ADP-ribose pyrophosphatase from Mycobacterium tuberculosis (Mt-ADPRase), and similar proteins; Mycobacterium tuberculosis ADP-ribose pyrophosphatase mt-ADPRase(also called Rv1700) is a NUDIX protein that catalyzes the hydrolysis of ADP-ribose and a variety of additional ADP-sugar conjugates to AMP and ribose-5-phosphate. In humans, there are four distinct ADPRase activities, three putative cytosolic enzymes (ADPRase-I, -II, and -Mn) and a single mitochondrial enzyme (ADPRase-m). Human ADPRase-II is also referred to as NUDT5. It lacks the N-terminal target sequence unique to mitochondrial ADPRase. The different cytosolic types are distinguished by their specificities for substrate and specific requirement for metal ions. NUDT5 forms a homodimer. It also contains a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V) which functions as a metal binding site/catalytic site. In addition to the NUDIX motif, there are additional conserved amino acid residues, distal from the signature sequence, that correlate with substrate specificity. UDP-glucose pyrophosphatase (UGPPase) (EC 3.6.1.45; also known as nucleoside diphosphate-linked moiety X)) motif 14; Nudt14) hydrolyzes the pyrophosphate of the nucleoside diphosphate sugar to generate glucose-1-P and UMP. In mammals, UDP-glucose is the glucosyl donor for the synthesis of the storage polysaccharide glycogen. UGPPase, as a regulator of UDP-glucose, could play a regulatory role, but it has been shown to prefer ADP-ribose over UDP-glucose. Like other members of the NUDIX hydrolase superfamily, it requires a divalent cation, such as Mg2+, for its activity. It also contains a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V) which functions as a metal binding site/catalytic site.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A        7 ETISSETLHTGAIFALRRDQVRMPGGGIVTREVVEHFGAVAIVAMDDNGNIPMVYQYRHTYGRRLWELPAGLLDVAGEPP 86
Cdd:cd24158   1 PVLSSEVVYEGAIWDVRRDTVDLPGGGTVTREYVEHPGAVAVVALDDDGRVLLIRQYRHPVRRRLWELPAGLLDVAGEPP 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A       87 HLTAARELREEVGLQASTWQVLVDLDTAPGFSDESVRVYLATGLREVG---RPEAHHEEADMTMGWYPIAEAARRVLRGE 163
Cdd:cd24158  81 LEAAARELAEEADLEAARWEVLVDLFTSPGFSSEAVRVYLARGLSEVPeadRHEREDEEADMTLRWVPLDEAVAAVLAGR 160

                       170
                ....*....|....
1MQW_A      164 IVNSIAIAGVLAVH 177
Cdd:cd24158 161 ITNSTAVAGVLAAA 174

ADP-ribose pyrophosphatase from Mycobacterium tuberculosis (Mt-ADPRase), and similar proteins; Mycobacterium tuberculosis ADP-ribose pyrophosphatase mt-ADPRase(also called Rv1700) is a NUDIX protein that catalyzes the hydrolysis of ADP-ribose and a variety of additional ADP-sugar conjugates to AMP and ribose-5-phosphate. In humans, there are four distinct ADPRase activities, three putative cytosolic enzymes (ADPRase-I, -II, and -Mn) and a single mitochondrial enzyme (ADPRase-m). Human ADPRase-II is also referred to as NUDT5. It lacks the N-terminal target sequence unique to mitochondrial ADPRase. The different cytosolic types are distinguished by their specificities for substrate and specific requirement for metal ions. NUDT5 forms a homodimer. It also contains a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V) which functions as a metal binding site/catalytic site. In addition to the NUDIX motif, there are additional conserved amino acid residues, distal from the signature sequence, that correlate with substrate specificity. UDP-glucose pyrophosphatase (UGPPase) (EC 3.6.1.45; also known as nucleoside diphosphate-linked moiety X)) motif 14; Nudt14) hydrolyzes the pyrophosphate of the nucleoside diphosphate sugar to generate glucose-1-P and UMP. In mammals, UDP-glucose is the glucosyl donor for the synthesis of the storage polysaccharide glycogen. UGPPase, as a regulator of UDP-glucose, could play a regulatory role, but it has been shown to prefer ADP-ribose over UDP-glucose. Like other members of the NUDIX hydrolase superfamily, it requires a divalent cation, such as Mg2+, for its activity. It also contains a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V) which functions as a metal binding site/catalytic site.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A        7 ETISSETLHTGAIFALRRDQVRMPGGGIVTREVVEHFGAVAIVAMDDNGNIPMVYQYRHTYGRRLWELPAGLLDVAGEPP 86
Cdd:cd24158   1 PVLSSEVVYEGAIWDVRRDTVDLPGGGTVTREYVEHPGAVAVVALDDDGRVLLIRQYRHPVRRRLWELPAGLLDVAGEPP 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A       87 HLTAARELREEVGLQASTWQVLVDLDTAPGFSDESVRVYLATGLREVG---RPEAHHEEADMTMGWYPIAEAARRVLRGE 163
Cdd:cd24158  81 LEAAARELAEEADLEAARWEVLVDLFTSPGFSSEAVRVYLARGLSEVPeadRHEREDEEADMTLRWVPLDEAVAAVLAGR 160

                       170
                ....*....|....
1MQW_A      164 IVNSIAIAGVLAVH 177
Cdd:cd24158 161 ITNSTAVAGVLAAA 174

adenosine nucleotide hydrolase NudE; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A        28 RMPGGGIvtrevvehfGAVAIVAMDDNGNIPMVYQYR---HTYgrrlwEL--PAGLLDvAGEPPHLTAARELREEVGLQA 102
Cdd:PRK11762  41 RMRPSGR---------GAVMIVPILDDDTLLLIREYAagtERY-----ELgfPKGLID-PGETPLEAANRELKEEVGFGA 105

                         90       100
                 ....*....|....*....|....*...
1MQW_A       103 STWQVLVDLDTAPGFSDESVRVYLATGL 130
Cdd:PRK11762 106 RQLTFLKELSLAPSYFSSKMNIVLAEDL 133

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A          5 DFETISSETLHTGAIFALR-RDQVRMPGGG---IVTREVVEHFGAVAIVAMD-DNGNIPMVYQYR-HTYGRR----LWEL 74
Cdd:TIGR00052   2 QQEIIIKDTLYSGFFSLLHnIFYHRLFKGGesiRVTREIYDRGNAAAVLLYDpKKDTVVLIEQFRiAAYVNGeepwLLEL 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A         75 PAGLLDvAGEPPHLTAARELREEVGLQASTWQVLVDLDTAPGFSDESVRVYLAtglrEVGRPEAHH-----EEADMTMGW 149
Cdd:TIGR00052  82 SAGMVE-KGESPEDVARREAIEEAGYQVKNLRKLLSFYMSPGGVTELIHLFIA----EVDDNQAAGigggaDEEEIEVLH 156

                         170       180
                  ....*....|....*....|....*...
1MQW_A        150 YPIAEAARRVLRGEIVNSIAIAGVLAVH 177
Cdd:TIGR00052 157 LVFSQALQWIKEGKIDNGKTVILLQWLQ 184

ADP-ribose pyrophosphatase from Mycobacterium tuberculosis (Mt-ADPRase), and similar proteins; Mycobacterium tuberculosis ADP-ribose pyrophosphatase mt-ADPRase(also called Rv1700) is a NUDIX protein that catalyzes the hydrolysis of ADP-ribose and a variety of additional ADP-sugar conjugates to AMP and ribose-5-phosphate. In humans, there are four distinct ADPRase activities, three putative cytosolic enzymes (ADPRase-I, -II, and -Mn) and a single mitochondrial enzyme (ADPRase-m). Human ADPRase-II is also referred to as NUDT5. It lacks the N-terminal target sequence unique to mitochondrial ADPRase. The different cytosolic types are distinguished by their specificities for substrate and specific requirement for metal ions. NUDT5 forms a homodimer. It also contains a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V) which functions as a metal binding site/catalytic site. In addition to the NUDIX motif, there are additional conserved amino acid residues, distal from the signature sequence, that correlate with substrate specificity. UDP-glucose pyrophosphatase (UGPPase) (EC 3.6.1.45; also known as nucleoside diphosphate-linked moiety X)) motif 14; Nudt14) hydrolyzes the pyrophosphate of the nucleoside diphosphate sugar to generate glucose-1-P and UMP. In mammals, UDP-glucose is the glucosyl donor for the synthesis of the storage polysaccharide glycogen. UGPPase, as a regulator of UDP-glucose, could play a regulatory role, but it has been shown to prefer ADP-ribose over UDP-glucose. Like other members of the NUDIX hydrolase superfamily, it requires a divalent cation, such as Mg2+, for its activity. It also contains a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V) which functions as a metal binding site/catalytic site.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A        7 ETISSETLHTGAIFALRRDQVRMPGGGIVTREVVEHFGAVAIVAMDDNGNIPMVYQYRHTYGRRLWELPAGLLDVAGEPP 86
Cdd:cd24158   1 PVLSSEVVYEGAIWDVRRDTVDLPGGGTVTREYVEHPGAVAVVALDDDGRVLLIRQYRHPVRRRLWELPAGLLDVAGEPP 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A       87 HLTAARELREEVGLQASTWQVLVDLDTAPGFSDESVRVYLATGLREVG---RPEAHHEEADMTMGWYPIAEAARRVLRGE 163
Cdd:cd24158  81 LEAAARELAEEADLEAARWEVLVDLFTSPGFSSEAVRVYLARGLSEVPeadRHEREDEEADMTLRWVPLDEAVAAVLAGR 160

                       170
                ....*....|....
1MQW_A      164 IVNSIAIAGVLAVH 177
Cdd:cd24158 161 ITNSTAVAGVLAAA 174

NUDIX family Ndx2; NUDIX family protein Ndx2 found in Thermus thermophilus has ADP-ribose pyrophosphatase (ADPRase) as well as flavin adenine dinucleotide (FAD) activity. ADPRase (EC 3.6.1.13) catalyzes the hydrolysis of ADP-ribose to AMP and ribose-5-P. Like other members of the NUDIX hydrolase superfamily of enzymes, it is thought to require a divalent cation, such as Mg2+, for its activity. It also contains a 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V) which functions as a metal binding site/catalytic site. In addition to the NUDIX motif, there are additional conserved amino acid residues, distal from the signature sequence, that correlate with substrate specificity.Members of the NUDIX hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of NUDIX hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance _ "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A       45 AVAIVAMDDNGNIPMVYQYRHTYGRRLWELPAGLLDvAGEPPHLTAARELREEVGLQASTWQVLVDLDTAPGFSDESVRV 124
Cdd:cd24161   5 AVGVLPITDDGEVVLVEQYRYPLGGWSWEIPAGGWP-EGEDPEEAARRELREETGLRAERWTPLGRFYPSNGVSDERAHV 83

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|...
1MQW_A      125 YLATGLREvGRPEAHHEEADMTMGWYPIAEAARRVLRGEIVNSIAIAGVLAVH 177
Cdd:cd24161  84 FLATGLTP-GEPAPEETEEDLEVRRVPLAEALAMVLDGEITDAMSVAALLLAR 135

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A       34 IVTREVVEHFGAVAIVAMDDNGNIPMVYQYRHTYGRRLWELPAGLLDvAGEPPHLTAARELREEVGLQASTWQVLVDLdT 113
Cdd:COG0494   4 ILSSEPEHYRPAVVVVLLDDDGRVLLVRRYRYGVGPGLWEFPGGKIE-PGESPEEAALRELREETGLTAEDLELLGEL-P 81

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*.
1MQW_A      114 APGFSDESVRVYLATGLREVGRPEAHHEEADMTMGWYPIAEAARRVLRGEIVNSIA 169
Cdd:COG0494  82 SPGYTDEKVHVFLARGLGPGEEVGLDDEDEFIEVRWVPLDEALALVTAGEIAKTLA 137

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A        5 DFETISSETLHTGaIFALRRDQVRMP---GG--GIVTREVVEHFGAVAIVAMD-DNGNIPMVYQYR---HTYGRRLW--E 73
Cdd:cd24155   1 DVEILSKETVYDG-FFRLERYRLRHRrfdGGwsAPLTREIFERGDAVAVLPYDpVRDEVVLIEQFRigaLARDESPWllE 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A       74 LPAGLLDvAGEPPHLTAARELREEVGLQASTWQVLVDLDTAPGFSDESVRVYLA----TGLREVGRPEAHHEeaDMTMGW 149
Cdd:cd24155  80 IVAGMID-AGETPEDVARREAEEEAGLTLDALEPIASYYPSPGGSTERVHLYLGlvdlSDLGGIHGLAEEGE--DIRVHV 156

                       170       180
                ....*....|....*....|.
1MQW_A      150 YPIAEAARRVLRGEIVNSIAI 170
Cdd:cd24155 157 VPFDEAMALLDDGEIDNAPLI 177

NUDIX domain family NudE found in Escherichia coli, and similar proteins; The adenosine nucleotide hydrolase NudE protein in Escherichia coli is a NUDIX hydrolase family member active against ADP ribose, NADH, AP2A and AP3A33, and is classified as a hydrolase (E.C. 3.6.1.-) based on gene annotations. It is an ADPRase (EC 3.6.1.13) catalyzes the hydrolysis of ADP-ribose to AMP and ribose-5-P. Like other members of the NUDIX hydrolase superfamily of enzymes, it is thought to require a divalent cation, such as Mg2+, for its activity. It also contains a 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V) which functions as a metal binding site/catalytic site. In addition to the NUDIX motif, there are additional conserved amino acid residues, distal from the signature sequence, that correlate with substrate specificity. Members of the NUDIX hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of NUDIX hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance _ "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A       44 GAVAIVAMDDNGNIPMVYQYRHTYGRRLWELPAGLLDvAGEPPHLTAARELREEVGLQASTWQVLVDLDTAPGFSDESVR 123
Cdd:cd24156   3 GAVMIVPILDDDHLLLIREYAAGTERYELGFPKGLID-PGETPEEAANRELKEEIGFGARQLTLLRELSLAPSYMSHKMH 81

                ....*..
1MQW_A      124 VYLATGL 130
Cdd:cd24156  82 IVLARDL 88

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A       45 AVAIVAMDDNGNIPMVYQYRHTYGRrLWELPAGLLDvAGEPPHLTAARELREEVGLQASTWQVLVDLDTAPGFSDESVR- 123
Cdd:cd02883   2 AVGAVVFDDEGRVLLVRRSDGPGPG-GWELPGGGVE-PGETPEEAAVREVREETGLDVEVLRLLGVYEFPDPDEGRHVVv 79

                        90       100
                ....*....|....*....|..
1MQW_A      124 -VYLATGLREVGRPEAHHEEAD 144
Cdd:cd02883  80 lVFLARVVGGEPPPLDDEEISE 101

NUDIX domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A         45 AVAIVAMDDNGNIPMVYQYRHTYgRRLWELPAGLLDvAGEPPHLTAARELREEVGLQASTWQVLVDLDTAPG----FSDE 120
Cdd:pfam00293   5 AVGVVLLNEKGRVLLVRRSKKPF-PGWWSLPGGKVE-PGETPEEAARRELEEETGLEPELLELLGSLHYLAPfdgrFPDE 82

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
1MQW_A        121 SVRVYLATGLREvGRPEAHHEEADMTMGWYPIAEAARRVLR 161
Cdd:pfam00293  83 HEILYVFLAEVE-GELEPDPDGEVEEVRWVPLEELLLLKLA 122

diadenosine hexaphosphate (Ap6A) hydrolase; Diadenosine hexaphosphate (Ap6A) hydrolase is a member of the NUDIX hydrolase superfamily. Ap6A hydrolase specifically hydrolyzes diadenosine polyphosphates, but not ATP or diadenosine triphosphate, and it generates ATP as the product. Ap6A, the most preferred substrate, hydrolyzes to produce two ATP molecules, which is a novel hydrolysis mode for Ap6A. These results indicate that Ap6A hydrolase is a diadenosine polyphosphate hydrolase. It requires the presence of a divalent cation, such as Mn2+, Mg2+, Zn2+, and Co2+, for activity. Members of the NUDIX hydrolase superfamily are recognized by a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A       31 GGGIVTREVvEHFGAVAIVamddngnipmvyqYRHTYGRrlWELPAGLLDvAGEPPHLTAARELREEVGLQAStwqVLVD 110
Cdd:cd03673   4 AGGVVWRGR-GGGGEVLLI-------------HRPRYDD--WSLPKGKLE-PGETPEEAAVREVEEETGLRVR---LGRP 63

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*.
1MQW_A      111 L-DTAPGFSDESVRV------YLATGLREVGRPeAHHEEADMtMGWYPIAEAARRV 159
Cdd:cd03673  64 LgTTRYTYTRKGKGIlkkvhyWLMRALGGEFLP-QPEEEIDE-VRWLPPDEARRLL 117

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
                ....*....|....*....|....*....|....*....|....*....|....*.
1MQW_A       45 AVAIVAMDDNGNIpmVYQYRHtyGRRLWELPAGLLDvAGEPPHLTAARELREEVGL 100
Cdd:cd04676  19 SVAAVILNEDGRI--LLQRKG--GLGLWSLPAGAIE-PGEHPAEAVIREVREETGL 69

nudix hydrolase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A        44 GAVAI-VAMDDNGNIPMVY--QYRHTYGRRLWELPAGLLDVAGEPPHLTAARELREEVGLQASTwQVLVDLDT------- 113
Cdd:PLN03143 129 PAVAVlILLESEGETYAVLteQVRVPVGKFVLELPAGMLDDDKGDFVGTAVREVEEETGIKLKL-EDMVDLTAfldpstg 207

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
1MQW_A       114 -----APGFSDESVRVYL----------------ATGLREVG 134
Cdd:PLN03143 208 crmfpSPGGCDEEISLFLyrghvdketirqlqgkETGLRDHG 249

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
                ....*....|....*....|....*....|....*....|....
1MQW_A       72 WELPAGLLDvAGEPPHLTAARELREEVGLQASTWQVLVdLDTAP 115
Cdd:cd18876  25 WELPGGVVE-AGESPLQAARREVREELGLDVPVGRLLA-VDWVP 66

GDP-mannose hydrolase (GDPMK), and similar proteins; GDP-mannose hydrolase (GDPMK) is a NUDIX enzyme that uses GDP-mannose as the preferred substrate. It is distinct from Nudix ADP-ribose hydrolases. GDPMK and ADP-ribose pyrophosphatase seem to use similar catalytic mechanism. However, GDPMK hydrolysis does not rely on a single glutamate as the catalytic base; rather, it is dependent on residues that coordinate the magnesium ions and residues that position the substrate properly for catalysis. Members of the NUDIX hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of NUDIX hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance _ "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A       71 LWELPAGLLDvaGEPPHLTAARELREEVGLQASTWQVLVDLDTAPGFSDESVRVYLATgLREVGRPE----AHHEEADMT 146
Cdd:cd24157  38 LIEACAGLLD--GDDPEDCIRREAEEETGYRLGDLEKVFTAYSSPGIVTERIHLFIAE-YSSADRVGagggLAEEGEDIE 114

                        90
                ....*....|....*....
1MQW_A      147 MGWYPIAEAARRVLRGEIV 165
Cdd:cd24157 115 VLELPLDEALAMIETGEIR 133

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
                ....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A       47 AIVAMDDNGNIpmvyQY---RHTYGRRlWELPAGLLDvAGEPPHLTAARELREEVGLQAS 103
Cdd:cd03428   7 AIIYRRDNGEI----EFlllQHSYGGH-WDFPKGHVE-PGESELETALRETKEETGLTVD 60

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A       53 DNGNIPMVYqyRHTYGRRLWELPAGLLDvAGEPPHLTAARELREEVGLQASTWQVlvdLDTAPGFSDESVRVYLAT-GLR 131
Cdd:cd04699  11 DNGRVLLLR--RSRAGAGEWELPGGRLE-PGESPEEALKREVKEETGLDVSVGEL---LDTWTFELDPDKGVFIVTyLCR 84

                        90       100       110
                ....*....|....*....|....*....|...
1MQW_A      132 EVGRP---EAHHEEAdmtmGWYPIAEAARRVLR 161
Cdd:cd04699  85 LVGGEvtlSDEHEEY----EWVTPEELAELELP 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A       77 GLLDV-------AGEPPHLTAARELREEVGLQASTWQVL------VDLDTAPGFSDESVRVYLATGLREVGRPEAHHEEA 143
Cdd:cd04692  55 GLWDIsaaghidAGETYEEAAVRELEEELGLTVSPEDLIflgvirEEVIGGDFIDNEFVHVYLYETDRPLEEFKLQPEEV 134

                ....*....
1MQW_A      144 DMtMGWYPI 152
Cdd:cd04692 135 AG-VVFVDL 142

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A       72 WELPAGLLDvAGEPPHLTAARELREEVGLQASTWQVLVDLDTapgFSDESVR-----VYLAT---GLREVGRPEAHHEea 143
Cdd:cd04679  29 WGLPGGKVD-WLETVEDAVRREILEELGLEIELTRLLCVVDQ---IDAADGEhwvapVYLAEifsGEPRLMEPEKHGG-- 102

                        90
                ....*....|.
1MQW_A      144 dmtMGWYPIAE 154
Cdd:cd04679 103 ---IGWFALDA 110

nucleoside diphosphate-linked moiety X)) motif 17; Nucleoside diphosphate-linked moiety X)) motif 17 (EC 3.6.1.-) encoded by the NUDT17 gene on chromosome 1q21.1 and encodes an enzyme thought to hydrolyse some nucleoside diphosphate derivatives. Members of the NUDIX hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of NUDIX hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance _ "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1MQW_A       45 AVAIVAMDDNGNIpMVYQyRHTYGR---RLWELPAGLLDVaGEPPHLTAARELREEVGLqastwQVLVDLDTAPGFSDES 121
Cdd:cd04694   4 GVVVLIEDSDDRV-LLTR-RAKHMRtfpGVWVPPGGHVEL-GESLLEAGLRELQEETGL-----EVSDIQSLSLLGLWES 75

                        90
                ....*....|....*....
1MQW_A      122 VRVYLATGlrevGRPEAHH 140
Cdd:cd04694  76 VYPTLLSI----GLPKRHH 90