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 1191800980  25 YRQNGTQKSWDFVKTHDSVTLLMFNASRRSLVLVKQFRPAVYAGAVERLFPGSLVaaDQDRPrelpaalPGSAGVTFELC 104
Cdd:cd18887     1 YKQNGKKKTWDFVKSHDSVAILLYNKTRDAFVLVKQFRPAVYASQVRAAERNGGK--DTEKY-------PPELGYTYELC 71

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1191800980 105 AGLVDQPgLSLEEVACKEAWEECGYRLAPSDLRRVASY 142
Cdd:cd18887    72 AGLVDKD-KSLEEIAQEEILEECGYDVPLEDLEKITSF 108

UDP-glucose pyrophosphatase; UDP-glucose pyrophosphatase (UGPPase) (EC 3.6.1.45; also known as NUDIX (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 1191800980  25 YRQNGTQKSWDFVKTHDSVTLLMFNASRRSLVLVKQFRPAVYAGAVERLFPGSLVaaDQDRPrelpaalPGSAGVTFELC 104
Cdd:cd18887     1 YKQNGKKKTWDFVKSHDSVAILLYNKTRDAFVLVKQFRPAVYASQVRAAERNGGK--DTEKY-------PPELGYTYELC 71

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1191800980 105 AGLVDQPgLSLEEVACKEAWEECGYRLAPSDLRRVASY 142
Cdd:cd18887    72 AGLVDKD-KSLEEIAQEEILEECGYDVPLEDLEKITSF 108

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1191800980  41 DSVTLLMFNASRRsLVLVKQFRPAVYAGAVErlFPGslvaadqdrprelpaalpgsagvtfelcaGLVDqPGLSLEEVAC 120
Cdd:COG0494    14 PAVVVVLLDDDGR-VLLVRRYRYGVGPGLWE--FPG-----------------------------GKIE-PGESPEEAAL 60

                          90       100
                  ....*....|....*....|....*...
gi 1191800980 121 KEAWEECGYRlaPSDLRRVASYKAPGPC 148
Cdd:COG0494    61 RELREETGLT--AEDLELLGELPSPGYT 86

UDP-glucose pyrophosphatase; UDP-glucose pyrophosphatase (UGPPase) (EC 3.6.1.45; also known as NUDIX (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 1191800980  25 YRQNGTQKSWDFVKTHDSVTLLMFNASRRSLVLVKQFRPAVYAGAVERLFPGSLVaaDQDRPrelpaalPGSAGVTFELC 104
Cdd:cd18887     1 YKQNGKKKTWDFVKSHDSVAILLYNKTRDAFVLVKQFRPAVYASQVRAAERNGGK--DTEKY-------PPELGYTYELC 71

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1191800980 105 AGLVDQPgLSLEEVACKEAWEECGYRLAPSDLRRVASY 142
Cdd:cd18887    72 AGLVDKD-KSLEEIAQEEILEECGYDVPLEDLEKITSF 108

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 1191800980  41 DSVTLLMFNASRRSLVLVKQFRPAVYAGaverlfpgslvaadqdrprelpaalpGSAGVTFELCAGLVDqpGLSLEEVAC 120
Cdd:cd24157     5 DAAAVLLYDPKRKTVVLVRQFRAPAYLG--------------------------GGDGWLIEACAGLLD--GDDPEDCIR 56

                          90       100
                  ....*....|....*....|....*..
gi 1191800980 121 KEAWEECGYRLapSDLRRVAS-YKAPG 146
Cdd:cd24157    57 REAEEETGYRL--GDLEKVFTaYSSPG 81

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 1191800980  39 THDSVTLLMFNASRRsLVLVKQFRPAVyagaverlfpgslvaadqdrprelpaalpgsAGVTFELCAGLVDqPGLSLEEV 118
Cdd:cd03424     1 HPGAVAVLAITDDGK-VVLVRQYRHPV-------------------------------GRVLLELPAGKID-PGEDPEEA 47

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1191800980 119 ACKEAWEECGYRlaPSDLRRVAS-YKAPGPCS 149
Cdd:cd03424    48 ARRELEEETGYT--AGDLELLGSfYPSPGFSD 77

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1191800980  41 DSVTLLMFNASRRsLVLVKQFRPAVYAGAVErlFPGslvaadqdrprelpaalpgsagvtfelcaGLVDqPGLSLEEVAC 120
Cdd:COG0494    14 PAVVVVLLDDDGR-VLLVRRYRYGVGPGLWE--FPG-----------------------------GKIE-PGESPEEAAL 60

                          90       100
                  ....*....|....*....|....*...
gi 1191800980 121 KEAWEECGYRlaPSDLRRVASYKAPGPC 148
Cdd:COG0494    61 RELREETGLT--AEDLELLGELPSPGYT 86

RNA pyrophosphohydrolase; The initiation of mRNA degradation often requires deprotection of its 5' end. In eukaryotes, the 5'-methylguanosine (cap) structure is principally removed by the NUDIX family decapping enzyme Dcp2, yielding a 5'-monophosphorylated RNA that is a substrate for 5' exoribonucleases. In bacteria, the 5'-triphosphate group of primary transcripts is also converted to a 5' monophosphate by a NUDIX protein called RNA pyrophosphohydrolase (RppH), allowing access to both endo- and 5' exoribonucleases. NUDIX hydrolase is a superfamily of enzymes found in all three kingdoms of life, and it catalyzes the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+ for their activity. Members of this family are recognized by a highly conserved 23-residue NUDIX motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site. Substrates of NUDIX hydrolase include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the NUDIX hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance and "house-cleaning" enzymes. Substrate specificity is used to define child families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required. This superfamily consists of at least nine families: IPP (isopentenyl diphosphate) isomerase, ADP ribose pyrophosphatase, mutT pyrophosphohydrolase, coenzyme-A pyrophosphatase, MTH1-7,8-dihydro-8-oxoguanine-triphosphatase, diadenosine tetraphosphate hydrolase, NADH pyrophosphatase, GDP-mannose hydrolase and the c-terminal portion of the mutY adenine glycosylase.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1191800980 100 TFELCAGLVdQPGLSLEEVACKEAWEECGYRLapSDLRRVASYKAPGP 147
Cdd:cd04665    23 GWEFPGGKR-EPGETIEEAARRELYEETGAVI--FELKPLGQYSVHGK 67