Ankyrin repeat [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545492572  15 FHYSAAEGDIARLTVILSHSPSLlNETSENGWTALMYAARNGHPDVVQFLLDKGCDRSIVNKSRQTALDIAKFWGYKHIA 94
Cdd:COG0666  157 LHLAAANGNLEIVKLLLEAGADV-NARDNDGETPLHLAAENGHLEIVKLLLEAGADVNAKDNDGKTALDLAAENGNLEIV 235

                 ....*..
gi 545492572  95 NLLANAK 101
Cdd:COG0666  236 KLLLEAG 242

NADH pyrophosphatase; NADH pyrophosphatase, also known as NUDIX (nucleoside diphosphate linked moiety X)) motif 13/Nudt13, is thought to have NADH pyrophosphatase activity, be involved in NADH metabolic process and NADP catabolic process, catalyzing the cleavage of NADH into reduced nicotinamide mononucleotide (NMNH) and AMP, and located in mitochondrion. Like other members of the NUDIX family, it requires a divalent cation, such as Mg2+ or Mn2+, for activity. Members of this family are also recognized by 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. A block of 8 conserved amino acids downstream of the NUDIX motif is thought to give NADH pyrophosphatase its specificity for NADH. NADH pyrophosphatase forms a dimer.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545492572 320 DPVVIMQVIHPDGtKCLLGRQKRFPPGMFTCLAGFIEPGETIEDAVRREVEEESGVKVGHVQYVSCQPWPMPSSLMIGCL 399
Cdd:cd03429    1 DPAVIVLVTNGED-KILLARQPRWPPGRYSLLAGFVEPGETLEEAVRREVKEEVGLRVKNVRYVGSQPWPFPSSLMLGFT 79

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 545492572 400 AVAVSTEIKVDKNEIEDARWFTREQVVDVLtkgkqqafFVPPSRAIAHQLLKHWI 454
Cdd:cd03429   80 AEADSGEITVDDDELEDARWFSRDELPEAL--------FLPPPGSIARRLIRAWL 126

NUDIX domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545492572  327 VIHPDGTKCLLGRQ-KRFPPGMFTCLAGFIEPGETIEDAVRREVEEESGVKVGHVQYVSCQ--------PWPMPSSLMIG 397
Cdd:pfam00293   9 VLLNEKGRVLLVRRsKKPFPGWWSLPGGKVEPGETPEEAARRELEEETGLEPELLELLGSLhylapfdgRFPDEHEILYV 88

                          90       100
                  ....*....|....*....|....*....
gi 545492572  398 CLAVAVSTEIKVDKNEIEDARWFTREQVV 426
Cdd:pfam00293  89 FLAEVEGELEPDPDGEVEEVRWVPLEELL 117

Ankyrin repeats (3 copies);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545492572   15 FHYSAAEGDIARLTVILSHSPSLlNETSENGWTALMYAARNGHPDVVQFLLDKgCDRSIVNKSRqTALDIAKFWGYKHIA 94
Cdd:pfam12796   1 LHLAAKNGNLELVKLLLENGADA-NLQDKNGRTALHLAAKNGHLEIVKLLLEH-ADVNLKDNGR-TALHYAARSGHLEIV 77

                  ....*
gi 545492572   95 NLLAN 99
Cdd:pfam12796  78 KLLLE 82

ankyrin repeat protein; Provisional

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 545492572  38 LNETSENGWTALMYAARNGHPDVVQFLLDKGCDRSIVNKSRQTALDIAKFWGYKHIANLLANAK 101
Cdd:PHA03100 185 INIKDVYGFTPLHYAVYNNNPEFVKYLLDLGANPNLVNKYGDTPLHIAILNNNKEIFKLLLNNG 248

NADH pyrophosphatase; NADH pyrophosphatase, also known as NUDIX (nucleoside diphosphate linked moiety X)) motif 13/Nudt13, is thought to have NADH pyrophosphatase activity, be involved in NADH metabolic process and NADP catabolic process, catalyzing the cleavage of NADH into reduced nicotinamide mononucleotide (NMNH) and AMP, and located in mitochondrion. Like other members of the NUDIX family, it requires a divalent cation, such as Mg2+ or Mn2+, for activity. Members of this family are also recognized by 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. A block of 8 conserved amino acids downstream of the NUDIX motif is thought to give NADH pyrophosphatase its specificity for NADH. NADH pyrophosphatase forms a dimer.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545492572 320 DPVVIMQVIHPDGtKCLLGRQKRFPPGMFTCLAGFIEPGETIEDAVRREVEEESGVKVGHVQYVSCQPWPMPSSLMIGCL 399
Cdd:cd03429    1 DPAVIVLVTNGED-KILLARQPRWPPGRYSLLAGFVEPGETLEEAVRREVKEEVGLRVKNVRYVGSQPWPFPSSLMLGFT 79

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 545492572 400 AVAVSTEIKVDKNEIEDARWFTREQVVDVLtkgkqqafFVPPSRAIAHQLLKHWI 454
Cdd:cd03429   80 AEADSGEITVDDDELEDARWFSRDELPEAL--------FLPPPGSIARRLIRAWL 126

NUDIX domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545492572  327 VIHPDGTKCLLGRQ-KRFPPGMFTCLAGFIEPGETIEDAVRREVEEESGVKVGHVQYVSCQ--------PWPMPSSLMIG 397
Cdd:pfam00293   9 VLLNEKGRVLLVRRsKKPFPGWWSLPGGKVEPGETPEEAARRELEEETGLEPELLELLGSLhylapfdgRFPDEHEILYV 88

                          90       100
                  ....*....|....*....|....*....
gi 545492572  398 CLAVAVSTEIKVDKNEIEDARWFTREQVV 426
Cdd:pfam00293  89 FLAEVEGELEPDPDGEVEEVRWVPLEELL 117

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 545492572 327 VIHPDGTKCLLGRQKRFP-PGMFTCLAGFIEPGETIEDAVRREVEEESGVKVGHVQYVSCQPWPMP----SSLMIGCLAV 401
Cdd:cd02883    6 VVFDDEGRVLLVRRSDGPgPGGWELPGGGVEPGETPEEAAVREVREETGLDVEVLRLLGVYEFPDPdegrHVVVLVFLAR 85

                         90       100
                 ....*....|....*....|.
gi 545492572 402 AVSTEIKV-DKNEIEDARWFT 421
Cdd:cd02883   86 VVGGEPPPlDDEEISEVRWVP 106

Ankyrin repeat [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545492572  16 HYSAAEGDIARLTVILSHSPSLlNETSENGWTALMYAARNGHPDVVQFLLDKGCDRSIVNKSRQTALDIAKFWGYKHIAN 95
Cdd:COG0666  125 HLAAYNGNLEIVKLLLEAGADV-NAQDNDGNTPLHLAAANGNLEIVKLLLEAGADVNARDNDGETPLHLAAENGHLEIVK 203

                 ....*.
gi 545492572  96 LLANAK 101
Cdd:COG0666  204 LLLEAG 209

Ankyrin repeat [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545492572  15 FHYSAAEGDIARLTVILSHSPSLlNETSENGWTALMYAARNGHPDVVQFLLDKGCDRSIVNKSRQTALDIAKFWGYKHIA 94
Cdd:COG0666   91 LHAAARNGDLEIVKLLLEAGADV-NARDKDGETPLHLAAYNGNLEIVKLLLEAGADVNAQDNDGNTPLHLAAANGNLEIV 169

                 ....*..
gi 545492572  95 NLLANAK 101
Cdd:COG0666  170 KLLLEAG 176

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 545492572 346 GMFTCLAGFIEPGETIEDAVRREVEEESGV--KVGHVQYVSCQPWPMPSS-LMIGCLAVAVSTEIKVDKNEIEDARWFTR 422
Cdd:cd04691   26 GRWTLPGGFVEEGETLDEAIVREVLEETGIdaKPVGIIGVRSGVIRDGKSdNYVVFLLEYVGGEPKPDERENSEAGFLTL 105

                 ....
gi 545492572 423 EQVV 426
Cdd:cd04691  106 EEAL 109

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 545492572 327 VIHPDGtKCLLGRQKRFPPGMFTCLAGFIEPGETIEDAVRREVEEESGVKvghVQYVSC----QPWPMP---SSLMIGCL 399
Cdd:cd04670    9 VINENN-EVLVVQEKYGGPGGWKLPGGLVDPGEDIGEAAVREVFEETGID---TEFVSIlgfrHQHPGRfgkSDLYFVCR 84

                         90       100
                 ....*....|....*....|..
gi 545492572 400 AVAVS-TEIKVDKNEIEDARWF 420
Cdd:cd04670   85 LRPLSdEEIKICPEEIAEAKWM 106

Ankyrin repeats (many copies);

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 545492572   30 ILSHSPSLLNETSENGWTALMYAARNGHPDVVQFLLDKGCDRSIVNKSRQTALDIA 85
Cdd:pfam13857   1 LLEHGPIDLNRLDGEGYTPLHVAAKYGALEIVRVLLAYGVDLNLKDEEGLTALDLA 56

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 545492572 322 VVIMqVIHPDGtKCLLGRQKRFPPGMFTcL---AGFIEPGETIEDAVRREVEEESGVKVGHVQYVsCQPWPMP---SSLM 395
Cdd:cd03424    5 VAVL-AITDDG-KVVLVRQYRHPVGRVL-LelpAGKIDPGEDPEEAARRELEEETGYTAGDLELL-GSFYPSPgfsDERI 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 545492572 396 IGCLA--VAVSTEIKVDKNEIEDARWFTREQVVDVLTKGK 433
Cdd:cd03424   81 HLFLAedLTPVSEQALDEDEFIEVVLVPLEEALEMIEDGE 120

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 545492572 345 PGMFTCLAGFIEPGETIEDAVRREVEEESGVKVGHVQYVSCQPWPMPSSLMIGCLAVAVSTEI-KVDKNEIEDARWFTRE 423
Cdd:cd18882   29 PGYWGLFGGHLEPGETPEEAIRRELEEEIGYEPGEFRFFLLYTEDDGEDRIRHVFHAPLDVDLsDLVLNEGQALRLFSPE 108

                 ....
gi 545492572 424 QVVD 427
Cdd:cd18882  109 EILQ 112

Isopentenyldiphosphate isomerase [Lipid transport and metabolism]; Isopentenyldiphosphate isomerase is part of the Pathway/BioSystem: Isoprenoid biosynthesis

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545492572 327 VIHPDGtKCLLGR---QKRFPPGMFTCL-AGFIEPGETIEDAVRREVEEESGV-------KVGHVQYVScqpwPMPSSLM 395
Cdd:COG1443   36 VFNSDG-RLLLQRralTKDHWPGLWDNTvCGHPRAGETYEEAAVRELEEELGItvdddlrPLGTFRYRA----VDANGLV 110

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 545492572 396 ----IGCLAVAVSTEIKVDKNEIEDARWFTREQVVDVLTKGKQQafFVPPSRAI 445
Cdd:COG1443  111 enefCHVFVARLDGPLTPQPEEVAEVRWVTLEELLALLEAGPEA--FTPWFRLY 162

MutT homolog 2; MutT Homolog 2 (MTH2; EC 3.6.1.9), also known as NUDIX (nucleoside diphosphate-linked moiety X)) motif 15/Nudt15, may catalyze the hydrolysis of nucleoside diphosphates, triphosphates including dGTP, dTTP, dCTP, their oxidized forms like 8-oxo-dGTP, and prodrug thiopurine derivatives 6-thio-dGTP and 6-thio-GTP. MTH2 may also play a role in DNA synthesis and cell cycle progression by stabilizing PCNA. 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 545492572 317 PRVDPVVImqVIHPDGtKCLLGRQK-RFPPGMFtCLA-GFIEPGETIEDAVRREVEEESGVKVGHVQYVSCQpwpmpSSL 394
Cdd:cd04678    1 PRVGVGVI--VLNDDG-KVLLGRRKgSHGAGTW-ALPgGHLEFGESFEECAAREVLEETGLEIRNVRFLTVT-----NDV 71

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 545492572 395 M---------IGCLAVAVSTEIKV--DKNEIEDARWFTREQV 425
Cdd:cd04678   72 FeeegkhyvtIFVLAEVDDGEPEEnmEPDKCEGWEWFSWDEL 113

Ankyrin repeats (3 copies);

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 545492572   16 HYSAAEG--DIARLtvILSHSPSllnETSENGWTALMYAARNGHPDVVQFLLDKGCD 70
Cdd:pfam12796  35 HLAAKNGhlEIVKL--LLEHADV---NLKDNGRTALHYAARSGHLEIVKLLLEKGAD 86

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 545492572 353 GFIEPGETIEDAVRREVEEESG--VKVGH---VQYVSCQPWPMPSSLMI---GCLAVAVSTEIKVDKNEIEDARWFTREQ 424
Cdd:cd18876   30 GVVEAGESPLQAARREVREELGldVPVGRllaVDWVPPAGGGDDAVLFVfdgGVLTPEQAAAIRLQDEELSAYRFVTPEE 109

                 ....*.
gi 545492572 425 VVDVLT 430
Cdd:cd18876  110 AAELLP 115

MutT homolog-1 and similar proteins; MutT homolog-1 (MTH1), also known as NUDIX (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
                 ....*....|....*....|....*....|....*....|....*..
gi 545492572 336 LLGRQKRFPPGMFTCLAGFIEPGETIEDAVRREVEEESGVKVGHVQY 382
Cdd:cd18886   15 LLNRNKKPNMGKWNGVGGKLEPGESPEECAIREVFEETGLELEDLQL 61

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 545492572 327 VIHPDGTKCLLGRqkRFPPGMFTCLAGFIEPGETIEDAVRREVEEESGVKV-----------GHVQYVS---CQpwpmps 392
Cdd:cd18879   24 VVLRDAGRVLLVR--RADNGRWTPVTGIVEPGEQPADAAVREVLEETGVDVeverlasvgasPPVTYPNgdqCQ------ 95

                         90       100
                 ....*....|....*....|....*...
gi 545492572 393 SLMIGCLAVAVSTEIKVDKNEIEDARWF 420
Cdd:cd18879   96 YLDLTFRCRPVGGEARVNDDESLEVGWF 123

ADP-ribose pyrophosphatase NudF; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545492572 345 PGMFTCLAGFIEPGETIEDAVRREVEEESGVKVGHVQ----YVSCqpwpmP------SSLMIGCLAVAVSTEIKVDKNEI 414
Cdd:PRK10729  81 PWLLEMVAGMIEEGESVEDVARREAIEEAGLIVGRTKpvlsYLAS-----PggtserSSIMVGEVDATTASGIHGLADEN 155

                         90
                 ....*....|..
gi 545492572 415 EDAR--WFTREQ 424
Cdd:PRK10729 156 EDIRvhVVSREQ 167

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 545492572 335 CLLGRQKrfPPGMFTCLAGFIEPGETIEDAVRREVEEESGVKVGHVQYVSCQ---------PW-PMPSSLMIGCLAVAVS 404
Cdd:cd04664   17 LLLKRTD--DGGFWQSVTGGIEDGETPWQAALRELKEETGLDPLELQLIDLNvsnfyeifdDWrPGVTVNTEHVFAVEVP 94

                         90       100
                 ....*....|....*....|....*.
gi 545492572 405 TEIKVDKN-EIEDARWFTREQVVDVL 429
Cdd:cd04664   95 EEQPIRLSpEHTDYRWLPYEEAAELL 120

Ankyrin repeat; Ankyrins are multifunctional adaptors that link specific proteins to the membrane-associated, spectrin- actin cytoskeleton. This repeat-domain is a 'membrane-binding' domain of up to 24 repeated units, and it mediates most of the protein's binding activities.

                          10        20
                  ....*....|....*....|....*..
gi 545492572   44 NGWTALMYAARNGHPDVVQFLLDKGCD 70
Cdd:pfam13606   1 DGNTPLHLAARNGRLEIVKLLLENGAD 27

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 545492572 316 YPRVDPVVIMqVIHPDGTKCLLGRQKRFP------PGMFT--ClAGFIEpGETIEDAVRREVEEESGVKVGHVQYVScQP 387
Cdd:cd24157    1 YDRGDAAAVL-LYDPKRKTVVLVRQFRAPaylgggDGWLIeaC-AGLLD-GDDPEDCIRREAEEETGYRLGDLEKVF-TA 76

                 ....*...
gi 545492572 388 WPMPSSLM 395
Cdd:cd24157   77 YSSPGIVT 84

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        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 545492572 353 GFIEPGETIEDAVRREVEEESGVKVGHVQYV---SCQPWPMPSSLMIgCLAVAVSTEIKVDKNEIEDARWFTR 422
Cdd:cd04665   29 GKREPGETIEEAARRELYEETGAVIFELKPLgqySVHGKGQEFFGAV-YYAEVKSFEPILPYFETAEVRLFDE 100

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 545492572 327 VIHPDGtKCLLGRQKRFPpGMFTCLAGFIEPGETIEDAVRREVEEESGVKVGHVQYVSCQP 387
Cdd:cd03671   10 LFNRDG-QVLVGRRIDVP-GAWQFPQGGIDEGEDPEEAALRELYEETGLSPEDVEIIAETP 68

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 545492572 319 VDPVVIMQVIH-PDGTKCL-LGRQKRFPPGMFtCL---AGFIEPGETIEDAVRREVEEESGVKVGHVQYVS 384
Cdd:cd18888    2 VDAVAIIAILKrKLKPPELvLVKQYRPPVNAY-TIefpAGLVDPGESPEQAALRELKEETGYTGEKVLSVS 71