NAD(+) diphosphatase;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254   5 TLTGGEKGWWTVSLGGRVWLPKGELPFGLATDWGLVGKQAKIVGEWQGENVWLIYDK--MESDMCSPRLIASQDEKLFKL 82
Cdd:PRK00241   6 DLEALDAGWWVVSHEQQLWLPDGELPFGAAANLDLPGLRALQIGEWQGEPVWLVRQDplRGHEMGSLRQLLDLDDGLFQL 85

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254  83 VGRGVQLAEFYRSHRFCGYCGAKMRHSESEWACLCDNCHERYYPQIAPCIIVGIRNKDKILLAHHVRHKhSPLYTVLAGF 162
Cdd:PRK00241  86 LGRAVQLAEFYRSHRFCGYCGHPMHPSKTEWAMLCPHCRERYYPRIAPCIIVAVRRGDEILLARHPRHR-NGVYTVLAGF 164

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254 163 VEVGESLEDAVAREVFEESHIHIRNIRYVSSQPWPFPHSLMMGFLADYAGGELRHDPSELISAAWYRYDELPQIPPSDTI 242
Cdd:PRK00241 165 VEVGETLEQCVAREVMEESGIKVKNLRYVGSQPWPFPHSLMLGFHADYDSGEIVFDPKEIADAQWFRYDELPLLPPSGTI 244

                        250
                 ....*....|..
gi 490367254 243 ARRLIEDTIANI 254
Cdd:PRK00241 245 ARRLIEDTVALC 256

NAD(+) diphosphatase;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254   5 TLTGGEKGWWTVSLGGRVWLPKGELPFGLATDWGLVGKQAKIVGEWQGENVWLIYDK--MESDMCSPRLIASQDEKLFKL 82
Cdd:PRK00241   6 DLEALDAGWWVVSHEQQLWLPDGELPFGAAANLDLPGLRALQIGEWQGEPVWLVRQDplRGHEMGSLRQLLDLDDGLFQL 85

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254  83 VGRGVQLAEFYRSHRFCGYCGAKMRHSESEWACLCDNCHERYYPQIAPCIIVGIRNKDKILLAHHVRHKhSPLYTVLAGF 162
Cdd:PRK00241  86 LGRAVQLAEFYRSHRFCGYCGHPMHPSKTEWAMLCPHCRERYYPRIAPCIIVAVRRGDEILLARHPRHR-NGVYTVLAGF 164

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254 163 VEVGESLEDAVAREVFEESHIHIRNIRYVSSQPWPFPHSLMMGFLADYAGGELRHDPSELISAAWYRYDELPQIPPSDTI 242
Cdd:PRK00241 165 VEVGETLEQCVAREVMEESGIKVKNLRYVGSQPWPFPHSLMLGFHADYDSGEIVFDPKEIADAQWFRYDELPLLPPSGTI 244

                        250
                 ....*....|..
gi 490367254 243 ARRLIEDTIANI 254
Cdd:PRK00241 245 ARRLIEDTVALC 256

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 490367254 129 APCIIVGIRN-KDKILLAHHVRHKhSPLYTVLAGFVEVGESLEDAVAREVFEESHIHIRNIRYVSSQPWPFPHSLMMGFL 207
Cdd:cd03429    1 DPAVIVLVTNgEDKILLARQPRWP-PGRYSLLAGFVEPGETLEEAVRREVKEEVGLRVKNVRYVGSQPWPFPSSLMLGFT 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 490367254 208 ADYAGGELRHDPSELISAAWYRYDELPQI---PPSDTIARRLIED 249
Cdd:cd03429   80 AEADSGEITVDDDELEDARWFSRDELPEAlflPPPGSIARRLIRA 124

NAD(+) diphosphatase;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254   5 TLTGGEKGWWTVSLGGRVWLPKGELPFGLATDWGLVGKQAKIVGEWQGENVWLIYDK--MESDMCSPRLIASQDEKLFKL 82
Cdd:PRK00241   6 DLEALDAGWWVVSHEQQLWLPDGELPFGAAANLDLPGLRALQIGEWQGEPVWLVRQDplRGHEMGSLRQLLDLDDGLFQL 85

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254  83 VGRGVQLAEFYRSHRFCGYCGAKMRHSESEWACLCDNCHERYYPQIAPCIIVGIRNKDKILLAHHVRHKhSPLYTVLAGF 162
Cdd:PRK00241  86 LGRAVQLAEFYRSHRFCGYCGHPMHPSKTEWAMLCPHCRERYYPRIAPCIIVAVRRGDEILLARHPRHR-NGVYTVLAGF 164

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254 163 VEVGESLEDAVAREVFEESHIHIRNIRYVSSQPWPFPHSLMMGFLADYAGGELRHDPSELISAAWYRYDELPQIPPSDTI 242
Cdd:PRK00241 165 VEVGETLEQCVAREVMEESGIKVKNLRYVGSQPWPFPHSLMLGFHADYDSGEIVFDPKEIADAQWFRYDELPLLPPSGTI 244

                        250
                 ....*....|..
gi 490367254 243 ARRLIEDTIANI 254
Cdd:PRK00241 245 ARRLIEDTVALC 256

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 490367254 129 APCIIVGIRN-KDKILLAHHVRHKhSPLYTVLAGFVEVGESLEDAVAREVFEESHIHIRNIRYVSSQPWPFPHSLMMGFL 207
Cdd:cd03429    1 DPAVIVLVTNgEDKILLARQPRWP-PGRYSLLAGFVEPGETLEEAVRREVKEEVGLRVKNVRYVGSQPWPFPSSLMLGFT 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 490367254 208 ADYAGGELRHDPSELISAAWYRYDELPQI---PPSDTIARRLIED 249
Cdd:cd03429   80 AEADSGEITVDDDELEDARWFSRDELPEAlflPPPGSIARRLIRA 124

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254 138 NKDKILLahhVRHKHSPL---YTVLAGFVEVGESLEDAVAREVFEES--HIHIRNIRYVSSQPWPFP-HSLMMGFLADYA 211
Cdd:cd04691   10 KEGKVLL---VKRAYGPGkgrWTLPGGFVEEGETLDEAIVREVLEETgiDAKPVGIIGVRSGVIRDGkSDNYVVFLLEYV 86

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 490367254 212 GGELRHDPSELISAAWYRYDELPQIPPSDTIARRLI 247
Cdd:cd04691   87 GGEPKPDERENSEAGFLTLEEALANEDIADMSRELI 122

NUDIX domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254  126 PQIAPCIIVgIRNKDKILLAHHVRHKHSPLYTVLAGFVEVGESLEDAVAREVFEESHIHIRNIRYVSSQ--------PWP 197
Cdd:pfam00293   2 RRVAVGVVL-LNEKGRVLLVRRSKKPFPGWWSLPGGKVEPGETPEEAARRELEEETGLEPELLELLGSLhylapfdgRFP 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 490367254  198 FPHSLMMGFLADYAGGELRHDPSELISAAWYRYDELpQIPPSDTIARRLIED 249
Cdd:pfam00293  81 DEHEILYVFLAEVEGELEPDPDGEVEEVRWVPLEEL-LLLKLAPGDRKLLPW 131

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 490367254 132 IIVGIRNKDKILLahhVRHKHSP---LYTVLAGFVEVGESLEDAVAREVFEESHIHIRNIRYV---------SSQPWPFp 199
Cdd:cd04673    4 VGAVVFRDGRVLL---VRRGNPPdagLWSFPGGKVELGETLEDAALRELREETGLEAEVVGLLtvvdvierdEAGRVRF- 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 490367254 200 HSLMMGFLADYAGGELRhDPSELISAAWYRYDELPQIPPSDTiARRLIE 248
Cdd:cd04673   80 HYVILDFLAEWVSGEPV-AGDDALDARWFSLEELDGLPLTPG-TRDVLE 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 490367254 124 YYPQIAPCIIVGIRNKDKILLAhhVRHKhSPLYTVLA---GFVEVGESLEDAVAREVFEESHIHIRNIRYVSSQPWPFP- 199
Cdd:cd04681    1 YFHNVAAAVGVIIRNEGEILFV--RRAK-EPGKGKLDlpgGFVDPGESAEEALRRELREELGLKIPKLRYLCSLPNTYLy 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 490367254 200 -----HSLMMGFLADY-AGGELRHDPSELISAAWYRYDELP 234
Cdd:cd04681   78 kgityKTCDLFFTAELdEKPKLKKAEDEVAELEWLDLEEIE 118

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 490367254 130 PCIIVG--IRNKD-KILLahhVR-HKHSPLYTVLAGFVEVGESLEDAVAREVFEESHIHIRNIRYVSSQPWPFP------ 199
Cdd:cd18874    1 PEPTVGalIFNPDgKVLL---VRsHKWNDLYGIPGGKVEWGETLEEALKREVKEETGLDITDIRFILVQESINSeefhkp 77

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 490367254 200 -HSLMMGFLADYAGGELRhDPSELISAAWYRYDELPQIpPSDTIARRLIE 248
Cdd:cd18874   78 aHFVFVDYLARTDSSEVV-LNEEAVEYLWVEPEEALKY-PLNSFTRLLLE 125

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 490367254 132 IIVG---IRNKDKILLAHhvRHKHSPLytvlAGF-------VEVGESLEDAVAREVFEESHIHIRNIRYV--SSQPWPFP 199
Cdd:cd03425    1 IEVVaaiIVDDGRVLIAQ--RPEGKHL----AGLwefpggkVEPGETPEQALVRELREELGIEVEVGEPLgtVEHDYPDF 74

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 490367254 200 HSLMMGFLADYAGGELRhdPSELISAAWYRYDELPQ--IPPSDT-IARRLI 247
Cdd:cd03425   75 HVRLHVYLCTLWSGEPQ--LLEHQELRWVTPEELDDldWLPADIpIVEALL 123

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 490367254 126 PQIAPCIIVGIRNK-DKILLAHhvRhKHSPLYTVLAGFVEVGESLEDAVAREVFEESHIHIRN---IRYVSSQPWPF--P 199
Cdd:cd04677    9 PLILVGAAVIILNEqGRILLQK--R-TDTGDWGLPGGAMELGESLEETARREVFEETGLTVEElelLGVYSGKDLYYtyP 85

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 490367254 200 H-----SLMMGFLADYAGGELRHDPSELISAAWYRYDELPQI 236
Cdd:cd04677   86 NgdevyNVTAVYLVRDVSGELKVDDEESLELRFFSLDELPEN 127

ADP-ribose pyrophosphatase, UDP-glucose pyrophosphatase, and similar proteins; ADP-ribose pyrophosphatase (ADPRase) ( NUDIX (Nucleoside diphosphate-linked moiety X)) motif 5; Nudt5) catalyzes the hydrolysis of ADP-ribose and a variety of additional ADP-sugar conjugates to AMP and ribose-5-phosphate. In humans, there are four distinct ADPRase activities, three putative cytosolic enzymes (ADPRase-I, -II, and -Mn) and a single mitochondrial enzyme (ADPRase-m). Human ADPRase-II is also referred to as NUDT5. It lacks the N-terminal target sequence unique to mitochondrial ADPRase. The different cytosolic types are distinguished by their specificities for substrate and specific requirement for metal ions. NUDT5 forms a homodimer. It also contains a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V) which functions as a metal binding site/catalytic site. In addition to the NUDIX motif, there are additional conserved amino acid residues, distal from the signature sequence, that correlate with substrate specificity. UDP-glucose pyrophosphatase (UGPPase) (EC 3.6.1.45; also known as nucleoside diphosphate-linked moiety X)) motif 14; Nudt14) hydrolyzes the pyrophosphate of the nucleoside diphosphate sugar to generate glucose-1-P and UMP. In mammals, UDP-glucose is the glucosyl donor for the synthesis of the storage polysaccharide glycogen. UGPPase, as a regulator of UDP-glucose, could play a regulatory role, but it has been shown to prefer ADP-ribose over UDP-glucose. Like other members of the NUDIX hydrolase superfamily, it requires a divalent cation, such as Mg2+, for its activity. It also contains a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V) which functions as a metal binding site/catalytic site.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254 131 CIIVGIRNKDKILLAHHVRHkhsPLYTVL----AGFVEVGESLEDAVAREVFEESHIHIRNIRYVSSqpwPFPHSLMMG- 205
Cdd:cd03424    5 VAVLAITDDGKVVLVRQYRH---PVGRVLlelpAGKIDPGEDPEEAARRELEEETGYTAGDLELLGS---FYPSPGFSDe 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 490367254 206 ----FLAD--YAGGELRHDPSELISAAWYRYDELPQIppsdtIARRLIED--TIA 252
Cdd:cd03424   79 rihlFLAEdlTPVSEQALDEDEFIEVVLVPLEEALEM-----IEDGEITDakTLA 128

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254 128 IAPCIIvgIRNKDKILLAHHVRHKHSPLYTVLAGFVEVGESLEDAVAREVFEESHIHIRNIRYVSSQpWPFPHSLMMGFL 207
Cdd:cd04671    2 VVAAVI--INEQGEVLMIQEAKRSCRGKWYLPAGRVEPGESIVEAAKREVKEETGLKCEPSTLLSVE-EAGGSWYRFVFT 78

                         90       100
                 ....*....|....*....|....*
gi 490367254 208 ADYAGGELRHDP---SELISAAWYR 229
Cdd:cd04671   79 GNITGGKLKTPAdadSESLQAFWID 103

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254 136 IRNKDKILLahhVRHKH--SPLYTVLAGFVEVGESLEDAVAREVFEE--SHIHIRNIRYVS---SQPWPFpHSLMMGFLA 208
Cdd:cd18880    8 IIEDGKLLL---VKHRDegGIFYILPGGGQEHGETLPEALKRECLEEtgLDVEVGDLLFVReyiGPNKPV-HQVELFFLC 83

                         90       100       110
                 ....*....|....*....|....*....|..
gi 490367254 209 DYAGGELR--HDPSE-LISAAWYRYDELPQIP 237
Cdd:cd18880   84 TLEGGELTlgSDPDLnQVGVEWIPLEELDSIR 115

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 490367254 131 CIIVGIR-NKDKILLahhVRHKHSPLYTVLA---GFVEVGESLEDAVAREVFEESHIHIRNIR--YVSSQPW--PFPHSL 202
Cdd:cd18873    7 CVIFGFDdGELKVLL---IKRKNEPFKGGWAlpgGFVREDETLEDAARRELREETGLKDIYLEqlGTFGDPDrdPRGRVI 83

                         90       100       110
                 ....*....|....*....|....*....|...
gi 490367254 203 MMGFLADYAGGELRHDPSELIS-AAWYRYDELP 234
Cdd:cd18873   84 SVAYLALVPEEDLAPKAGDDAAeARWFPVDELL 116

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 490367254 136 IRNKDKILLahhV--RHKHSPLYTVLAGFVEVGESLEDAVAREVFEESHI-----HIRNIRYvsSQPWPFPHS-LMMGFL 207
Cdd:cd04670   10 INENNEVLV---VqeKYGGPGGWKLPGGLVDPGEDIGEAAVREVFEETGIdtefvSILGFRH--QHPGRFGKSdLYFVCR 84

                         90       100
                 ....*....|....*....|....*..
gi 490367254 208 AD-YAGGELRHDPSELISAAWYRYDEL 233
Cdd:cd04670   85 LRpLSDEEIKICPEEIAEAKWMPLEEY 111

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254 136 IRNKDKILLahhVRHKHSPlYTVLAGFVEVGESLEDAVAREVFEESHIHIRNIRYVSSQPWPF-PHSLmmgFLADYAGGE 214
Cdd:cd04667    7 CRRGDRILL---VARRGGR-WLLPGGKIEPGESPLEAAIRELKEETGLAALSLLYLFEHEGPHkLHHV---FLAEAPDGG 79

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 490367254 215 LRHDPSELISAAWYRYDELPQIPPSdTIARRLIED 249
Cdd:cd04667   80 RPRPGNEIARCRWVSADQLRDLNLS-RATRLIVRR 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 490367254 136 IRNKDKILLAHHvRHKHSPLY-----TVLAGFVEVGESLEDAVAREVFEESHIHIRNIRYVSSQPWPFPHSLMMG--FLA 208
Cdd:cd04697   33 VRNAAGRLLVQK-RTMDKDYCpgyldPATGGVVGAGESYEENARRELEEELGIDGVPLRPLFTFYYEDDRSRVWGalFEC 111

                         90       100
                 ....*....|....*....|....*
gi 490367254 209 DYAgGELRHDPSELISAAWYRYDEL 233
Cdd:cd04697  112 VYD-GPLKLQPEEVAEVDWMSEDEI 135

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254 160 AGFVEVGESLEDAVAREVFEESHIHIRNIRYVSSQPWPFPHS----LMMGFLADYaggeLRHDP-----SELISAAWYRY 230
Cdd:cd03675   30 AGHLEPGESLLEAAIRETLEETGWEVEPTALLGIYQWTAPDNgvtyLRFAFAGEL----LEHLPdqpldSGIIRAHWLTL 105

                 ...
gi 490367254 231 DEL 233
Cdd:cd03675  106 EEI 108

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254 132 IIVGIRNKDKILLahhVRHKHSPLYTVLAGFVEVGESLEDAVAREVFEESHIHIRNIRYV 191
Cdd:cd04665    3 VVVIARYKGKWLF---TRHKERRGWEFPGGKREPGETIEEAARRELYEETGAVIFELKPL 59

UDP-X diphosphatase; UDP-X diphosphatase hydrolyzes UDP-N-acetylmuramic acid and UDP-N-acetylmuramoyl-L-alanine, the last step of the Mur pathway of peptidoglycan biosynthesis. 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 490367254 136 IRNKDKILLahhVRHKHSPLYTVLAGFVEVGESLEDAVAREVFEES--HIHIRNIRYV----SSQPWPFP-HSLMMGFLA 208
Cdd:cd18891    9 IQNENKVLL---VQDKHTKEWALPGGFAEVGLSPKENILKEVKEETglHVEVERLLAVfdtdLRQDIPQSfQYYKFIFAC 85

                         90       100
                 ....*....|....*....|....*.
gi 490367254 209 DYAGGElRHDPSELISAAWYRYDELP 234
Cdd:cd18891   86 KILDGE-FQENSETSDLQYFSLDQLP 110

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 490367254 161 GFVEVGESLEDAVAREVFEESHIHIR--NIRYVSSQPWPFPHSLMMGFLA--------------DYAGGELRHDPSEL 222
Cdd:cd04674   36 GYIEYGETWQEAAVRELREETGVEADaaEVRLFAVRSAPDGTLLIFGLLPerpvadlppfaptdEATEWVVLTEPVEL 113

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 490367254 140 DKILLAHHVR-----HKHSP-LYTVLAGFVEVGESLEDAVAREVFEESHIHIRNIRYVSS 193
Cdd:cd24155   56 DEVVLIEQFRigalaRDESPwLLEIVAGMIDAGETPEDVARREAEEEAGLTLDALEPIAS 115

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 490367254 136 IRNKDKILLAHHVRHKHSPLYTVLAGFVEVGESLEDAVAREVFEESHIHIRNIRY--VSSQ--PWPFPHSLMMGFLADYA 211
Cdd:cd04679    9 ILDDGRLLLVLRLRAPEAGHWGLPGGKVDWLETVEDAVRREILEELGLEIELTRLlcVVDQidAADGEHWVAPVYLAEIF 88

                         90       100
                 ....*....|....*....|....*
gi 490367254 212 GGELR-HDPSELISAAWYRYDELPQ 235
Cdd:cd04679   89 SGEPRlMEPEKHGGIGWFALDALPQ 113

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 490367254 130 PCIIVGIRNKD-KILLAHHVRHKHS---PlytvlAGFVEVGESLEDAVAREVFEESHIHIRNIRYVSSQP-W---PFPHS 201
Cdd:cd03671    4 PNVGIVLFNRDgQVLVGRRIDVPGAwqfP-----QGGIDEGEDPEEAALRELYEETGLSPEDVEIIAETPdWltyDLPED 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 490367254 202 LMM-GFLADYAGGELR-----------------HDPSELISAAWYRYDELPQI 236
Cdd:cd03671   79 LIRkGWGGKYRGQKQKwflfrftgddseinldtHEHPEFDAWRWVDLEELPDL 131

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 490367254 136 IRNKDKILLahhVRHKHSPLYTVLAGFVEVGESLEDAVAREVFEEShihirNIRyVSSQPWPFP-HSLMMGFLADYAG-- 212
Cdd:cd04680    8 LDDAGRVLL---VRHTYVPGWYLPGGGVDKGETAEEAARRELREEA-----GVV-LTGPPRLFGvYFNRRVSPRDHVAly 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 490367254 213 -------GELRHDPSELISAAWYRYDELPQiPPSDTIARRLIE 248
Cdd:cd04680   79 rvrefeqTEPPEPNGEIAEAGFFALDALPE-DTTPATRRRLAE 120

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 490367254 136 IRNKDKILLAHHVRHKHSpLYTVLAGFVEVGESLEDAVAREVFEE 180
Cdd:cd18884   16 VEHDGHIVLARNKAWPEG-WYGLVTGFLEAGESPEEAVLREVKEE 59