PLD-like domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147   44 VLKTITTAQQEIRL-MGYSFTSPEVAGALVRARQRGVDVKVVLD-HKANTGERNKASRAAMNLLVSAGIPVRTVDTY-KI 120
Cdd:pfam13091   1 LIDLINSAKKSIDIaTYYFVPDREIIDALIAAAKRGVDVRIILDsNKDDAGGPKKASLKELRSLLRAGVEIREYQSFlRS 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 695808147  121 LHDKVIIADGRNTEVGSFNFSRAADRANSENvLVVWDDPVVAQRYLQHWSSRW 173
Cdd:pfam13091  81 MHAKFYIIDGKTVIVGSANLTRRALRLNLEN-NVVIKDPELAQELEKEFDRLW 132

nuclease NucT; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  48 ITTAQQEIRLMGYSFTSPEVAGALVRARQRGVDVKVVLDHKANTGerNKASRAA-------MNLLVSAGIPVRTVDTYKI 120
Cdd:PRK13912  42 ISNARSSIKIAIYSFTHKDIAKALKSAAKRGVKISIIYDYESNHN--NDQSTIGyldkypnIKVCLLKGLKAKNGKYYGI 119

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 695808147 121 LHDKVIIADGRNTEVGSFNFSRAADRANSENVLVVwDDPVVAQRYLQHWSS 171
Cdd:PRK13912 120 MHQKVAIIDDKIVVLGSANWSKNAFENNYEVLLIT-DDTETILKAKEYFQK 169

Catalytic domain of EDTA-resistant nuclease Nuc, vertebrate phospholipase D6, and similar proteins; Catalytic domain of EDTA-resistant nuclease Nuc, vertebrate phospholipase D6 (PLD6, EC 3.1.4.4), and similar proteins. Nuc is an endonuclease from Salmonella typhimurium and the smallest known member of the PLD superfamily. It cleaves both single- and double-stranded DNA. PLD6 selectively hydrolyzes the terminal phosphodiester bond of phosphatidylcholine (PC), with the formation of phosphatidic acid and alcohols. Phosphatidic acid is an essential compound involved in signal transduction. PLD6 also catalyzes the transphosphatidylation of phospholipids to acceptor alcohols, by which various phospholipids can be synthesized. Both Nuc and PLD6 belong to the phospholipase D (PLD) superfamily. They contain a short conserved sequence motif, the HKD motif (H-x-K-x(4)-D, where x represents any amino acid residue), which is essential for catalysis. PLDs utilize a two-step mechanism to cleave phosphodiester bonds: Upon substrate binding, the bond is first attacked by a histidine residue from one HKD motif to form a covalent phosphohistidine intermediate, which is then hydrolyzed by water with the aid of a second histidine residue from the other HKD motif in the opposite subunit. This subfamily also includes some uncharacterized hypothetical proteins, which have two HKD motifs in a single polypeptide chain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  35 SPEGTGQQLVLKTITTAQQEIRLMGYSFTSPEVAGALVRARQRGVDVKVVLDHKANtgeRNKASRAAMNLLVSAGIPVRT 114
Cdd:cd09116    5 RPQDNLERLIVALIANAKSSIDVAMYALTDPEIAEALKRAAKRGVRVRIILDKDSL---ADNLSITLLALLSNLGIPVRT 81

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 695808147 115 VDTYKILHDKVIIADGRNTEVGSFNFSRAADRANSENVLVVWDDPVVAQrYLQHW 169
Cdd:cd09116   82 DSGSKLMHHKFIIIDGKIVITGSANWTKSGFHRNDENLLIIDDPKLAAS-FEEEF 135

Catalytic domain of vertebrate phospholipase D6 and similar proteins; Catalytic domain of vertebrate phospholipase D6 (PLD6, EC 3.1.4.4), a homolog of the EDTA-resistant nuclease Nuc from Salmonella typhimurium, and similar proteins. PLD6 can selectively hydrolyze the terminal phosphodiester bond of phosphatidylcholine (PC) with the formation of phosphatidic acid and alcohols. Phosphatidic acid is an essential compound involved in signal transduction. It also catalyzes the transphosphatidylation of phospholipids to acceptor alcohols, by which various phospholipids can be synthesized. PLD6 belongs to the phospholipase D (PLD) superfamily. Its monomer contains a short conserved sequence motif, H-x-K-x(4)-D (where x represents any amino acid residue), termed the HKD motif, which is essential in catalysis. PLD6 is more closely related to the nuclease Nuc than to other vertebrate phospholipases, which have two copies of the HKD motif in a single polypeptide chain. Like Nuc, PLD6 may utilize a two-step mechanism to cleave phosphodiester bonds: Upon substrate binding, the bond is first attacked by a histidine residue from the HKD motif of one subunit to form a covalent phosphohistidine intermediate, which is then hydrolyzed by water with the aid of a second histidine residue from the other HKD motif in the opposite subunit.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  34 FSPEGTGQQLVLKTITTAQQEIRLMGYSFTSPEVAGALVRARQRGVDVKVVLDHKANTGERNKasraaMNLLVSAGIPVR 113
Cdd:cd09171    3 FFPGETSLSKLLRYLLSARKSLDVCVFTITCDDLADAILDLHRRGVRVRIITDDDQMEDKGSD-----IGKLRKAGIPVR 77

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147 114 TVDTYKILHDKVIIADGRNTEVGSFNFSRAADRANSENVLVVwDDPVVAQRYLQHWSSRW 173
Cdd:cd09171   78 TDLSSGHMHHKFAVIDGKILITGSFNWTRQAVTGNQENVLIT-NDPKLVKPFTEEFEKLW 136

Phosphatidylserine/phosphatidylglycerophosphate/cardiolipin synthase [Lipid transport and metabolism]; Phosphatidylserine/phosphatidylglycerophosphate/cardiolipin synthase is part of the Pathway/BioSystem: Phospholipid biosynthesis

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147   5 LRRWCLPGLVSLSLYAPLPTVYAASIETG-FSPEGTGQQLVLKTITTAQQEIRLMGYSFT-SPEVAGALVRARQRGVDVK 82
Cdd:COG1502  168 AEDWNFATGEALPFPEPAGDVRVQVVPSGpDSPRETIERALLAAIASARRRIYIETPYFVpDRSLLRALIAAARRGVDVR 247

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  83 VVLDHKANTGERNKASRAAMNLLVSAGIPVRtvdTYK--ILHDKVIIADGRNTEVGSFNFSRAADRANSENVLVVwDDPV 160
Cdd:COG1502  248 ILLPAKSDHPLVHWASRSYYEELLEAGVRIY---EYEpgFLHAKVMVVDDEWALVGSANLDPRSLRLNFEVNLVI-YDPE 323

                        170
                 ....*....|....*..
gi 695808147 161 VAQRYLQHWSSRWSKGT 177
Cdd:COG1502  324 FAAQLRARFEEDLAHSR 340

Putative catalytic domain, repeat 1, of uncharacterized hypothetical proteins similar to Nuc, an endonuclease from Salmonella typhimurium; Putative catalytic domain, repeat 1, of uncharacterized hypothetical proteins, which show high sequence homology to the endonuclease from Salmonella typhimurium and vertebrate phospholipase D6. Nuc and PLD6 belong to the phospholipase D (PLD) superfamily. They contain a short conserved sequence motif, the HKD motif (H-x-K-x(4)-D, where x represents any amino acid residue), which characterizes the PLD superfamily and is essential for catalysis. Nuc and PLD6 utilize a two-step mechanism to cleave phosphodiester bonds: Upon substrate binding, the bond is first attacked by a histidine residue from one HKD motif to form a covalent phosphohistidine intermediate, which is then hydrolyzed by water with the aid of a second histidine residue from the other HKD motif in the opposite subunit. However, proteins in this subfamily have two HKD motifs in a single polypeptide chain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  42 QLVLKTITTAQQEIRLMGYSFTSPEVAGALVRARQRGVDVKVVLDHKANTGeRNKASRAAMNLLVSAGIPVRTVDTYKIL 121
Cdd:cd09172   12 LAFLDEARSAGSSIRLAIYELDDPEIIDALKAAKDRGVRVRIILDDSSVTG-DPTEESAAATLSKGPGALVKRRHSSGLM 90

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 695808147 122 HDKVIIADGRNTEV----GSFNFSRAADRANSENVLVVwDDPVVAQRYLQHWS 170
Cdd:cd09172   91 HNKFLVVDRKDGPNrvltGSTNFTTSGLYGQSNNVLIF-RNPAFAAAYLAYWN 142

Phosphatidylserine/phosphatidylglycerophosphate/cardiolipin synthase [Lipid transport and metabolism]; Phosphatidylserine/phosphatidylglycerophosphate/cardiolipin synthase is part of the Pathway/BioSystem: Phospholipid biosynthesis

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  17 SLYAPLPTVYAASIETGFSPEGTGQQLvLKTITTAQQEIRLMGYSFTSPE----VAGALVRARQRGVDVKVVLDHKANTG 92
Cdd:COG1502    4 PLAAGLPLVGGNRVTLLVDGDEAFAAL-LEAIEAARRSIDLEYYIFDDDEvgrrLADALIAAARRGVKVRVLLDGIGSRA 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  93 ernkASRAAMNLLVSAGIPVRTVDTYKIL--------HDKVIIADGRNTEVGSFN-----FSRAADRANSENVLVVWDDP 159
Cdd:COG1502   83 ----LNRDFLRRLRAAGVEVRLFNPVRLLfrrlngrnHRKIVVIDGRVAFVGGANitdeyLGRDPGFGPWRDTHVRIEGP 158

                        170       180
                 ....*....|....*....|...
gi 695808147 160 VVAQ---RYLQHWSSRWSKGTDW 179
Cdd:COG1502  159 AVADlqaVFAEDWNFATGEALPF 181

Catalytic domain of phospholipase D superfamily proteins; Catalytic domain of phospholipase D (PLD) superfamily proteins. The PLD superfamily is composed of a large and diverse group of proteins including plant, mammalian and bacterial PLDs, bacterial cardiolipin (CL) synthases, bacterial phosphatidylserine synthases (PSS), eukaryotic phosphatidylglycerophosphate (PGP) synthase, eukaryotic tyrosyl-DNA phosphodiesterase 1 (Tdp1), and some bacterial endonucleases (Nuc and BfiI), among others. PLD enzymes hydrolyze phospholipid phosphodiester bonds to yield phosphatidic acid and a free polar head group. They can also catalyze the transphosphatidylation of phospholipids to acceptor alcohols. The majority of members in this superfamily contain a short conserved sequence motif (H-x-K-x(4)-D, where x represents any amino acid residue), called the HKD signature motif. There are varying expanded forms of this motif in different family members. Some members contain variant HKD motifs. Most PLD enzymes are monomeric proteins with two HKD motif-containing domains. Two HKD motifs from two domains form a single active site. Some PLD enzymes have only one copy of the HKD motif per subunit but form a functionally active dimer, which has a single active site at the dimer interface containing the two HKD motifs from both subunits. Different PLD enzymes may have evolved through domain fusion of a common catalytic core with separate substrate recognition domains. Despite their various catalytic functions and a very broad range of substrate specificities, the diverse group of PLD enzymes can bind to a phosphodiester moiety. Most of them are active as bi-lobed monomers or dimers, and may possess similar core structures for catalytic activity. They are generally thought to utilize a common two-step ping-pong catalytic mechanism, involving an enzyme-substrate intermediate, to cleave phosphodiester bonds. The two histidine residues from the two HKD motifs play key roles in the catalysis. Upon substrate binding, a histidine from one HKD motif could function as the nucleophile, attacking the phosphodiester bond to create a covalent phosphohistidine intermediate, while the other histidine residue from the second HKD motif could serve as a general acid, stabilizing the leaving group.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  42 QLVLKTITTAQQEIRLMGYSF---TSPEVAGALVRARQRGVDVKVVLDHKANTGERNKASRAAMNLlvSAGIPVRTVDT- 117
Cdd:cd00138    1 EALLELLKNAKESIFIATPNFsfnSADRLLKALLAAAERGVDVRLIIDKPPNAAGSLSAALLEALL--RAGVNVRSYVTp 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 695808147 118 ---YKILHDKVIIADGRNTEVGSFNFSRAADRANSENVLVV 155
Cdd:cd00138   79 phfFERLHAKVVVIDGEVAYVGSANLSTASAAQNREAGVLV 119

Putative catalytic domain of uncharacterized phospholipase D-like proteins; Putative catalytic domain of uncharacterized phospholipase D (PLD, EC 3.1.4.4)-like proteins. Members of this subfamily contain one copy of HKD motif (H-x-K-x(4)-D, where x represents any amino acid residue) that characterizes the PLD superfamily.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  42 QLVLKTITTAQQEIRLMGYSFTS-PEVAGALVRARQRGVDVKVVLD-HKANTGERNKASRAAM-NLLVSAGIPVRTVDTY 118
Cdd:cd09132    2 QVLLELIEGAERSLLIVGYSAYKvSELLQALAAALERGVQVRVVVEsSEKAGSVLSLDEDELMwPKLAGATLYVWPEKKR 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 695808147 119 K----ILHDKVIIADGRNTEVGSFNFSRAADRANSE-NVLV 154
Cdd:cd09132   82 PgkraSLHAKVIVADRRRLLVTSANLTGAGMERNIEaGVLV 122

Catalytic domain, repeat 2, of Escherichia coli cardiolipin synthase and similar proteins; Catalytic domain, repeat 2, of Escherichia coli cardiolipin (CL) synthase and similar proteins. Escherichia coli CL synthase (EcCLS), specified by the cls gene, is the prototype of this family. EcCLS is a multi-pass membrane protein that catalyzes reversible phosphatidyl group transfer between two phosphatidylglycerol molecules to form cardiolipin (CL) and glycerol. The monomer of EcCLS consists of two catalytic domains. Each catalytic domain contains one copy of the conserved HKD motif (H-x-K-x(4)-D, where x represents any amino acid residue) that characterizes the phospholipase D (PLD) superfamily. Two HKD motifs from two domains form a single active site involved in phosphatidyl group transfer. EcCLS can be stimulated by phosphate and inhibited by CL, the product of the reaction, and by phosphatidate. Phosphate stimulation may be unique to enzymes with CL synthase activity belonging to the PLD superfamily. Like other PLD enzymes, EcCLS utilizes a common two-step ping-pong catalytic mechanism involving an enzyme-substrate intermediate to cleave phosphodiester bonds. The two histidine residues from the two HKD motifs play key roles in the catalysis. Upon substrate binding, a histidine residue from one HKD motif could function as the nucleophile, attacking the phosphodiester bond to create a covalent phosphohistidine intermediate, while the other histidine residue from the second HKD motif could serve as a general acid, stabilizing the leaving group.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  36 PEGTGQQLVLKTITTAQQEIRLmgysfTSP------EVAGALVRARQRGVDVKVVLDHKANTGERNKASRAAMNLLVSAG 109
Cdd:cd09158    8 PTENIPQLLLSAIHAARRRVVI-----TTPyfvpdeSLLQALCTAALRGVEVTLILPAKNDSFLVGAASRSYYEELLEAG 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147 110 IPVRTvdtYK--ILHDKVIIADGRNTEVGSFNFSRAADRANSENVLVVWDDPVVAQ------RY--------LQHWSSRW 173
Cdd:cd09158   83 VKIYL---YRggLLHAKTVTVDDEVALVGSSNFDIRSFALNFEISLILYDKEFTAQlraiqeRYlarsdpltLEEWKKRP 159

Catalytic domain, repeat 1, of bacterial cardiolipin synthase and similar proteins; Catalytic domain, repeat 1, of bacterial cardiolipin (CL) synthase and a few homologs found in eukaryotes and archaea. Bacterial CL synthases catalyze the reversible phosphatidyl group transfer between two phosphatidylglycerol molecules to form CL and glycerol. The monomer of bacterial CL synthase consists of two catalytic domains. Each catalytic domain contains one copy of the conserved HKD motif (H-x-K-x(4)-D, where x represents any amino acid residue) that characterizes the phospholipase D (PLD) superfamily. Two HKD motifs from two domains form a single active site involved in phosphatidyl group transfer. Bacterial CL synthases can be stimulated by phosphate and inhibited by CL, the product of the reaction, and by phosphatidate. Phosphate stimulation may be unique to enzymes with CL synthase activity belonging to the PLD superfamily. Like other PLD enzymes, bacterial CL synthases utilize a common two-step ping-pong catalytic mechanism involving an enzyme-substrate intermediate to cleave phosphodiester bonds. The two histidine residues from the two HKD motifs play key roles in the catalysis. Upon substrate binding, a histidine residue from one HKD motif could function as the nucleophile, attacking the phosphodiester bond to create a covalent phosphohistidine intermediate, while the other histidine residue from the second HKD motif could serve as a general acid, stabilizing the leaving group.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  45 LKTITTAQQEIRLMGYSFTSPEVAG----ALVRARQRGVDVKVVLDHkanTGERnKASRAAMNLLVSAGIPVRT------ 114
Cdd:cd09110   11 LEAIRAARHSIHLEYYIFRDDEIGRrfrdALIEKARRGVEVRLLYDG---FGSL-GLSRRFLRELREAGVEVRAfnplsf 86

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 695808147 115 -VDTYKIL---HDKVIIADGRNTEVGSFNFSRaaDRANSENVLVVWDD-------PVVAQ---RYLQHW 169
Cdd:cd09110   87 pLFLLRLNyrnHRKILVIDGKIAFVGGFNIGD--EYLGKDPGFGPWRDthvriegPAVADlqaAFLEDW 153

Catalytic domain, repeat 2, of vertebrate phospholipases, PLD1 and PLD2, and similar proteins; Catalytic domain, repeat 2, of phospholipase D (PLD, EC 3.1.4.4) found in yeast, plants, and vertebrates, and their bacterial homologs. PLDs are involved in signal transduction, vesicle formation, protein transport, and mitosis by participating in phospholipid metabolism. They hydrolyze the terminal phosphodiester bond of phospholipids resulting in the formation of phosphatidic acid and alcohols. Phosphatidic acid is an essential compound involved in signal transduction. PLDs also catalyze the transphosphatidylation of phospholipids to acceptor alcohols, by which various phospholipids can be synthesized. Both prokaryotic and eukaryotic PLDs have two HKD motifs (H-x-K-x(4)-D, where x represents any amino acid residue) that characterizes the phospholipase D (PLD) superfamily. PLDs are active as bi-lobed monomers. Each monomer contains two domains, each of which carries one copy of the HKD motif. Two HKD motifs from two domains form a single active site. PLDs utilize a common two-step ping-pong catalytic mechanism involving an enzyme-substrate intermediate to cleave phosphodiester bonds. The two histidine residues from the two HKD motifs play key roles in the catalysis. Upon substrate binding, a histidine residue from one HKD motif could function as the nucleophile, attacking the phosphodiester bond to create a covalent phosphohistidine intermediate, while the other histidine residue from the second HKD motif could serve as a general acid, stabilizing the leaving group.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  42 QLVLKTITTAQQEIRLMGYSFTSPEVAGALVRA--RQRGVDVKVVLDHK-----ANTGERNKASRAAMNLLVSAGIPVR- 113
Cdd:cd09105   11 DAYLKAIRNARRYIYIEDQYLWSPELLDALAEAlkANPGLRVVLVLPALpdavaFGADDGLDALALLALLLLADAAPDRv 90

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 695808147 114 ----------TVDTYKIL--HDKVIIADGRNTEVGSFNFSRAADRANSENVLVVWD 157
Cdd:cd09105   91 avfslathrrGLLGGPPIyvHSKVVIVDDEWATVGSANLNRRSMTWDTELNLAVVD 146

Putative catalytic domain, repeat 2, of Pseudomonas aeruginosa cardiolipin synthase and similar proteins; Putative catalytic domain, repeat 2, of Pseudomonas aeruginosa cardiolipin (CL) synthase (PaCLS) and similar proteins. Although PaCLS and similar proteins have not been functionally characterized, members in this subfamily show high sequence homology to bacterial CL synthases, which catalyze the reversible phosphatidyl group transfer between two phosphatidylglycerol molecules to form CL and glycerol. Moreover, PaCLS and other members of this subfamily contain two HKD motifs (H-x-K-x(4)-D, where x represents any amino acid residue) that characterizes the phospholipase D (PLD) superfamily. The two motifs may be part of the active site and may be involved in phosphatidyl group transfer.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  45 LKTITTAQQEIRLmgysfTSP------EVAGALVRARQRGVDVKVVLDHKANTGERNKASRAAMNLLVSAGIPV-RTVDT 117
Cdd:cd09161   17 VQAINAAQKRLWI-----ASPyfvpdeGVLAALQLAALRGVDVRILIPERPDHLLVYLASFSYLPELIRAGVKVyRYQPG 91

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 695808147 118 YkiLHDKVIIADGRNTEVGSFNFSRAADRANSENVLVVWDDPVVAQ 163
Cdd:cd09161   92 F--LHQKVVLVDDELAAVGTANLDNRSFRLNFEITALVADPGFAQE 135

Catalytic domain, repeat 1, of Escherichia coli cardiolipin synthase and similar proteins; Catalytic domain, repeat 1, of Escherichia coli cardiolipin (CL) synthase and similar proteins. Escherichia coli CL synthase (EcCLS), specified by the cls gene, is the prototype of this family. EcCLS is a multi-pass membrane protein that catalyzes reversible phosphatidyl group transfer between two phosphatidylglycerol molecules to form cardiolipin (CL) and glycerol. The monomer of EcCLS consists of two catalytic domains. Each catalytic domain contains one copy of the conserved HKD motif (H-x-K-x(4)-D, where x represents any amino acid residue) that characterizes the phospholipase D (PLD) superfamily. Two HKD motifs from two domains form a single active site involved in phosphatidyl group transfer. EcCLS can be stimulated by phosphate and inhibited by CL, the product of the reaction, and by phosphatidate. Phosphate stimulation may be unique to enzymes with CL synthase activity belonging to the PLD superfamily. Like other PLD enzymes, EcCLS utilizes a common two-step ping-pong catalytic mechanism involving an enzyme-substrate intermediate to cleave phosphodiester bonds. The two histidine residues from the two HKD motifs play key roles in the catalysis. Upon substrate binding, a histidine residue from one HKD motif could function as the nucleophile, attacking the phosphodiester bond to create a covalent phosphohistidine intermediate, while the other histidine residue from the second HKD motif could serve as a general acid, stabilizing the leaving group.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  48 ITTAQQEIRLMGYSF----TSPEVAGALVRARQRGVDVKVVLDHkanTGERNKASRAAMNLLVSAGIPVRTVDTYKIL-- 121
Cdd:cd09152   21 IDAAKHHVHLLFYIWaddgTGDRVAEALERAAKRGVTCRLLLDA---VGSRAFFRSSLWKRLREAGVEVVEALPLRLFrr 97

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 695808147 122 ---------HDKVIIADGRNTEVGSFNFSRAADRANSENvlVVWDD-------PVVAQ 163
Cdd:cd09152   98 rlarfdlrnHRKIAVIDGRIAYTGSQNIIDPEFFKKAGG--GPWVDlmvrvegPVVSQ 153

Putative catalytic domain, repeat 2, of uncharacterized proteins similar to bacterial cardiolipin synthase; Putative catalytic domain, repeat 2, of uncharacterized proteins similar to bacterial cardiolipin (CL) synthases, which catalyze the reversible phosphatidyl group transfer between two phosphatidylglycerol molecules to form CL and glycerol. Members of this subfamily contain two HKD motifs (H-x-K-x(4)-D, where x represents any amino acid residue) that characterizes the phospholipase D (PLD) superfamily. The two motifs may be part of the active site and may be involved in phosphatidyl group transfer.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  36 PEGTGQQL---VLKTITTAQQEIRLMGYSFTSPEV-AGALVRARQRGVDVKVVLDHKANTGERNKASRAAMNLLVSAGIP 111
Cdd:cd09162    5 PDVPGDPLyeaLLSAIFEAEHRIWIVTPYFVPDEVlLRALRLAARRGVDVRLIVPKRSNHRIADLARGSYLRDLQEAGAE 84

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 695808147 112 VRTVdTYKILHDKVIIADGRNTEVGSFNFSRAADRANSENVLVVWDDPVVAqrylqhWSSRWSKG 176
Cdd:cd09162   85 IYLY-QPGMLHAKAVVVDDKLALVGSANLDMRSLFLNYEVAVFFYSPADIK------ELSDWIES 142

Putative catalytic domain, repeat 1, of vertebrate phospholipases, PLD3, PLD4 and PLD5, viral envelope proteins K4 and p37, and similar proteins; Putative catalytic domain, repeat 1, of vertebrate phospholipases D, PLD3, PLD4, and PLD5 (EC 3.1.4.4), viral envelope proteins (vaccinia virus proteins K4 and p37), and similar proteins. Most family members contain two copies of the HKD motifs (H-x-K-x(4)-D, where x represents any amino acid residue), and have been classified into the phospholipase D (PLD) superfamily. Proteins in this subfamily are associated with Golgi membranes, altering their lipid content by the conversion of phospholipids into phosphatidic acid, which is thought to be involved in the regulation of lipid movement. ADP ribosylation factor (ARF), a small guanosine triphosphate binding protein, might be required activity. The vaccinia virus p37 protein, encoded by the F13L gene, is also associated with Golgi membranes and is required for the envelopment and spread of the extracellular enveloped virus (EEV). The vaccinia virus protein K4, encoded by the HindIII K4L gene, remains to be characterized. Sequence analysis indicates that the vaccinia virus proteins K4 and p37 might have evolved from one or more captured eukaryotic genes involved in cellular lipid metabolism. Up to date, no catalytic activity of PLD3 has been shown. Furthermore, due to the lack of functional important histidine and lysine residues in the HKD motif, mammalian PLD5 has been characterized as an inactive PLD. The poxvirus p37 proteins may also lack PLD enzymatic activity, since they contain only one partially conserved HKD motif (N-x-K-x(4)-D).

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 695808147  70 ALVRARQRGVDVKVVLDHKANTGERNKASRaamnLLVSAGIPVRTVDTYK-----ILHDKVIIADGRNTEVGSFNFS 141
Cdd:cd09106   64 ALLEAAKRGVKIRILQDKPSKDKPDEDDLE----LAALGGAEVRSLDFTKligggVLHTKFWIVDGKHFYLGSANLD 136

Putative catalytic domain, repeat 2, of uncharacterized phospholipase D-like proteins; Putative catalytic domain, repeat 2, of uncharacterized phospholipase D (PLD, EC 3.1.4.4)-like proteins. PLD enzymes hydrolyze phospholipid phosphodiester bonds to yield phosphatidic acid and a free polar head group. They can also catalyze transphosphatidylation of phospholipids to acceptor alcohols. Members of this subfamily contain two HKD motifs (H-x-K-x(4)-D, where x represents any amino acid residue) that characterizes the PLD superfamily. The two motifs may be part of the active site and may be involved in phosphatidyl group transfer.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  37 EGTGQQLVLKTITTAQQ--EIRLMGYSFTSPEVAGALVRARQRGVDVKVVLD-------HKANtGERNKASRAAMNLLVS 107
Cdd:cd09130    3 EGKIGEALLKEINSARAgdKIWIGMFYLADRDVIKALIDAANRGVDVRLILDpnkdafgREKN-GIPNRPVAAELMKKTK 81

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 695808147 108 AGIPVRTVDTYK-ILHDKVIIADGRNTEV---GSFNFSR 142
Cdd:cd09130   82 GKIQIRWYNTGGeQFHTKLLLIKKKGQAIiigGSANFTR 120

N-terminal phospholipase D-like domain of proteins from the Family with sequence similarity 83; N-terminal phospholipase D (PLD)-like domain of vetebrate proteins from the Family with sequence similarity 83 (FAM83), which is comprised of 8 members, designated FAM83A through FAM83H. Since the N-terminal PLD-like domain of FAM83 proteins shows only trace similarity to the PLD catalytic domain and lacks the functionally important histidine residue, the FAM83 proteins may share a similar three-dimensional fold with PLD enzymes, but are unlikely to carry PLD activity. Members of the FAM83 are mostly uncharacterized proteins. FAM83A, also known as tumor antigen BJ-TSA-9, is a novel tumor-specific gene highly expressed in human lung adenocarcinoma. FAM83D, also known as spindle protein CHICA, is a cell-cycle-regulated spindle component which localizes to the mitotic spindle and is both upregulated and phosphorylated during mitosis. The gene encoding protein FAM83H is the first gene involved in the etiology of amelogenesis imperfecta (AI), that encodes a non-secreted protein due to the absence of a signal peptide. Defects in gene FAM83H cause autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI). FAM83B, FAM83C, FAM83F, and FAM83G are uncharacterized proteins present across vertebrates while FAM83E is an uncharacterized protein found only in mammals.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  29 SIETGFSPEGTGQ----QLVLKTITTAQQEIRLMGYSFTSPEVAGALVRA-RQRGVDVKVVLDHKANTGERNKASRAAMN 103
Cdd:cd09119  108 RATVHFQPPKEGApnikDLVRRMIQQAQKVIAVVMDVFTDVDIFCDLLEAaNKRGVAVYILLDQGNVKHFLEMCDKLQLS 187

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 695808147 104 LLVSAGIPVRTV--DTY------KI---LHDKVIIADGRNTEVGSFNFSRAADRANSeNVLVVWDDPVV 161
Cdd:cd09119  188 DEHLKNMRVRSVggKTYcsrsgkKFkgqMKEKFLLVDGDRVVSGSYSFTWSDAKLHR-SMLSVLTGQVV 255

Middle phospholipase D-like domain of the transcriptional regulator TrmB and similar proteins; Middle phospholipase D (PLD)-like domain of the transcriptional regulator TrmB and similar proteins. TrmB acts as a bifunctional sugar-sensing transcriptional regulator which controls two operons encoding maltose/trehalose and maltodextrin ABC transporters of Pyrococcus fruiosus. It functions as a dimer. Full length TrmB includes an N-terminal DNA-binding domain, a C-terminal sugar-binding domain and middle region that has been named as a PLD-like domain. The middle domain displays homology to PLD enzymes, which contain one or two HKD motifs (H-x-K-x(4)-D, where x represents any amino acid residue) per chain. The HKD motif characterizes the PLD superfamily. Due to the lack of key residues related to PLD activity in the PLD-like domain, members of this subfamily are unlikely to carry PLD activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  48 ITTAQQEIRLMGYSFTSPEVAGALVRARQRGVDVKVVLDHKANTGErnkasraamnlLVSAGIPVRTvdTYKILHDKVII 127
Cdd:cd09124   19 INSAKEEIYISLPSEELEELLEELEKAAERGVKVVIIIFGDDDLDD-----------LDSPAIEVRV--REGGGRPFLLI 85

                         90       100
                 ....*....|....*....|....*....
gi 695808147 128 ADGRNTEVGSFNFSRAADRANSENVLVVW 156
Cdd:cd09124   86 VDSKEALIGPSSEEEETYALYTENPALVL 114

Putative catalytic domain, repeat 1, of Escherichia coli uncharacterized protein ymdC and similar proteins; Putative catalytic domain, repeat 1, of Escherichia coli uncharacterized protein ymdC and similar proteins. In Escherichia coli, there are two genes, f413 (ybhO) and o493 (ymdC), which are homologous to gene cls that encodes the Escherichia coli cardiolipin (CL) synthase. The prototype of this subfamily is an uncharacterized protein ymdC specified by the o493 (ymdC) gene. Although the functional characterization of ymdC and similar proteins remains unknown, members of this subfamily show high sequence homology to bacterial CL synthases, which catalyze the reversible phosphatidyl group transfer between two phosphatidylglycerol molecules to form CL and glycerol. Moreover, ymdC and its similar proteins contain two HKD motifs (H-x-K-x(4)-D, where x represents any amino acid residue) that characteriszes the phospholipase D (PLD) superfamily. The two motifs may be part of the active site and may be involved in phosphatidyl group transfer.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  48 ITTAQQEIRLMGYSFTSPE----VAGALVRARQRGVDVKVVLDHKANTGernkaSRAAMNLLVS-AGIPVRTVDTYKI-- 120
Cdd:cd09111   15 IRSAERSIDLQYYIWHDDEsgrlLLGELLEAADRGVRVRLLLDDLGTSG-----RDRLLAALDAhPNIEVRLFNPFRNrg 89

                         90       100
                 ....*....|....*....|....*..
gi 695808147 121 ----------------LHDKVIIADGR 131
Cdd:cd09111   90 grllefltdfsrlnrrMHNKLFIVDGA 116

Phospholipase D. Active site motifs; Phosphatidylcholine-hydrolyzing phospholipase D (PLD) isoforms are activated by ADP-ribosylation factors (ARFs). PLD produces phosphatidic acid from phosphatidylcholine, which may be essential for the formation of certain types of transport vesicles or may be constitutive vesicular transport to signal transduction pathways. PC-hydrolysing PLD is a homologue of cardiolipin synthase, phosphatidylserine synthase, bacterial PLDs, and viral proteins. Each of these appears to possess a domain duplication which is apparent by the presence of two motifs containing well-conserved histidine, lysine, aspartic acid, and/or asparagine residues which may contribute to the active site. An E. coli endonuclease (nuc) and similar proteins appear to be PLD homologues but possess only one of these motifs. The profile contained here represents only the putative active site regions, since an accurate multiple alignment of the repeat units has not been achieved.

                           10        20
                   ....*....|....*....|....*
gi 695808147   120 ILHDKVIIADGRNTEVGSFNFSRAA 144
Cdd:smart00155   4 VLHTKLMIVDDEIAYIGSANLDGRS 28

Sugar-specific transcriptional regulator TrmB [Transcription];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 695808147  48 ITTAQQEIRLMGYS--FTSPEVAGALVRARQRGVDVKVVLDhkantgernKASRAAMNLLVSAGIPVRTVDTYKIlhdKV 125
Cdd:COG1378  126 IASAEEEILIVLSPpeLLLEELEEALEEALERGVKVRVLVS---------PEVLEVPERLEEEGEEVRVLPGLPG---RL 193

                 ....*.
gi 695808147 126 IIADGR 131
Cdd:COG1378  194 LIVDDK 199