLA 217
Cdd:cd04686    12 DKLLLIRKTRGPyQGRYDLPGGSQEFGESLEDALKREFAEETGMTVTSYD 61

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 2195104096 169 DELLLVQHATGP-TGLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYFGSQPWAISGPGV-LLAGFTARAADSGTE 246
Cdd:cd04679    13 GRLLLVLRLRAPeAGHWGLPGGKVDWLETVEDAVRREILEELGLEIELTRLLCVVDQIDAADGEhWVAPVYLAEIFSGEP 92

                          90       100
                  ....*....|....*....|...
gi 2195104096 247 PVVDGRELTRAQWFGLDELPAQL 269
Cdd:cd04679    93 RLMEPEKHGGIGWFALDALPQPL 115

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2195104096 169 DELLLVQHATGPTglWALVAGFVEAGETLEAAVHREVGEEVGL--PVDR-LAYFGSQPWAISGPGVLLAGFTARAADSGT 245
Cdd:cd18876    12 GRVLLVKPTYKDG--WELPGGVVEAGESPLQAARREVREELGLdvPVGRlLAVDWVPPAGGGDDAVLFVFDGGVLTPEQA 89

                          90       100
                  ....*....|....*....|....*...
gi 2195104096 246 EPVV-DGRELTRAQWFGLDELPAQLPPA 272
Cdd:cd18876    90 AAIRlQDEELSAYRFVTPEEAAELLPPR 117

dihydroneopterin hydrolase; DHNTP pyrophosphatase (DHNTPase) catalyzes the hydrolysis of dihydroneopterin triphosphate (DHNTP) to dihydroneopterin monophosphate (DHNMP) and pyrophosphate,the second step in the pterin branch of the folate synthesis pathway in bacteria. 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 2195104096 155 VLVAITRPGPPGhvdELLLVQHATGPtGLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYF 219
Cdd:cd04664     3 VLVVIYRKDEEG---EVLLLKRTDDG-GFWQSVTGGIEDGETPWQAALRELKEETGLDPLELQLI 63

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 2195104096 171 LLLVQHATGPTGLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYFG--SQPWAISGPGVLLAGFTARaADSG--TE 246
Cdd:cd18886    14 LLLNRNKKPNMGKWNGVGGKLEPGESPEECAIREVFEETGLELEDLQLRGivTFPSFDGGEDWLMYVFLAE-AFSGelVE 92

                          90       100
                  ....*....|....*....|
gi 2195104096 247 PVVDGrELtraQWFGLDELP 266
Cdd:cd18886    93 SDREG-IL---AWVPIDWLL 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 2195104096 172 LLVQHATGpTGLWALVAGFVEAGETLEAAVHREVGEEVGL---PVDRLAYFGSQPWAISGPGVLLAGFTARAAD----SG 244
Cdd:cd04676    31 ILLQRKGG-LGLWSLPAGAIEPGEHPAEAVIREVREETGLlvkPTRLLGVFGGKEFRYTYPNGDQVEYTVIAFKcvvtGG 109

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 2195104096 245 TEPVVDGrELTRAQWFGLDELPA-QLP-PAYSISR 277
Cdd:cd04676   110 TLNAIDG-ETSELRYFSRTQMPTlALPyPDEIFFI 143

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 2195104096 165 PGHVDELLLVQHATGP-TGLWALVAGFVEAGETLEAAVHREVGEEVGLPVD 214
Cdd:cd04511     9 PEWEGKVLLCRRAIEPrKGYWTLPAGFMELGETTEQGAARETREEAGARVE 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 2195104096 186 LVAGFVEAGETLEAAVHREVGEEVGLPVD--RLAYFGSqpwaISGPGVLLAGFTARA----ADSGTEPVVDgRELTRAQW 259
Cdd:cd04690    27 LPGGKREPGETPLQALVRELKEELGLDLDpdSLRFLGT----FEAPAANEPGTTVRMtcftADYDGEPQPA-AEIEELRW 101

                          90
                  ....*....|....
gi 2195104096 260 FGLDE-LPAQLPPA 272
Cdd:cd04690   102 LDPADpDDDRLAPL 115

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

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 2195104096 182 GLWALVAGFVEAGETLEAAVHREVGEEVGLPVDRLAYFGSQP 223
Cdd:cd03671    27 GAWQFPQGGIDEGEDPEEAALRELYEETGLSPEDVEIIAETP 68