PIPS_MYCTU
ID PIPS_MYCTU Reviewed; 217 AA.
AC P9WPG7; L0TBS2; Q79FC5; Q7D6W6;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 42.
DE RecName: Full=Phosphatidylinositol phosphate synthase {ECO:0000303|PubMed:31098408};
DE Short=PIP synthase {ECO:0000303|PubMed:31098408};
DE EC=2.7.8.- {ECO:0000269|PubMed:26510127, ECO:0000269|PubMed:31098408};
DE AltName: Full=CDP-diacylglycerol--D-myo-inositol-3-phosphate 3-phosphatidyltransferase;
GN Name=pgsA1 {ECO:0000303|PubMed:31098408, ECO:0000312|EMBL:CCP45409.1};
GN Synonyms=pgsA {ECO:0000303|PubMed:10889206}; OrderedLocusNames=Rv2612c;
OS Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83332;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=9634230; DOI=10.1038/31159;
RA Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA Barrell B.G.;
RT "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT genome sequence.";
RL Nature 393:537-544(1998).
RN [2]
RP SEQUENCE REVISION.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=12368430; DOI=10.1099/00221287-148-10-2967;
RA Camus J.-C., Pryor M.J., Medigue C., Cole S.T.;
RT "Re-annotation of the genome sequence of Mycobacterium tuberculosis
RT H37Rv.";
RL Microbiology 148:2967-2973(2002).
RN [3]
RP PRELIMINARY FUNCTION.
RC STRAIN=H37Rv;
RX PubMed=10889206; DOI=10.1074/jbc.m004658200;
RA Jackson M., Crick D.C., Brennan P.J.;
RT "Phosphatidylinositol is an essential phospholipid of mycobacteria.";
RL J. Biol. Chem. 275:30092-30099(2000).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21969609; DOI=10.1074/mcp.m111.011627;
RA Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT mass spectrometry.";
RL Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND PATHWAY.
RX PubMed=26510127; DOI=10.1038/ncomms9505;
RA Clarke O.B., Tomasek D., Jorge C.D., Dufrisne M.B., Kim M., Banerjee S.,
RA Rajashankar K.R., Shapiro L., Hendrickson W.A., Santos H., Mancia F.;
RT "Structural basis for phosphatidylinositol-phosphate biosynthesis.";
RL Nat. Commun. 6:8505-8505(2015).
RN [6] {ECO:0007744|PDB:6H53, ECO:0007744|PDB:6H59, ECO:0007744|PDB:6H5A}
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF APOENZYME AND IN COMPLEXES WITH
RP MAGNESIUM; CDP-DAG AND CITRATE-MANGANESE, FUNCTION, CATALYTIC ACTIVITY,
RP COFACTOR, PATHWAY, SUBUNIT, SUBCELLULAR LOCATION, REACTION MECHANISM,
RP ACTIVE SITE, AND MUTAGENESIS OF ALA-90; ARG-94; TYR-133 AND ARG-137.
RC STRAIN=H37Rv;
RX PubMed=31098408; DOI=10.1038/s42003-019-0427-1;
RA Grave K., Bennett M.D., Hoegbom M.;
RT "Structure of Mycobacterium tuberculosis phosphatidylinositol phosphate
RT synthase reveals mechanism of substrate binding and metal catalysis.";
RL Commun. Biol. 2:175-175(2019).
CC -!- FUNCTION: Catalyzes the conjugation of the 1'-hydroxyl group of D-myo-
CC inositol-3-phosphate (also named L-myo-inositol-1-phosphate) with a
CC lipid tail of cytidine diphosphate diacylglycerol (CDP-DAG), forming
CC phosphatidylinositol phosphate (PIP) and CMP. PIP is a precursor of
CC phosphatidylinositol (PI) which is an essential lipid for mycobacteria
CC required for formation of their cell wall.
CC {ECO:0000269|PubMed:26510127, ECO:0000269|PubMed:31098408}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1D-myo-inositol 3-phosphate + a CDP-1,2-diacyl-sn-glycerol = a
CC 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + CMP +
CC H(+); Xref=Rhea:RHEA:60504, ChEBI:CHEBI:15378, ChEBI:CHEBI:58088,
CC ChEBI:CHEBI:58332, ChEBI:CHEBI:58401, ChEBI:CHEBI:60377;
CC Evidence={ECO:0000269|PubMed:26510127, ECO:0000269|PubMed:31098408};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1,2-di-(9Z-octadecenoyl)-sn-glycero-3-cytidine-5'-diphosphate
CC + 1D-myo-inositol 3-phosphate = 1,2-di-(9Z-octadecenoyl)-sn-glycero-
CC 3-phospho-(1D-myo-inositol-3-phosphate) + CMP + H(+);
CC Xref=Rhea:RHEA:61216, ChEBI:CHEBI:15378, ChEBI:CHEBI:58401,
CC ChEBI:CHEBI:60377, ChEBI:CHEBI:85356, ChEBI:CHEBI:144472;
CC Evidence={ECO:0000269|PubMed:26510127, ECO:0000269|PubMed:31098408};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:31098408};
CC Note=Contains a di-nuclear catalytic Mg(2+) center.
CC {ECO:0000269|PubMed:31098408};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=243 uM for 1D-myo-inositol 3-phosphate
CC {ECO:0000269|PubMed:26510127};
CC KM=60 uM for CDP-dioleoylglycerol {ECO:0000269|PubMed:26510127};
CC Vmax=39 nmol/min/mg enzyme {ECO:0000269|PubMed:26510127};
CC -!- PATHWAY: Phospholipid metabolism; phosphatidylinositol phosphate
CC biosynthesis. {ECO:0000269|PubMed:26510127,
CC ECO:0000269|PubMed:31098408}.
CC -!- SUBUNIT: Homodimer. {ECO:0000305|PubMed:31098408}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:31098408};
CC Multi-pass membrane protein {ECO:0000269|PubMed:31098408}.
CC -!- MISCELLANEOUS: M.tuberculosis PgsA1 has been identified as a promising
CC candidate for drug development because of its vital role in growth and
CC proliferation of the pathogen as well as the differences between
CC eukaryotic and mycobacterial PI biosynthesis pathways.
CC {ECO:0000305|PubMed:31098408}.
CC -!- SIMILARITY: Belongs to the CDP-alcohol phosphatidyltransferase class-I
CC family. {ECO:0000255|HAMAP-Rule:MF_02241, ECO:0000305}.
CC -!- CAUTION: Was orginally thought to be a phosphatidylinositol (PI)
CC synthase. {ECO:0000305|PubMed:10889206}.
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DR EMBL; AL123456; CCP45409.1; -; Genomic_DNA.
DR PIR; C70571; C70571.
DR RefSeq; WP_003413482.1; NZ_NVQJ01000023.1.
DR RefSeq; YP_177894.1; NC_000962.3.
DR PDB; 6H53; X-ray; 2.90 A; A/B=1-217.
DR PDB; 6H59; X-ray; 1.80 A; A/B=1-217.
DR PDB; 6H5A; X-ray; 1.88 A; A/B=1-217.
DR PDBsum; 6H53; -.
DR PDBsum; 6H59; -.
DR PDBsum; 6H5A; -.
DR AlphaFoldDB; P9WPG7; -.
DR SMR; P9WPG7; -.
DR STRING; 83332.Rv2612c; -.
DR PaxDb; P9WPG7; -.
DR DNASU; 888209; -.
DR GeneID; 888209; -.
DR KEGG; mtu:Rv2612c; -.
DR TubercuList; Rv2612c; -.
DR eggNOG; COG0558; Bacteria.
DR OMA; DGNMARQ; -.
DR PhylomeDB; P9WPG7; -.
DR BioCyc; MetaCyc:G185E-6855-MON; -.
DR BRENDA; 2.7.8.B13; 3445.
DR UniPathway; UPA00220; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005887; C:integral component of plasma membrane; IEA:UniProtKB-UniRule.
DR GO; GO:0009274; C:peptidoglycan-based cell wall; IDA:UniProtKB.
DR GO; GO:0003881; F:CDP-diacylglycerol-inositol 3-phosphatidyltransferase activity; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IEA:UniProtKB-UniRule.
DR GO; GO:0046474; P:glycerophospholipid biosynthetic process; IMP:MTBBASE.
DR GO; GO:0008654; P:phospholipid biosynthetic process; IDA:UniProtKB.
DR Gene3D; 1.20.120.1760; -; 1.
DR HAMAP; MF_02241; PIP_synthase; 1.
DR InterPro; IPR000462; CDP-OH_P_trans.
DR InterPro; IPR043130; CDP-OH_PTrfase_TM_dom.
DR InterPro; IPR044268; PIP_synthase_PgsA1.
DR Pfam; PF01066; CDP-OH_P_transf; 1.
DR PROSITE; PS00379; CDP_ALCOHOL_P_TRANSF; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Lipid biosynthesis; Lipid metabolism;
KW Magnesium; Membrane; Metal-binding; Phospholipid biosynthesis;
KW Phospholipid metabolism; Reference proteome; Transferase; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..217
FT /note="Phosphatidylinositol phosphate synthase"
FT /id="PRO_0000393108"
FT TRANSMEM 30..48
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:31098408"
FT TRANSMEM 54..77
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:31098408"
FT TRANSMEM 83..110
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:31098408"
FT TRANSMEM 115..140
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:31098408"
FT TRANSMEM 152..166
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:31098408"
FT TRANSMEM 176..200
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:31098408"
FT ACT_SITE 93
FT /note="Proton acceptor"
FT /evidence="ECO:0000305|PubMed:31098408"
FT BINDING 31..34
FT /ligand="a CDP-1,2-diacyl-sn-glycerol"
FT /ligand_id="ChEBI:CHEBI:58332"
FT /evidence="ECO:0000269|PubMed:31098408"
FT BINDING 68
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:31098408"
FT BINDING 68
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:31098408"
FT BINDING 71
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:31098408"
FT BINDING 72
FT /ligand="a CDP-1,2-diacyl-sn-glycerol"
FT /ligand_id="ChEBI:CHEBI:58332"
FT /evidence="ECO:0000269|PubMed:31098408"
FT BINDING 76
FT /ligand="a CDP-1,2-diacyl-sn-glycerol"
FT /ligand_id="ChEBI:CHEBI:58332"
FT /evidence="ECO:0000269|PubMed:31098408"
FT BINDING 82
FT /ligand="a CDP-1,2-diacyl-sn-glycerol"
FT /ligand_id="ChEBI:CHEBI:58332"
FT /evidence="ECO:0000269|PubMed:31098408"
FT BINDING 89
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:31098408"
FT BINDING 89
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:31098408"
FT BINDING 93
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:31098408"
FT MUTAGEN 90
FT /note="A->Y: Large decrease in catalytic activity."
FT /evidence="ECO:0000269|PubMed:31098408"
FT MUTAGEN 94
FT /note="R->K: Large decrease in catalytic activity."
FT /evidence="ECO:0000269|PubMed:31098408"
FT MUTAGEN 94
FT /note="R->Q: Almost loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:31098408"
FT MUTAGEN 133
FT /note="Y->E: Almost loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:31098408"
FT MUTAGEN 133
FT /note="Y->F: No change in catalytic activity."
FT /evidence="ECO:0000269|PubMed:31098408"
FT MUTAGEN 137
FT /note="R->K: No change in catalytic activity."
FT /evidence="ECO:0000269|PubMed:31098408"
FT MUTAGEN 137
FT /note="R->Q: 2-fold decrease in catalytic activity."
FT /evidence="ECO:0000269|PubMed:31098408"
FT HELIX 9..12
FT /evidence="ECO:0007829|PDB:6H5A"
FT TURN 13..15
FT /evidence="ECO:0007829|PDB:6H5A"
FT HELIX 16..26
FT /evidence="ECO:0007829|PDB:6H59"
FT HELIX 30..48
FT /evidence="ECO:0007829|PDB:6H59"
FT HELIX 49..51
FT /evidence="ECO:0007829|PDB:6H59"
FT HELIX 54..67
FT /evidence="ECO:0007829|PDB:6H59"
FT HELIX 69..77
FT /evidence="ECO:0007829|PDB:6H59"
FT HELIX 83..110
FT /evidence="ECO:0007829|PDB:6H59"
FT HELIX 115..140
FT /evidence="ECO:0007829|PDB:6H59"
FT HELIX 152..166
FT /evidence="ECO:0007829|PDB:6H59"
FT STRAND 169..171
FT /evidence="ECO:0007829|PDB:6H59"
FT HELIX 176..200
FT /evidence="ECO:0007829|PDB:6H59"
FT TURN 203..206
FT /evidence="ECO:0007829|PDB:6H59"
FT TURN 215..217
FT /evidence="ECO:0007829|PDB:6H5A"
SQ SEQUENCE 217 AA; 23252 MW; 49BCA9781E35AF2C CRC64;
MSKLPFLSRA AFARITTPIA RGLLRVGLTP DVVTILGTTA SVAGALTLFP MGKLFAGACV
VWFFVLFDML DGAMARERGG GTRFGAVLDA TCDRISDGAV FCGLLWWIAF HMRDRPLVIA
TLICLVTSQV ISYIKARAEA SGLRGDGGFI ERPERLIIVL TGAGVSDFPF VPWPPALSVG
MWLLAVASVI TCVQRLHTVW TSPGAIDRMA IPGKGDR
