coenzyme A pyrophosphatase and similar proteins; Coenzyme A pyrophosphatase (CoAse; EC 3.6.1.1), also called nucleoside diphosphate-linked moiety X)) motif 7, is a member of the NUDIX hydrolase superfamily, functions to catalyze the elimination of oxidized inactive CoA, which can inhibit CoA-utilizing enzymes. The need of CoAses mainly arises under conditions of oxidative stress. CoAse has a conserved NUDIX fold and requires a single divalent cation for catalysis. In addition to a signature NUDIX motif G[X5]E[X7]REUXEEXGU, where U is Ile, Leu, or Val, CoAse contains an additional motif upstream called the NuCoA motif (LLTXT(SA)X3RX3GX3FPGG) which is postulated to be involved in CoA recognition. CoA plays a central role in lipid metabolism. It is involved in the initial steps of fatty acid sythesis in the cytosol, in the oxidation of fatty acids and the citric acid cycle in the mitochondria, and in the oxidation of long-chain fatty acids in peroxisomes. CoA has the important role of activating fatty acids for further modification into key biological signalling molecules.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246742956 115 RFASVLMPLVNTSQGASLLLTQRSPNLRSHAGQMCFPGGRVEPSDGSHYYAALRETYEEIGFLPNFFTYLTTFPPLFTRD 194
Cdd:cd03426     1 RRAAVLIPLVEGDGELHVLLTKRASHLRSHPGQIAFPGGKREPGDESPVETALRETEEEIGLPPESVEVLGRLDPLYTPS 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1246742956 195 eKTEIRAYLAFSVQTSLPSLGTGEVKDLFYVPLTSFLNPKHQKISRFRNTDL---LYVEFNIDKIPRIWGITAVILN 268
Cdd:cd03426    81 -GFVVTPFVGLLDDPPPLRPNPDEVAEVFTVPLSFLLDPEPRRYETFLRSGPrgtYRVPFYPYEGYVIWGLTARILS 156

coenzyme A pyrophosphatase and similar proteins; Coenzyme A pyrophosphatase (CoAse; EC 3.6.1.1), also called nucleoside diphosphate-linked moiety X)) motif 7, is a member of the NUDIX hydrolase superfamily, functions to catalyze the elimination of oxidized inactive CoA, which can inhibit CoA-utilizing enzymes. The need of CoAses mainly arises under conditions of oxidative stress. CoAse has a conserved NUDIX fold and requires a single divalent cation for catalysis. In addition to a signature NUDIX motif G[X5]E[X7]REUXEEXGU, where U is Ile, Leu, or Val, CoAse contains an additional motif upstream called the NuCoA motif (LLTXT(SA)X3RX3GX3FPGG) which is postulated to be involved in CoA recognition. CoA plays a central role in lipid metabolism. It is involved in the initial steps of fatty acid sythesis in the cytosol, in the oxidation of fatty acids and the citric acid cycle in the mitochondria, and in the oxidation of long-chain fatty acids in peroxisomes. CoA has the important role of activating fatty acids for further modification into key biological signalling molecules.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246742956 115 RFASVLMPLVNTSQGASLLLTQRSPNLRSHAGQMCFPGGRVEPSDGSHYYAALRETYEEIGFLPNFFTYLTTFPPLFTRD 194
Cdd:cd03426     1 RRAAVLIPLVEGDGELHVLLTKRASHLRSHPGQIAFPGGKREPGDESPVETALRETEEEIGLPPESVEVLGRLDPLYTPS 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1246742956 195 eKTEIRAYLAFSVQTSLPSLGTGEVKDLFYVPLTSFLNPKHQKISRFRNTDL---LYVEFNIDKIPRIWGITAVILN 268
Cdd:cd03426    81 -GFVVTPFVGLLDDPPPLRPNPDEVAEVFTVPLSFLLDPEPRRYETFLRSGPrgtYRVPFYPYEGYVIWGLTARILS 156

NUDIX domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246742956 114 TRFASVLMPLVNTSQgaSLLLTQRSpnLRSHAGQMCFPGGRVEPSDgSHYYAALRETYEEIGFLPNFFTYLTTFPPLFTR 193
Cdd:pfam00293   1 KRRVAVGVVLLNEKG--RVLLVRRS--KKPFPGWWSLPGGKVEPGE-TPEEAARRELEEETGLEPELLELLGSLHYLAPF 75

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1246742956 194 DE----KTEIRAYLAFSVQTSLPSLGTGEVKDLFYVPLTSFLNPKHQKISR 240
Cdd:pfam00293  76 DGrfpdEHEILYVFLAEVEGELEPDPDGEVEEVRWVPLEELLLLKLAPGDR 126

coenzyme A pyrophosphatase and similar proteins; Coenzyme A pyrophosphatase (CoAse; EC 3.6.1.1), also called nucleoside diphosphate-linked moiety X)) motif 7, is a member of the NUDIX hydrolase superfamily, functions to catalyze the elimination of oxidized inactive CoA, which can inhibit CoA-utilizing enzymes. The need of CoAses mainly arises under conditions of oxidative stress. CoAse has a conserved NUDIX fold and requires a single divalent cation for catalysis. In addition to a signature NUDIX motif G[X5]E[X7]REUXEEXGU, where U is Ile, Leu, or Val, CoAse contains an additional motif upstream called the NuCoA motif (LLTXT(SA)X3RX3GX3FPGG) which is postulated to be involved in CoA recognition. CoA plays a central role in lipid metabolism. It is involved in the initial steps of fatty acid sythesis in the cytosol, in the oxidation of fatty acids and the citric acid cycle in the mitochondria, and in the oxidation of long-chain fatty acids in peroxisomes. CoA has the important role of activating fatty acids for further modification into key biological signalling molecules.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246742956 115 RFASVLMPLVNTSQGASLLLTQRSPNLRSHAGQMCFPGGRVEPSDGSHYYAALRETYEEIGFLPNFFTYLTTFPPLFTRD 194
Cdd:cd03426     1 RRAAVLIPLVEGDGELHVLLTKRASHLRSHPGQIAFPGGKREPGDESPVETALRETEEEIGLPPESVEVLGRLDPLYTPS 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1246742956 195 eKTEIRAYLAFSVQTSLPSLGTGEVKDLFYVPLTSFLNPKHQKISRFRNTDL---LYVEFNIDKIPRIWGITAVILN 268
Cdd:cd03426    81 -GFVVTPFVGLLDDPPPLRPNPDEVAEVFTVPLSFLLDPEPRRYETFLRSGPrgtYRVPFYPYEGYVIWGLTARILS 156

NUDIX domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246742956 114 TRFASVLMPLVNTSQgaSLLLTQRSpnLRSHAGQMCFPGGRVEPSDgSHYYAALRETYEEIGFLPNFFTYLTTFPPLFTR 193
Cdd:pfam00293   1 KRRVAVGVVLLNEKG--RVLLVRRS--KKPFPGWWSLPGGKVEPGE-TPEEAARRELEEETGLEPELLELLGSLHYLAPF 75

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1246742956 194 DE----KTEIRAYLAFSVQTSLPSLGTGEVKDLFYVPLTSFLNPKHQKISR 240
Cdd:pfam00293  76 DGrfpdEHEILYVFLAEVEGELEPDPDGEVEEVRWVPLEELLLLKLAPGDR 126

nudix hydrolase

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246742956 132 LLLTQRSPNLRSHAGQMCFPGGRVEPSDGSHYYAALRETYEEIGFLPNFFTYLTTFPPlFTRDEKTEIRAYLAFSVQTSL 211
Cdd:PLN02709   53 VILTKRSSTLSSHPGEVALPGGKRDEEDKDDIATALREAREEIGLDPSLVTIISVLEP-FVNKKGMSVAPVIGFLHDKKA 131

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1246742956 212 --PSLGTGEVKDLFYVPLTSFLNPKHQKISRFRNTD----LLYVEFNIDKIPR---IWGITAVIL 267
Cdd:PLN02709  132 fkPLPNPAEVEEIFDVPLEMFLKDKNKRAEEREHEGerylLQYFDYYSEDKERnfiIWALTAGIL 196

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 1246742956 132 LLLTQRSPnlRSHAGQMCFPGGRVEPsDGSHYYAALRETYEEIGFLPNFFTYLTTFPPLFTRDEKTEIRA-YLAFSVQTS 210
Cdd:cd02883    14 VLLVRRSD--GPGPGGWELPGGGVEP-GETPEEAAVREVREETGLDVEVLRLLGVYEFPDPDEGRHVVVLvFLARVVGGE 90

                          90
                  ....*....|....*.
gi 1246742956 211 LPSLGTGEVKDLFYVP 226
Cdd:cd02883    91 PPPLDDEEISEVRWVP 106

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 1246742956 150 FPGGRVEPsDGSHYYAALRETYEEIGFLPNFFTYLTTFPPL--FTrDEKteIRAYLAF-SVQTSLPSLGTGEVKDLFYVP 226
Cdd:cd03424    33 LPAGKIDP-GEDPEEAARRELEEETGYTAGDLELLGSFYPSpgFS-DER--IHLFLAEdLTPVSEQALDEDEFIEVVLVP 108

                  .
gi 1246742956 227 L 227
Cdd:cd03424   109 L 109

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
                  ....*....|....*....|....*....|....*....|....*
gi 1246742956 132 LLLTQRSPNlRSHAGQMCFPGGRVEPsdG-SHYYAALRETYEEIG 175
Cdd:cd03425    14 VLIAQRPEG-KHLAGLWEFPGGKVEP--GeTPEQALVRELREELG 55

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
                  ....*....|....*....|....*....|....*....|....*.
gi 1246742956 132 LLLTQRS--PNlrshAGQMCFPGGRVEPSDgSHYYAALRETYEEIG 175
Cdd:cd04673    14 VLLVRRGnpPD----AGLWSFPGGKVELGE-TLEDAALRELREETG 54

pyrimidine (deoxy)nucleoside triphosphate diphosphatase;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1246742956 132 LLLTQRSPNlRSHAGQMCFPGGRVEPSDgSHYYAALRETYEEIG 175
Cdd:PRK10546   17 ILLAQRPAH-SDQAGLWEFAGGKVEPGE-SQPQALIRELREELG 58

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
                  ....*....|....*....|....*.
gi 1246742956 150 FPGGRVEPSDGShYYAALRETYEEIG 175
Cdd:cd04665    26 FPGGKREPGETI-EEAARRELYEETG 50

diadenosine tetraphosphate; Diadenosine tetraphosphate (Ap4A; EC 3.6.1.17), also called NUDIX (nucleoside diphosphate-linked moiety X)) motif 2/Nudt2, is a member of the NUDIX hydrolase superfamily. Ap4A hydrolases are well represented in a variety of prokaryotic and eukaryotic organisms. Phylogenetic analysis reveals two distinct subgroups where plant enzymes fall into one subfamily and fungi/animals/archaea enzymes, represented by this subfamily, fall into another. Bacterial enzymes are found in both subfamilies. Ap4A is a potential by-product of aminoacyl tRNA synthesis, and accumulation of Ap4A has been implicated in a range of biological events, such as DNA replication, cellular differentiation, heat shock, metabolic stress, and apoptosis. Ap4A hydrolase cleaves Ap4A asymmetrically into ATP and AMP. It is important in the invasive properties of bacteria and thus presents a potential target for inhibition of such invasive bacteria. Besides the signature NUDIX motif (G[X5]E[X7]REUXEEXGU, where U is Ile, Leu, or Val) that functions as a metal binding and catalytic site, and a required divalent cation, Ap4A hydrolase is structurally similar to the other members of the NUDIX hydrolase superfamily with some degree of variation. Several regions in the sequences are poorly defined and substrate and metal binding sites are only predicted based on kinetic studies.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246742956 150 FPGGRVEPSDgSHYYAALRETYEEIG----FLPNFFTYLTTFPPLFTRDekTEIRAYLAFSVQTSLPSLgTGEVKDLFYV 225
Cdd:cd03428    32 FPKGHVEPGE-SELETALRETKEETGltvdDLPPGFRETLTYSFKEGVE--KTVVYFLAELTPDVEVKL-SEEHQDYKWL 107

                          90       100
                  ....*....|....*....|....*..
gi 1246742956 226 PltsfLNPKHQKISrFRNTDLLYVEFN 252
Cdd:cd03428   108 P----YEEALQLLT-YENIKELLKEAN 129