putative NUDIX hydrolase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 589269146  66 VLVPLLARGgKLYLMFTVRSDKLKREPGEVCFPGGKRDPVDTDDTATALREAQEEVGLHPHQVEVVSHLVPYVFDNDALV 145
Cdd:PRK10707  34 VLIPIVRRP-QPTLLLTQRSIHLRKHAGQVAFPGGAVDPTDASLIATALREAQEEVAIPPSAVEVIGVLPPVDSSTGYQV 112

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 589269146 146 TPVVGFLDHNFQAQPNADEVKEVFFVPLDYFLHPQVYYQKQITQSGRDFIMHCFEYKDpetgvnYLIQGMT 216
Cdd:PRK10707 113 TPVVGIIPPDLPYRANEDEVAAVFEMPLAEALHLGRYHPLDIYRRGQSHRVWLSWYEQ------YFVWGMT 177

NUDIX domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 589269146   65 SVLVPLLARGGKLYLmftVRSdKLKREPGEVCFPGGKrdpVDTDDT--ATALREAQEEVGLHPHQVEVVSHL-----VPY 137
Cdd:pfam00293   5 AVGVVLLNEKGRVLL---VRR-SKKPFPGWWSLPGGK---VEPGETpeEAARRELEEETGLEPELLELLGSLhylapFDG 77

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 589269146  138 VFDNDALVTPVVGFLDHNFQAQPNADEVKEVFFVPLD 174
Cdd:pfam00293  78 RFPDEHEILYVFLAEVEGELEPDPDGEVEEVRWVPLE 114

putative NUDIX hydrolase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 589269146  66 VLVPLLARGgKLYLMFTVRSDKLKREPGEVCFPGGKRDPVDTDDTATALREAQEEVGLHPHQVEVVSHLVPYVFDNDALV 145
Cdd:PRK10707  34 VLIPIVRRP-QPTLLLTQRSIHLRKHAGQVAFPGGAVDPTDASLIATALREAQEEVAIPPSAVEVIGVLPPVDSSTGYQV 112

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 589269146 146 TPVVGFLDHNFQAQPNADEVKEVFFVPLDYFLHPQVYYQKQITQSGRDFIMHCFEYKDpetgvnYLIQGMT 216
Cdd:PRK10707 113 TPVVGIIPPDLPYRANEDEVAAVFEMPLAEALHLGRYHPLDIYRRGQSHRVWLSWYEQ------YFVWGMT 177

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 589269146  65 SVLVPLLARGGKLYLmftVRSDKLKREPGEVCFPGGKRDPVDTDdTATALREAQEEVGLHPHQVEVVSHLVPYVFDnDAL 144
Cdd:COG0494   15 AVVVVLLDDDGRVLL---VRRYRYGVGPGLWEFPGGKIEPGESP-EEAALRELREETGLTAEDLELLGELPSPGYT-DEK 89

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 589269146 145 VTPVVG-FLDHNFQAQPNA-DEVKEVFFVPLDYFL 177
Cdd:COG0494   90 VHVFLArGLGPGEEVGLDDeDEFIEVRWVPLDEAL 124

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 589269146  91 EPGEVCFPGGKRDPvDTDDTATALREAQEEVGLHphqVEVVSHLVPYVFDNDALVTPVVGF-----LDHNFQAQPNADEV 165
Cdd:cd02883   24 GPGGWELPGGGVEP-GETPEEAAVREVREETGLD---VEVLRLLGVYEFPDPDEGRHVVVLvflarVVGGEPPPLDDEEI 99

                 ....*..
gi 589269146 166 KEVFFVP 172
Cdd:cd02883  100 SEVRWVP 106

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 589269146  92 PGEVCFPGGKRDpvdTDDTA--TALREAQEEVGLHPHQVEVVShlvpyVFDNDALV---TPVVGFLDHNFQAQPNADEVK 166
Cdd:cd18877   46 GGTWALPGGARD---SGETPeaAALRETEEETGLDADTLRVVG-----THVDDHGGwsyTTVLASAPEPLPVRPANEESV 117

                         90
                 ....*....|....*..
gi 589269146 167 EVFFVPLD----YFLHP 179
Cdd:cd18877  118 ELRWVPLDevesLPLHP 134

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 589269146  98 PGGKRDPvDTDDTATALREAQEEVGLHphqVEVVSHLVPYVFDNDALVTPVVGF------LDHNF-------QAQPNADE 164
Cdd:cd03674   30 PGGHVEP-DEDPLEAALREAREETGLD---VELLSPLSPDPLDIDVHPIPANPGepahlhLDVRYlavadgdEALRKSDE 105

                         90
                 ....*....|....*..
gi 589269146 165 VKEVFFVPLDYFLHPQV 181
Cdd:cd03674  106 SSDVRWFPLDELEELSM 122

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 589269146  98 PGGKRDPVDTDDTAtALREAQEEVGLHPHQVEVVSHLVpYVFDNDALVTPVVGFLDHNFQAQPNA-DEVKEVFF----VP 172
Cdd:cd03427   32 FGGKVEPGETIEEA-AVRELEEEAGLTATELEKVGRLK-FEFPDDPEAMDVHVFRADSWTGEPQEtEEMRPQWFdlddIP 109

                 ..
gi 589269146 173 LD 174
Cdd:cd03427  110 YD 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 589269146  97 FPGGKRDPVDTDdTATALREAQEEVGLH-PHQVEVVSHLVPyVFDNDALVTpvvgfldHNFQAQPNADEVKEVFF----- 170
Cdd:cd04682   32 LPGGGREGDETP-FACVLRELREELGLAlPEDRLVWERVYP-SNHNPGRQS-------WFFVARLPADEVDAIRFgdegq 102

                         90
                 ....*....|....*.
gi 589269146 171 ----VPLDYFL-HPQV 181
Cdd:cd04682  103 ewalMPVDDFLaHPDA 118

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
                 ....*....|....*....|....*....|....*....
gi 589269146  97 FP-GGkrdpVDTDDT--ATALREAQEEVGLHPHQVEVVS 132
Cdd:cd03671   31 FPqGG----IDEGEDpeEAALRELYEETGLSPEDVEIIA 65

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 589269146  81 FTVRSDKLK-------REPGEVC--FPGGkrdPVDTDDT--ATALREAQEEVGLHPHQVEVVshlvpYVFDN---DALvT 146
Cdd:cd18873   10 FGFDDGELKvllikrkNEPFKGGwaLPGG---FVREDETleDAARRELREETGLKDIYLEQL-----GTFGDpdrDPR-G 80

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 589269146 147 PVV-----GFLDHNFQAQPNADEVKEVFFVPLDYFLHP 179
Cdd:cd18873   81 RVIsvaylALVPEEDLAPKAGDDAAEARWFPVDELLPP 118