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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742394769  45 YDRGDGAVILLFNRQAQTVILTRQFRFPVFVNGHDGMLIEAAAGLLDNASPEARIRAEAEEETGYFVQNVEKVFEAYMSP 124
Cdd:cd24157    1 YDRGDAAAVLLYDPKRKTVVLVRQFRAPAYLGGGDGWLIEACAGLLDGDDPEDCIRREAEEETGYRLGDLEKVFTAYSSP 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 742394769 125 GSVTEKLHFFVGEYQAGDRINEGGGVAAEGEDLEVLELPLAQALQAIRQGTIVDAKTIMLLQFVAL 190
Cdd:cd24157   81 GIVTERIHLFIAEYSSADRVGAGGGLAEEGEDIEVLELPLDEALAMIETGEIRDAKTIILLQYLRL 146

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742394769  45 YDRGDGAVILLFNRQAQTVILTRQFRFPVFVNGHDGMLIEAAAGLLDNASPEARIRAEAEEETGYFVQNVEKVFEAYMSP 124
Cdd:cd24157    1 YDRGDAAAVLLYDPKRKTVVLVRQFRAPAYLGGGDGWLIEACAGLLDGDDPEDCIRREAEEETGYRLGDLEKVFTAYSSP 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 742394769 125 GSVTEKLHFFVGEYQAGDRINEGGGVAAEGEDLEVLELPLAQALQAIRQGTIVDAKTIMLLQFVAL 190
Cdd:cd24157   81 GIVTERIHLFIAEYSSADRVGAGGGLAEEGEDIEVLELPLDEALAMIETGEIRDAKTIILLQYLRL 146

nudix-type nucleoside diphosphatase, YffH/AdpP family; Members of this family include proteins of about 200 amino acids, including the recently characterized nudix hydrolase YffH, shows to be highly active as a GDP-mannose pyrophosphatase. It also includes the C-terminal half of a 361-amino acid protein, TrgB from Rhodobacter sphaeroides, shown experimentally to help confer tellurite resistance. This model also hits a region near the C-terminus of a 1092-amino acid protein of C. elegans. [Unknown function, Enzymes of unknown specificity]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742394769    6 DRVRIVETRVLSDDWYLLKKTTFDFLRRDGVWQRQSRETYDRGDGAVILLFNRQAQTVILTRQFRFPVFVNG-HDGMLIE 84
Cdd:TIGR00052   2 QQEIIIKDTLYSGFFSLLHNIFYHRLFKGGESIRVTREIYDRGNAAAVLLYDPKKDTVVLIEQFRIAAYVNGeEPWLLEL 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742394769   85 AAAGLLDNASPEARIRAEAEEETGYFVQNVEKVFEAYMSPGSVTEKLHFFVGEYQAGDRINEGGGvaAEGEDLEVLELPL 164
Cdd:TIGR00052  82 SAGMVEKGESPEDVARREAIEEAGYQVKNLRKLLSFYMSPGGVTELIHLFIAEVDDNQAAGIGGG--ADEEEIEVLHLVF 159

                         170       180
                  ....*....|....*....|....*.
gi 742394769  165 AQALQAIRQGTIVDAKTIMLLQFVAL 190
Cdd:TIGR00052 160 SQALQWIKEGKIDNGKTVILLQWLQL 185

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742394769  45 YDRGDGAVILLFNRQAQTVILTRQFRFPVFVNGHDGMLIEAAAGLLDNASPEARIRAEAEEETGYFVQNVEKVFEAYMSP 124
Cdd:cd24157    1 YDRGDAAAVLLYDPKRKTVVLVRQFRAPAYLGGGDGWLIEACAGLLDGDDPEDCIRREAEEETGYRLGDLEKVFTAYSSP 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 742394769 125 GSVTEKLHFFVGEYQAGDRINEGGGVAAEGEDLEVLELPLAQALQAIRQGTIVDAKTIMLLQFVAL 190
Cdd:cd24157   81 GIVTERIHLFIAEYSSADRVGAGGGLAEEGEDIEVLELPLDEALAMIETGEIRDAKTIILLQYLRL 146

nudix-type nucleoside diphosphatase, YffH/AdpP family; Members of this family include proteins of about 200 amino acids, including the recently characterized nudix hydrolase YffH, shows to be highly active as a GDP-mannose pyrophosphatase. It also includes the C-terminal half of a 361-amino acid protein, TrgB from Rhodobacter sphaeroides, shown experimentally to help confer tellurite resistance. This model also hits a region near the C-terminus of a 1092-amino acid protein of C. elegans. [Unknown function, Enzymes of unknown specificity]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742394769    6 DRVRIVETRVLSDDWYLLKKTTFDFLRRDGVWQRQSRETYDRGDGAVILLFNRQAQTVILTRQFRFPVFVNG-HDGMLIE 84
Cdd:TIGR00052   2 QQEIIIKDTLYSGFFSLLHNIFYHRLFKGGESIRVTREIYDRGNAAAVLLYDPKKDTVVLIEQFRIAAYVNGeEPWLLEL 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742394769   85 AAAGLLDNASPEARIRAEAEEETGYFVQNVEKVFEAYMSPGSVTEKLHFFVGEYQAGDRINEGGGvaAEGEDLEVLELPL 164
Cdd:TIGR00052  82 SAGMVEKGESPEDVARREAIEEAGYQVKNLRKLLSFYMSPGGVTELIHLFIAEVDDNQAAGIGGG--ADEEEIEVLHLVF 159

                         170       180
                  ....*....|....*....|....*.
gi 742394769  165 AQALQAIRQGTIVDAKTIMLLQFVAL 190
Cdd:TIGR00052 160 SQALQWIKEGKIDNGKTVILLQWLQL 185

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 742394769  47 RGDGAVILLFNRQaQTVILTRQFRFPVfvnghDGMLIEAAAGLLD-NASPEARIRAEAEEETGYFVQNVEKVFEAYMSPG 125
Cdd:cd03424    1 HPGAVAVLAITDD-GKVVLVRQYRHPV-----GRVLLELPAGKIDpGEDPEEAARRELEEETGYTAGDLELLGSFYPSPG 74

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 742394769 126 SVTEKLHFFVGEyqagDRINEGGGVAAEGEDLEVLELPLAQALQAIRQGTIVDAKTIMLLQF 187
Cdd:cd03424   75 FSDERIHLFLAE----DLTPVSEQALDEDEFIEVVLVPLEEALEMIEDGEITDAKTLAALLL 132

ADP-ribose pyrophosphatase NudF; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742394769   4 TKDRVRIVETRVLSDDWYLLKKTTFDFLRRDGVWQRQ-SRETYDRGDGAVILLFNRQAQTVILTRQFRFPVFVNGHDGML 82
Cdd:PRK10729   4 TKNDVEIIARETLYRGFFSLDLYRFRHRLFNGEMSGEvRREIFERGHAAVLLPFDPVRDEVVLIEQIRIAAYDTSETPWL 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742394769  83 IEAAAGLLDNA-SPEARIRAEAEEETGYFVQNVEKVFEAYMSPGSVTEKLHFFVGEYQAgdRINEG-GGVAAEGEDLEVL 160
Cdd:PRK10729  84 LEMVAGMIEEGeSVEDVARREAIEEAGLIVGRTKPVLSYLASPGGTSERSSIMVGEVDA--TTASGiHGLADENEDIRVH 161

                        170       180       190
                 ....*....|....*....|....*....|.
gi 742394769 161 ELPLAQALQAIRQGTIVDAKTIMLLQFVALN 191
Cdd:PRK10729 162 VVSREQAYQWVEEGKIDNAASVIALQWLQLH 192

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742394769  46 DRGDGAVILLFNRQaQTVILTRQFRFPVfvnghDGMLIEAAAGLLDN-ASPEARIRAEAEEETGYFVQNVEKVFEAYMSP 124
Cdd:cd24161    1 EKNDAVGVLPITDD-GEVVLVEQYRYPL-----GGWSWEIPAGGWPEgEDPEEAARRELREETGLRAERWTPLGRFYPSN 74

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 742394769 125 GSVTEKLHFFVgeyqAGDrINEGGGVAAEGE-DLEVLELPLAQALQAIRQGTIVDAKTIMLLQFVAL 190
Cdd:cd24161   75 GVSDERAHVFL----ATG-LTPGEPAPEETEeDLEVRRVPLAEALAMVLDGEITDAMSVAALLLARL 136

ADP-ribose pyrophosphatase; ADP-ribose pyrophosphatase (ADPRase) (also known as 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742394769  63 VILTRQFRFPVfvnghDGMLIEAAAGLLD-NASPE-ARIRaEAEEETGYFVQNVEKVFEA-YMSPGSVTEKLHFFVGEYQ 139
Cdd:cd18888   20 LVLVKQYRPPV-----NAYTIEFPAGLVDpGESPEqAALR-ELKEETGYTGEKVLSVSPPlALDPGLSNANMKLVTVEVD 93

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 742394769 140 AGDRINEGGgVAA--EGEDLEVLELPLAQALQAIRQ-----GTIVDAK 180
Cdd:cd18888   94 GDDPENQNP-KQEleDGEFIEVILVPLNELLERLQElakeeGYAIDAR 140

Adp-ribose pyrophosphatase (ADPRase) found in Thermus thermophilus, and similar proteins; ADP-ribose pyrophosphatase (ADPRase) such as found in extreme thermophile Thermus thermophilus (TtADPRase) catalyzes the hydrolysis of ADPR to AMP and ribose 5'-phosphate in the presence of Mg2+ and Zn2+ ions. 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 742394769  51 AVILLfnrQAQTVILTRQFRFPVfvnghDGMLIEAAAGLLDNA-SPEARIRAEAEEETGyFVQNVEKVFEAYMSPGSVTE 129
Cdd:cd24160   25 AVLAL---REGRMLFVRQMRPAV-----GAATLEIPAGLIDPGeTPEEAARRELAEETG-LSGDLTYLTRFYVSPGFCDE 95

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 742394769 130 KLHFFVGEyqagdRINEGGGVAAEGEDLEVLELPLAQALQAIRQGTI 176
Cdd:cd24160   96 KLHVFLAE-----NLREVEAHPDEDEAIEVVWMRPEEVLERLRRGEV 137