Haloacid Dehalogenase-like Hydrolases; The haloacid dehalogenase (HAD) superfamily includes carbon and phosphorus hydrolases such as 2-haloalkonoate dehalogenase, epoxide hydrolase, phosphoserine phosphatase, phosphomannomutase, phosphoglycolate phosphatase, P-type ATPase, among others. These proteins catalyze nucleophilic substitution reactions at phosphorus or carbon centers, using a conserved Asp carboxylate in covalent catalysis. All members possess a conserve alpha/beta core domain, and many also possess a small cap domain, with varying folds and functions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855  78 TVFFDIDNTLYSKYTGVQRMMQESIQRYCVHELDLEPEYAHALMEQYYQEYGLSIRGIMqDFPDTDPLMFNAMvDDSLPL 157
Cdd:cd02604     1 VWFFDLDNTLYPLSTGLFDQIQARITEFVATKLGLSPEEARRLRKSYYKEYGTTLRGLM-AEHGIDPDEFLDR-VVHLIL 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855 158 QDAIKgPDLKLRRILLNLKQnknvtKLWLFTNAYKTHAIRCIRILGIADLFDGITYCDYSAPpdsiICKPDPRSFEMAKL 237
Cdd:cd02604    79 YDHLK-PDPKLRNLLLALPG-----RKIIFTNASKNHAIRVLKRLGLADLFDGIFDIEYAGP----DPKPHPAAFEKAIR 148

                         170       180       190
                  ....*....|....*....|....*....|..
gi 2130400855 238 QSGISSFEkAWFIDDSFPNIQTALNVGLNHCI 269
Cdd:cd02604   149 EAGLDPKR-AAFFDDSIRNLLAAKALGMKTVL 179

haloacid dehalogenase (HAD)-like 5'-nucleotidases similar to Saccharomyces cerevisiae Phm8p and Sdt1p; This family includes Saccharomyces cerevisiae Phm8p (phosphate metabolism protein 8) and Sdt1p (Suppressor of disruption of TFIIS). Phm8p participates in the ribose salvage pathway, it catalyzes the dephosphorylation of nucleotide monophosphates to nucleosides, its preferred substrates are nucleotide monophosphates AMP, GMP, CMP, and UMP. Phm8p is also a lysophosphatidic acid phosphatase, dephosphorylating lysophosphatidic acids (LPAs) to monoacylglycerol in response to phosphate starvation. Sdt1p is a pyrimidine and pyridine-specific 5'-nucleotidase; it is an NMN/NaMN 5'-nucleotidases involved in the production of nicotinamide riboside and nicotinic acid riboside, and is a pyrimidine 5'-nucleotidase with high specificity for UMP and CMP. This family belongs to the haloacid dehalogenase-like (HAD) hydrolases, a large superfamily of diverse enzymes that catalyze carbon or phosphoryl group transfer reactions on a range of substrates, using an active site aspartate in nucleophilic catalysis. Members of this superfamily include 2-L-haloalkanoic acid dehalogenase, azetidine hydrolase, phosphonoacetaldehyde hydrolase, phosphoserine phosphatase, phosphomannomutase, P-type ATPases and many others. HAD hydrolases are found in all three kingdoms of life, and most genomes are predicted to contain multiple HAD-like proteins. Members possess a highly conserved alpha/beta core domain, and many also possess a small cap domain, the fold and function of which is variable. HAD hydrolases are sometimes referred to as belonging to the DDDD superfamily of phosphohydrolases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855  78 TVFFDIDNTLYSKYTGVQRMMQESIQRYCVHELDLEPEYAHALMEQYYQEYGLSIRGIMqDFPDTDPLMFNAMvDDSLPL 157
Cdd:cd02604     1 VWFFDLDNTLYPLSTGLFDQIQARITEFVATKLGLSPEEARRLRKSYYKEYGTTLRGLM-AEHGIDPDEFLDR-VVHLIL 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855 158 QDAIKgPDLKLRRILLNLKQnknvtKLWLFTNAYKTHAIRCIRILGIADLFDGITYCDYSAPpdsiICKPDPRSFEMAKL 237
Cdd:cd02604    79 YDHLK-PDPKLRNLLLALPG-----RKIIFTNASKNHAIRVLKRLGLADLFDGIFDIEYAGP----DPKPHPAAFEKAIR 148

                         170       180       190
                  ....*....|....*....|....*....|..
gi 2130400855 238 QSGISSFEkAWFIDDSFPNIQTALNVGLNHCI 269
Cdd:cd02604   149 EAGLDPKR-AAFFDDSIRNLLAAKALGMKTVL 179

FMN and 5-amino-6-(5-phospho-D-ribitylamino)uracil phosphatase YigB, HAD superfamily (riboflavin biosynthesis) [Coenzyme transport and metabolism];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855  78 TVFFDIDNTLY-------------SKYTGVQRMMQESIQRYCVHELDLEPEY------AHALMEQYYQEYGLsirgimqD 138
Cdd:COG1011     3 AVLFDLDGTLLdfdpviaealralAERLGLLDEAEELAEAYRAIEYALWRRYergeitFAELLRRLLEELGL-------D 75

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855 139 FPDTDPLMFNAMVDDSLPLQdaikgPDLklRRILLNLKQNKnvTKLWLFTNAYKTHAIRCIRILGIADLFDGITYCDysa 218
Cdd:COG1011    76 LAEELAEAFLAALPELVEPY-----PDA--LELLEALKARG--YRLALLTNGSAELQEAKLRRLGLDDLFDAVVSSE--- 143

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855 219 ppDSIICKPDPRSFEMAKLQSGISSfEKAWFIDDSFP-NIQTALNVGLNHCIFidyeakhinkyedTSENLNAKSTVMAT 297
Cdd:COG1011   144 --EVGVRKPDPEIFELALERLGVPP-EEALFVGDSPEtDVAGARAAGMRTVWV-------------NRSGEPAPAEPRPD 207

                         250
                  ....*....|..
gi 2130400855 298 YSIPNIHELQSV 309
Cdd:COG1011   208 YVISDLAELLEL 219

haloacid dehalogenase (HAD)-like 5'-nucleotidases similar to Saccharomyces cerevisiae Phm8p and Sdt1p; This family includes Saccharomyces cerevisiae Phm8p (phosphate metabolism protein 8) and Sdt1p (Suppressor of disruption of TFIIS). Phm8p participates in the ribose salvage pathway, it catalyzes the dephosphorylation of nucleotide monophosphates to nucleosides, its preferred substrates are nucleotide monophosphates AMP, GMP, CMP, and UMP. Phm8p is also a lysophosphatidic acid phosphatase, dephosphorylating lysophosphatidic acids (LPAs) to monoacylglycerol in response to phosphate starvation. Sdt1p is a pyrimidine and pyridine-specific 5'-nucleotidase; it is an NMN/NaMN 5'-nucleotidases involved in the production of nicotinamide riboside and nicotinic acid riboside, and is a pyrimidine 5'-nucleotidase with high specificity for UMP and CMP. This family belongs to the haloacid dehalogenase-like (HAD) hydrolases, a large superfamily of diverse enzymes that catalyze carbon or phosphoryl group transfer reactions on a range of substrates, using an active site aspartate in nucleophilic catalysis. Members of this superfamily include 2-L-haloalkanoic acid dehalogenase, azetidine hydrolase, phosphonoacetaldehyde hydrolase, phosphoserine phosphatase, phosphomannomutase, P-type ATPases and many others. HAD hydrolases are found in all three kingdoms of life, and most genomes are predicted to contain multiple HAD-like proteins. Members possess a highly conserved alpha/beta core domain, and many also possess a small cap domain, the fold and function of which is variable. HAD hydrolases are sometimes referred to as belonging to the DDDD superfamily of phosphohydrolases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855  78 TVFFDIDNTLYSKYTGVQRMMQESIQRYCVHELDLEPEYAHALMEQYYQEYGLSIRGIMqDFPDTDPLMFNAMvDDSLPL 157
Cdd:cd02604     1 VWFFDLDNTLYPLSTGLFDQIQARITEFVATKLGLSPEEARRLRKSYYKEYGTTLRGLM-AEHGIDPDEFLDR-VVHLIL 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855 158 QDAIKgPDLKLRRILLNLKQnknvtKLWLFTNAYKTHAIRCIRILGIADLFDGITYCDYSAPpdsiICKPDPRSFEMAKL 237
Cdd:cd02604    79 YDHLK-PDPKLRNLLLALPG-----RKIIFTNASKNHAIRVLKRLGLADLFDGIFDIEYAGP----DPKPHPAAFEKAIR 148

                         170       180       190
                  ....*....|....*....|....*....|..
gi 2130400855 238 QSGISSFEkAWFIDDSFPNIQTALNVGLNHCI 269
Cdd:cd02604   149 EAGLDPKR-AAFFDDSIRNLLAAKALGMKTVL 179

haloacid dehalogenase superfamily, subfamily IA, variant 3 with third motif having DD or ED; This model represents part of one structural subfamily of the Haloacid Dehalogenase (HAD) superfamily of aspartate-nucleophile hydrolases. The superfamily is defined by the presence of three short catalytic motifs. The subfamilies are defined based on the location and the observed or predicted fold of a so-called "capping domain", or the absence of such a domain. Subfamily I consists of sequences in which the capping domain is found in between the first and second catalytic motifs. Subfamily II consists of sequences in which the capping domain is found between the second and third motifs. Subfamily III sequences have no capping domain in either of these positions. The Subfamily IA and IB capping domains are predicted by PSI-PRED to consist of an alpha helical bundle. Subfamily I encompasses such a wide region of sequence space (the sequences are highly divergent) that representing it with a single model is impossible, resulting in an overly broad description which allows in many unrelated sequences. Subfamily IA and IB are separated based on an aparrent phylogenetic bifurcation. Subfamily IA is still too broad to model, but cannot be further subdivided into large chunks based on phylogenetic trees. Of the three motifs defining the HAD superfamily, the third has three variant forms: (1) hhhhsDxxx(x)D, (2) hhhhssxxx(x)D and (3) hhhhDDxxx(x)s where _s_ refers to a small amino acid and _h_ to a hydrophobic one. All three of these variants are found in subfamily IA. Individual models were made based on seeds exhibiting only one of the variants each. Variant 3 (this model) is found in the enzymes beta-phosphoglucomutase (TIGR01990) and deoxyglucose-6-phosphatase, while many other enzymes of subfamily IA exhibit this variant as well as variant 1 (TIGR01549). These three variant models were created with the knowledge that there will be overlap among them - this is by design and serves the purpose of eliminating the overlap with models of more distantly related HAD subfamilies caused by an overly broad single model. [Unknown function, Enzymes of unknown specificity]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855  78 TVFFDIDNTLYSKYTGVQRMMQESIQRYCVHELDLEPEYAHALMEQYYQE--YGLSIRGIMQDFPdtdplmFNAMVDDSL 155
Cdd:TIGR01509   1 AILFDLDGVLVDTEFAIAKLINREELGLVPDELGVSAVGRLELALRRFKAqyGRTISPEDAQLLY------KQLFYEQIE 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855 156 PLQDAikGPDLKLRRILLNLKQNKnvTKLWLFTNAYKTHaIRCIRILGIADLFDGITYCDYSAPpdsiiCKPDPRSFEMA 235
Cdd:TIGR01509  75 EEAKL--KPLPGVRALLEALRARG--KKLALLTNSPRAH-KLVLALLGLRDLFDVVIDSSDVGL-----GKPDPDIYLQA 144

                         170       180       190
                  ....*....|....*....|....*....|....*.
gi 2130400855 236 KLQSGISSfEKAWFIDDSFPNIQTALNVGLnHCIFI 271
Cdd:TIGR01509 145 LKALGLEP-SECVFVDDSPAGIEAAKAAGM-HTVGV 178

haloacid dehalogenase-like hydrolase; This family is structurally different from the alpha/beta hydrolase family (pfam00561). This family includes L-2-haloacid dehalogenase, epoxide hydrolases and phosphatases. The structure of the family consists of two domains. One is an inserted four helix bundle, which is the least well conserved region of the alignment, between residues 16 and 96 of Swiss:P24069. The rest of the fold is composed of the core alpha/beta domain. Those members with the characteriztic DxD triad at the N-terminus are probably phosphatidylglycerolphosphate (PGP) phosphatases involved in cardiolipin biosynthesis in the mitochondria.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855  78 TVFFDIDNTLYSKYTGVQRMMQESIQRYCVHELDLE-PEYAHALMEQYYQEYGLSIRGIMQDFPDTDPLM---------- 146
Cdd:pfam00702   3 AVVFDLDGTLTDGEPVVTEAIAELASEHPLAKAIVAaAEDLPIPVEDFTARLLLGKRDWLEELDILRGLVetleaegltv 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855 147 FNAMVDDSLPLQDAIKgPDLKLRRILLNLKQNKNvtKLWLFTNAYKTHAIRCIRILGIADLFDGITYCDysappDSIICK 226
Cdd:pfam00702  83 VLVELLGVIALADELK-LYPGAAEALKALKERGI--KVAILTGDNPEAAEALLRLLGLDDYFDVVISGD-----DVGVGK 154

                         170       180       190
                  ....*....|....*....|....*....|....*...
gi 2130400855 227 PDPRSFEMAKLQSGIsSFEKAWFIDDSFPNIQTALNVG 264
Cdd:pfam00702 155 PKPEIYLAALERLGV-KPEEVLMVGDGVNDIPAAKAAG 191

Haloacid dehalogenase-like hydrolases; The haloacid dehalogenase-like (HAD) superfamily includes L-2-haloacid dehalogenase, epoxide hydrolase, phosphoserine phosphatase, phosphomannomutase, phosphoglycolate phosphatase, P-type ATPase, and many others. This superfamily includes a variety of enzymes that catalyze the cleavage of substrate C-Cl, P-C, and P-OP bonds via nucleophilic substitution pathways. All of which use a nucleophilic aspartate in their phosphoryl transfer reaction. They catalyze nucleophilic substitution reactions at phosphorus or carbon centers, using a conserved Asp carboxylate in covalent catalysis. All members possess a highly conserved alpha/beta core domain, and many also possess a small cap domain, the fold and function of which is variable. Members of this superfamily are sometimes referred to as belonging to the DDDD superfamily of phosphohydrolases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855 166 LKLRRILLNLKQNKnvTKLWLFTNAYKTHAIRCIRILGIADLFDGITYCDysappDSIICKPDPRSFEMAKLQSGIsSFE 245
Cdd:cd01427    10 LLAVELLKRLRAAG--IKLAIVTNRSREALRALLEKLGLGDLFDGIIGSD-----GGGTPKPKPKPLLLLLLKLGV-DPE 81

                          90       100
                  ....*....|....*....|....*
gi 2130400855 246 KAWFIDDSFPNIQTALNVGLNHCIF 270
Cdd:cd01427    82 EVLFVGDSENDIEAARAAGGRTVAV 106

N-terminal lipase phosphatase domain of human soluble epoxide hydrolase, Escherichia coli YihX/HAD4 alpha-D-glucose 1-phosphate phosphatase, and related domains, may be inactive; This family includes the N-terminal phosphatase domain of human soluble epoxide hydrolase (sEH). sEH is a bifunctional enzyme with two distinct enzyme activities, the C-terminal domain has epoxide hydrolysis activity and the N-terminal domain (Ntermphos), which belongs to this family, has lipid phosphatase activity. The latter prefers mono-phosphate esters, and lysophosphatidic acids (LPAs) are the best natural substrates found to date. In addition this family includes Gallus gallus sEH and Xenopus sEH which appears to lack phosphatase activity, and Escherichia coli YihX/HAD4 which selectively hydrolyzes alpha-Glucose-1-P, phosphatase, has significant phosphatase activity against pyridoxal phosphate, and has low beta phosphoglucomutase activity. This family belongs to the haloacid dehalogenase-like (HAD) hydrolases, a large superfamily of diverse enzymes that catalyze carbon or phosphoryl group transfer reactions on a range of substrates, using an active site aspartate in nucleophilic catalysis. Members of this superfamily include 2-L-haloalkanoic acid dehalogenase, azetidine hydrolase, phosphonoacetaldehyde hydrolase, phosphoserine phosphatase, phosphomannomutase, P-type ATPases and many others. HAD hydrolases are found in all three kingdoms of life, and most genomes are predicted to contain multiple HAD-like proteins. Members possess a highly conserved alpha/beta core domain, and many also possess a small cap domain, the fold and function of which is variable. HAD hydrolases are sometimes referred to as belonging to the DDDD superfamily of phosphohydrolases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855  78 TVFFDIDNTL-----------YSKYTGVQRMMQESIQRYCVHELDLE------PEYahalMEQYYQEYGL-SIRGIMQDf 139
Cdd:cd02603     3 AVLFDFGGVLidpdpaaavarFEALTGEPSEFVLDTEGLAGAFLELErgriteEEF----WEELREELGRpLSAELFEE- 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855 140 pdtdplMFNAMVDDSLPLQDAIKgpdlKLRRillnlkqnKNVtKLWLFTNAYKTHAI---RCIRILGiaDLFDGITY-CD 215
Cdd:cd02603    78 ------LVLAAVDPNPEMLDLLE----ALRA--------KGY-KVYLLSNTWPDHFKfqlELLPRRG--DLFDGVVEsCR 136

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2130400855 216 YSappdsiICKPDPRSFEMAKLQSGISSfEKAWFIDDSFPNIQTALNVGLN 266
Cdd:cd02603   137 LG------VRKPDPEIYQLALERLGVKP-EEVLFIDDREENVEAARALGIH 180

haloacid dehalogenase superfamily, subfamily IA, variant 1 with third motif having Dx(3-4)D or Dx(3-4)E; This model represents part of one structural subfamily of the Haloacid Dehalogenase (HAD) superfamily of aspartate-nucleophile hydrolases. The superfamily is defined by the presence of three short catalytic motifs. The subfamilies are defined based on the location and the observed or predicted fold of a so-called "capping domain", or the absence of such a domain. Subfamily I consists of sequences in which the capping domain is found in between the first and second catalytic motifs. Subfamily II consists of sequences in which the capping domain is found between the second and third motifs. Subfamily III sequences have no capping domain in either of these positions.The Subfamily IA and IB capping domains are predicted by PSI-PRED to consist of an alpha helical bundle. Subfamily I encompasses such a wide region of sequence space (the sequences are highly divergent) that representing it with a single model is impossible, resulting in an overly broad description which allows in many unrelated sequences. Subfamily IA and IB are separated based on an aparrent phylogenetic bifurcation. Subfamily IA is still too broad to model, but cannot be further subdivided into large chunks based on phylogenetic trees. Of the three motifs defining the HAD superfamily, the third has three variant forms: (1) hhhhsDxxx(x)(D/E), (2) hhhhssxxx(x)D and (3) hhhhDDxxx(x)s where _s_ refers to a small amino acid and _h_ to a hydrophobic one. All three of these variants are found in subfamily IA. Individual models were made based on seeds exhibiting only one of the variants each. Variant 1 (this model) is found in the enzymes phosphoglycolate phosphatase (TIGR01449) and enolase-phosphatase. These three variant models (see also TIGR01493 and TIGR01509) were created withthe knowledge that there will be overlap among them - this is by design and serves the purpose of eliminating the overlap with models of more distantly relatedHAD subfamilies caused by an overly broad single model. [Unknown function, Enzymes of unknown specificity]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855  78 TVFFDIDNTLYSKYTGVQRMMQesiqrYCVHELDLEPEyahaLMEQYYQEYGLSIRgIMQDFPDTDPLMFNAMVDDSLPL 157
Cdd:TIGR01549   1 AILFDIDGTLVDIKFAIRRAFP-----QTFEEFGLDPA----SFKALKQAGGLAEE-EWYRIATSALEELQGRFWSEYDA 70

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130400855 158 QDAIKGPDLKLrriLLNLKQNKnvTKLWLFTNAYKTHAIRCIRILGIADLFDGITycdYSAPPDSiicKPDPRSFEMAKL 237
Cdd:TIGR01549  71 EEAYIRGAADL---LARLKSAG--IKLGIISNGSLRAQKLLLRLFGLGDYFELIL---VSDEPGS---KPEPEIFLAALE 139

                         170       180
                  ....*....|....*....|....*..
gi 2130400855 238 QSGISsfEKAWFIDDSFPNIQTALNVG 264
Cdd:TIGR01549 140 SLGVP--PEVLHVGDNLNDIEGARNAG 164