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 648445267  19 ICWVDEEDNLLGHLVRSDLRQRGLIGRCTFIFLFNSLGELCVHRRTLSKAMYPGFWDTAAGGMVAAGESYAASAARELEE 98
Cdd:cd04697    1 VDIVDENNEVVGAATRAEMRRQKLIHRATYIVVRNAAGRLLVQKRTMDKDYCPGYLDPATGGVVGAGESYEENARRELEE 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 648445267  99 ELGVAGVELVEHDHFYFADGDSRLWCRSYSAVWDGPLRLQPEEVMEARFLPLETVLQEAEQKPYCPDAQEGLRRYLD 175
Cdd:cd04697   81 ELGIDGVPLRPLFTFYYEDDRSRVWGALFECVYDGPLKLQPEEVAEVDWMSEDEILQAARGEEFTPDGRVALERYLA 157

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 648445267  19 ICWVDEEDNLLGHLVRSDLRQRGLIGRCTFIFLFNSLGELCVHRRTLSKAMYPGFWDTAAGGMVAAGESYAASAARELEE 98
Cdd:cd04697    1 VDIVDENNEVVGAATRAEMRRQKLIHRATYIVVRNAAGRLLVQKRTMDKDYCPGYLDPATGGVVGAGESYEENARRELEE 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 648445267  99 ELGVAGVELVEHDHFYFADGDSRLWCRSYSAVWDGPLRLQPEEVMEARFLPLETVLQEAEQKPYCPDAQEGLRRYLD 175
Cdd:cd04697   81 ELGIDGVPLRPLFTFYYEDDRSRVWGALFECVYDGPLKLQPEEVAEVDWMSEDEILQAARGEEFTPDGRVALERYLA 157

NUDIX hydrolase YfcD; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 648445267  11 RAASDAELICWVDEEDNLLGHLVRSDLRQRGLIGRCTFIFLFNSLGELCVHRRTLSKAMYPGFWDTAAGGMVAAGESYAA 90
Cdd:PRK15393   4 RRLASTEWVDIVNENNEVIAQASREQMRAQCLRHRATYIVVHDGMGKILVQRRTETKDFLPGMLDATAGGVVQAGEQLLE 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 648445267  91 SAARELEEELGVAGVELVEHDHFYFADGDSRLWCRSYSAVWDGPLRLQPEEVMEARFLPLETVLQEAEQkpYCPDAQEGL 170
Cdd:PRK15393  84 SARREAEEELGIAGVPFAEHGQFYFEDENCRVWGALFSCVSHGPFALQEEEVSEVCWMTPEEITARCDE--FTPDSLKAL 161

                 ....
gi 648445267 171 RRYL 174
Cdd:PRK15393 162 ALWL 165

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 648445267  19 ICWVDEEDNLLGHLVRSDLRQRGLIGRCTFIFLFNSLGELCVHRRTLSKAMYPGFWDTAAGGMVAAGESYAASAARELEE 98
Cdd:cd04697    1 VDIVDENNEVVGAATRAEMRRQKLIHRATYIVVRNAAGRLLVQKRTMDKDYCPGYLDPATGGVVGAGESYEENARRELEE 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 648445267  99 ELGVAGVELVEHDHFYFADGDSRLWCRSYSAVWDGPLRLQPEEVMEARFLPLETVLQEAEQKPYCPDAQEGLRRYLD 175
Cdd:cd04697   81 ELGIDGVPLRPLFTFYYEDDRSRVWGALFECVYDGPLKLQPEEVAEVDWMSEDEILQAARGEEFTPDGRVALERYLA 157

NUDIX hydrolase YfcD; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 648445267  11 RAASDAELICWVDEEDNLLGHLVRSDLRQRGLIGRCTFIFLFNSLGELCVHRRTLSKAMYPGFWDTAAGGMVAAGESYAA 90
Cdd:PRK15393   4 RRLASTEWVDIVNENNEVIAQASREQMRAQCLRHRATYIVVHDGMGKILVQRRTETKDFLPGMLDATAGGVVQAGEQLLE 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 648445267  91 SAARELEEELGVAGVELVEHDHFYFADGDSRLWCRSYSAVWDGPLRLQPEEVMEARFLPLETVLQEAEQkpYCPDAQEGL 170
Cdd:PRK15393  84 SARREAEEELGIAGVPFAEHGQFYFEDENCRVWGALFSCVSHGPFALQEEEVSEVCWMTPEEITARCDE--FTPDSLKAL 161

                 ....
gi 648445267 171 RRYL 174
Cdd:PRK15393 162 ALWL 165

Isopentenyl diphosphate isomerase; Isopentenyl diphosphate (IPP) isomerase, a member of the NUDIX hydrolase superfamily, is a key enzyme in the isoprenoid biosynthetic pathway. Isoprenoids comprise a large family of natural products including sterols, carotenoids, dolichols and prenylated proteins. These compounds are synthesized from two precursors: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). IPP isomerase catalyzes the interconversion of IPP and DMAPP by a stereoselective antarafacial transposition of hydrogen. The enzyme requires one Mn2+ or Mg2+ ion in its active site to fold into an active conformation and also contains 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. The metal binding site is present within the active site and plays structural and catalytical roles. IPP isomerase is well represented in several bacteria, archaebacteria and eukaryotes, including fungi, mammals and plants. Despite sequence variations (mainly at the N-terminus), the core structure is highly conserved.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 648445267  22 VDEEDNLLGHLVRSDLRQRGLIGRCTF-IFLFNSLGELCVHRRTLSKAMYPGFWDTAAGGMVAAGESYAASAARELEEEL 100
Cdd:cd02885    5 VDEDDNPIGTAEKLEAHRKGTLLHRAFsVFLFNSKGELLLQRRALSKYTWPGLWTNTCCSHPLPGEGVEDAAQRRLREEL 84

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 648445267 101 GVAGVELVEHDHF-YFADGDSRL----WCRSYSAVWDGPLRLQPEEVMEARFLPLETVLQEAEQKPY 162
Cdd:cd02885   85 GIPVCDLEELPRFrYRATDDNGLveheIDHVFVGRADGDPVPNPEEVSDYRWVSLEELRELLAATPE 151

isopentenyl-diphosphate Delta-isomerase;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 648445267  50 FLFNSLGELCVHRRTLSKAMYPGFWDTAAGGMVAAGESYAASAARELEEELGVAGVEL-VEHDHF-YFADGDSRL----W 123
Cdd:PRK03759  40 YLFDADGRLLVTRRALSKKTWPGVWTNSCCGHPQPGESLEDAVIRRCREELGVEITDLeLVLPDFrYRATDPNGIveneV 119

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 648445267 124 CRSYSAVWDGPLRLQPEEVMEARFLPLETVLQEAEQKPY 162
Cdd:PRK03759 120 CPVFAARVTSALQPNPDEVMDYQWVDPADLLRAVDATPW 158

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 648445267  45 RCTFIFLFNSLGELCVHRRtlSKAMYPGFWDTAaGGMVAAGESYAASAARELEEELGVAGVELVEHDHFYFADGDSRLWC 124
Cdd:cd02883    1 VAVGAVVFDDEGRVLLVRR--SDGPGPGGWELP-GGGVEPGETPEEAAVREVREETGLDVEVLRLLGVYEFPDPDEGRHV 77

                         90       100
                 ....*....|....*....|....*....
gi 648445267 125 RS--YSAVWDG--PLRLQPEEVMEARFLP 149
Cdd:cd02883   78 VVlvFLARVVGgePPPLDDEEISEVRWVP 106

NUDIX domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 648445267   49 IFLFNSLGELCVHRRtlSKAMYPGFWDTAaGGMVAAGESYAASAARELEEELGV--AGVELVEHDHFYFA----DGDSRL 122
Cdd:pfam00293   8 VVLLNEKGRVLLVRR--SKKPFPGWWSLP-GGKVEPGETPEEAARRELEEETGLepELLELLGSLHYLAPfdgrFPDEHE 84

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 648445267  123 WCRSYSAVWDGPLRLQP-EEVMEARFLPLEtvlqEAEQKPYCPDAQEGLRRY 173
Cdd:pfam00293  85 ILYVFLAEVEGELEPDPdGEVEEVRWVPLE----ELLLLKLAPGDRKLLPWL 132

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 648445267  45 RCTFIFLFNSLGELCVHR--RTLSKAMYPGFwdtaaGGMVAAGESYAASAARELEEELG--VAGVELVEHDHFYFADGDS 120
Cdd:cd03427    2 LTTLVFVLRGDDRVLLGLkkRGFGAGKWNGF-----GGKVEPGETIEEAAVRELEEEAGltATELEKVGRLKFEFPDDPE 76

                         90       100
                 ....*....|....*....|....*..
gi 648445267 121 RLWCRSYSAV-WDGplrlQPEEVMEAR 146
Cdd:cd03427   77 AMDVHVFRADsWTG----EPQETEEMR 99

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 648445267  79 GGMVAAGESYAASAARELEEELGVAGVELVEHDHFYFADGDSRLWCRSYSA---VWDGPLRLQPEEVMEARFLPLETVLQ 155
Cdd:cd03424   35 AGKIDPGEDPEEAARRELEEETGYTAGDLELLGSFYPSPGFSDERIHLFLAedlTPVSEQALDEDEFIEVVLVPLEEALE 114

                 ....*
gi 648445267 156 EAEQK 160
Cdd:cd03424  115 MIEDG 119

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 648445267  65 LSKAMYPGFWDTAaGGMVAAGESYAASAARELEEELGVAGV--ELVEHDHFYFADGdsrlWCRSYSAVWDGP-------- 134
Cdd:cd18876   16 LVKPTYKDGWELP-GGVVEAGESPLQAARREVREELGLDVPvgRLLAVDWVPPAGG----GDDAVLFVFDGGvltpeqaa 90

                         90       100
                 ....*....|....*....|..
gi 648445267 135 -LRLQPEEVMEARFLPLETVLQ 155
Cdd:cd18876   91 aIRLQDEELSAYRFVTPEEAAE 112

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 648445267  45 RCTFIFLFNSLGELCVHRRtlskAMYPGFWDTAAGGMVAaGESYAASAARELEEELGVAG--VELV-EHDHFYFADGDSR 121
Cdd:cd03671    4 PNVGIVLFNRDGQVLVGRR----IDVPGAWQFPQGGIDE-GEDPEEAALRELYEETGLSPedVEIIaETPDWLTYDLPED 78

                         90
                 ....*....|..
gi 648445267 122 LWCRSYSAVWDG 133
Cdd:cd03671   79 LIRKGWGGKYRG 90

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 648445267  79 GGMVAAGESYAASAARELEEELGVAgVELVE-------HDHF------YFAdgdSRLWCRSYSAvwdgpLRLQPEEVMEA 145
Cdd:cd04670   33 GGLVDPGEDIGEAAVREVFEETGID-TEFVSilgfrhqHPGRfgksdlYFV---CRLRPLSDEE-----IKICPEEIAEA 103

                 ....*.
gi 648445267 146 RFLPLE 151
Cdd:cd04670  104 KWMPLE 109

Nudix family hydrolase;

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 648445267  51 LFNSLGELCVHRRTLSKAMyPGFWDTAaGGMVAAGESYAASAARELEEELGV 102
Cdd:PRK08999  12 IRDADGRILLARRPEGKHQ-GGLWEFP-GGKVEPGETVEQALARELQEELGI 61

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 648445267  72 GFWdTAAGGMVAAGESYAASAARELEEELG----VAGVELVEhdhFYFADGDSRLWCrsysAVW-----DGPLRLQPEEV 142
Cdd:cd04691   26 GRW-TLPGGFVEEGETLDEAIVREVLEETGidakPVGIIGVR---SGVIRDGKSDNY----VVFlleyvGGEPKPDEREN 97

                         90
                 ....*....|...
gi 648445267 143 MEARFLPLETVLQ 155
Cdd:cd04691   98 SEAGFLTLEEALA 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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 648445267  70 YPGFWDTAAGGMvAAGESYAASAARELEEELGVAgvelvehdhfyfADGDSRLWCRSYSAVWDGPL-------RLQPEEV 142
Cdd:cd04682   26 FPNLWDLPGGGR-EGDETPFACVLRELREELGLA------------LPEDRLVWERVYPSNHNPGRqswffvaRLPADEV 92

                 ....*
gi 648445267 143 MEARF 147
Cdd:cd04682   93 DAIRF 97

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 648445267  84 AGESYAASAARELEEELGVAGV---ELVEHDHFYFADGDSRL-WCRSYSA-VWDGPLRLQP-EEVMEARFLPLE 151
Cdd:cd03673   38 PGETPEEAAVREVEEETGLRVRlgrPLGTTRYTYTRKGKGILkKVHYWLMrALGGEFLPQPeEEIDEVRWLPPD 111

dihydroneopterin hydrolase; DHNTP pyrophosphatase (DHNTPase) catalyzes the hydrolysis of dihydroneopterin triphosphate (DHNTP) to dihydroneopterin monophosphate (DHNMP) and pyrophosphate,the second step in the pterin branch of the folate synthesis pathway in bacteria. Members of the NUDIX hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of NUDIX hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance _ "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 648445267  48 FIFLFNSLGELCVHRRTLSkamyPGFWDTAAGGmVAAGESYAASAARELEEELGVAGVEL----VEHDHFYFADGDSRLW 123
Cdd:cd04664    6 VIYRKDEEGEVLLLKRTDD----GGFWQSVTGG-IEDGETPWQAALRELKEETGLDPLELqlidLNVSNFYEIFDDWRPG 80

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 648445267 124 CRSYSAVW-------DGPLRLQPEEVmEARFLPLETVLQ 155
Cdd:cd04664   81 VTVNTEHVfavevpeEQPIRLSPEHT-DYRWLPYEEAAE 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
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 648445267  49 IFLFNSLGELCVHRRT-LSKAMYPGFWDTAaGGMVAAGESYAASAARELEEELGV 102
Cdd:cd18882    6 AILYDDRGKVLLQLRDdKPGIPYPGYWGLF-GGHLEPGETPEEAIRRELEEEIGY 59

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 648445267  79 GGMVAAGESYAASAARELEEELGVAG--------VELVEHD-------HFYFADgdsrLWCRSYSavwdGPLRLqPEEVM 143
Cdd:cd04673   32 GGKVELGETLEDAALRELREETGLEAevvglltvVDVIERDeagrvrfHYVILD----FLAEWVS----GEPVA-GDDAL 102

                         90
                 ....*....|....
gi 648445267 144 EARFLPLETVLQEA 157
Cdd:cd04673  103 DARWFSLEELDGLP 116

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 648445267  72 GFWDTAaGGMVAAGESYAASAARELEEELGV-----------------AGVELVEHDHFYFADGDSrlwcrsysavwDGP 134
Cdd:cd04681   31 GKLDLP-GGFVDPGESAEEALRRELREELGLkipklrylcslpntylyKGITYKTCDLFFTAELDE-----------KPK 98

                         90
                 ....*....|....*....
gi 648445267 135 LRLQPEEVMEARFLPLETV 153
Cdd:cd04681   99 LKKAEDEVAELEWLDLEEI 117