PPTT_MYCTU
ID PPTT_MYCTU Reviewed; 227 AA.
AC O33336; I6XFB3;
DT 02-DEC-2020, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 135.
DE RecName: Full=4'-phosphopantetheinyl transferase PptT {ECO:0000305};
DE Short=PPTase {ECO:0000303|PubMed:9831524};
DE EC=2.7.8.7 {ECO:0000269|PubMed:16709676, ECO:0000269|PubMed:25785780, ECO:0000269|PubMed:28203522, ECO:0000269|PubMed:9831524};
GN Name=pptT {ECO:0000303|PubMed:9831524};
GN OrderedLocusNames=Rv2794c {ECO:0000312|EMBL:CCP45593.1};
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 FUNCTION, AND CATALYTIC ACTIVITY.
RC STRAIN=CSU93;
RX PubMed=9831524; DOI=10.1016/s1074-5521(98)90291-5;
RA Quadri L.E.N., Sello J., Keating T.A., Weinreb P.H., Walsh C.T.;
RT "Identification of a Mycobacterium tuberculosis gene cluster encoding the
RT biosynthetic enzymes for assembly of the virulence-conferring siderophore
RT mycobactin.";
RL Chem. Biol. 5:631-645(1998).
RN [3]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=16709676; DOI=10.1073/pnas.0511129103;
RA Chalut C., Botella L., de Sousa-D'Auria C., Houssin C., Guilhot C.;
RT "The nonredundant roles of two 4'-phosphopantetheinyl transferases in vital
RT processes of Mycobacteria.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:8511-8516(2006).
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 IN VIRULENCE, AND IDENTIFICATION AS A DRUG TARGET.
RX PubMed=23308068; DOI=10.1371/journal.ppat.1003097;
RA Leblanc C., Prudhomme T., Tabouret G., Ray A., Burbaud S., Cabantous S.,
RA Mourey L., Guilhot C., Chalut C.;
RT "4'-phosphopantetheinyl transferase PptT, a new drug target required for
RT Mycobacterium tuberculosis growth and persistence in vivo.";
RL PLoS Pathog. 8:e1003097-e1003097(2012).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, AND COFACTOR.
RX PubMed=25785780; DOI=10.1021/bi501444e;
RA Zimhony O., Schwarz A., Raitses-Gurevich M., Peleg Y., Dym O., Albeck S.,
RA Burstein Y., Shakked Z.;
RT "AcpM, the meromycolate extension acyl carrier protein of Mycobacterium
RT tuberculosis, is activated by the 4'-phosphopantetheinyl transferase PptT,
RT a potential target of the multistep mycolic acid biosynthesis.";
RL Biochemistry 54:2360-2371(2015).
RN [7]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=28203522; DOI=10.1002/2211-5463.12140;
RA Jung J., Bashiri G., Johnston J.M., Baker E.N.;
RT "Mass spectral determination of phosphopantetheinylation specificity for
RT carrier proteins in Mycobacterium tuberculosis.";
RL FEBS Open Bio 6:1220-1226(2016).
RN [8]
RP STRUCTURAL MODELING.
RX PubMed=23930020; DOI=10.6026/97320630009685;
RA Rohini K., Srikumar P.S.;
RT "Insights from the docking and molecular dynamics simulation of the
RT Phosphopantetheinyl transferase (PptT) structural model from Mycobacterium
RT tuberculosis.";
RL Bioinformation 9:685-689(2013).
RN [9] {ECO:0007744|PDB:4QJK}
RP X-RAY CRYSTALLOGRAPHY (1.59 ANGSTROMS) IN COMPLEX WITH COENZYME A, AND
RP MUTAGENESIS OF ARG-48; ARG-56; ASP-114; GLU-116 AND GLU-157.
RX PubMed=24963544; DOI=10.1021/cb500263p;
RA Vickery C.R., Kosa N.M., Casavant E.P., Duan S., Noel J.P., Burkart M.D.;
RT "Structure, biochemistry, and inhibition of essential 4'-
RT phosphopantetheinyl transferases from two species of Mycobacteria.";
RL ACS Chem. Biol. 9:1939-1944(2014).
RN [10] {ECO:0007744|PDB:4QVH}
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) IN COMPLEX WITH COENZYME A AND
RP MAGNESIUM.
RC STRAIN=H37Rv;
RX PubMed=25450595; DOI=10.1016/j.jsb.2014.10.004;
RA Jung J., Bashiri G., Johnston J.M., Brown A.S., Ackerley D.F., Baker E.N.;
RT "Crystal structure of the essential Mycobacterium tuberculosis
RT phosphopantetheinyl transferase PptT, solved as a fusion protein with
RT maltose binding protein.";
RL J. Struct. Biol. 188:274-278(2014).
RN [11] {ECO:0007744|PDB:4U89}
RP X-RAY CRYSTALLOGRAPHY (1.40 ANGSTROMS) IN COMPLEX WITH COENZYME A.
RA Faille A., Gavalda S., Rottier K., Mourey L., Pedelacq J.D.;
RT "X-ray structure of the 4'-phosphopantetheinyl transferase PptT from
RT Mycobacterium tuberculosis.";
RL Submitted (AUG-2014) to the PDB data bank.
RN [12] {ECO:0007744|PDB:6CT5}
RP X-RAY CRYSTALLOGRAPHY (1.76 ANGSTROMS) IN COMPLEX WITH COENZYME A;
RP MAGNESIUM AND INHIBITOR 8918, ACTIVITY REGULATION, AND MUTAGENESIS OF
RP TRP-170.
RX PubMed=30705156; DOI=10.1126/science.aau8959;
RA Ballinger E., Mosior J., Hartman T., Burns-Huang K., Gold B., Morris R.,
RA Goullieux L., Blanc I., Vaubourgeix J., Lagrange S., Fraisse L., Sans S.,
RA Couturier C., Bacque E., Rhee K., Scarry S.M., Aube J., Yang G.,
RA Ouerfelli O., Schnappinger D., Ioerger T.R., Engelhart C.A.,
RA McConnell J.A., McAulay K., Fay A., Roubert C., Sacchettini J., Nathan C.;
RT "Opposing reactions in coenzyme A metabolism sensitize Mycobacterium
RT tuberculosis to enzyme inhibition.";
RL Science 363:0-0(2019).
RN [13]
RP ERRATUM OF PUBMED:30705156.
RX PubMed=31221826; DOI=10.1126/science.aay3546;
RA Ballinger E., Mosior J., Hartman T., Burns-Huang K., Gold B., Morris R.,
RA Goullieux L., Blanc I., Vaubourgeix J., Lagrange S., Fraisse L., Sans S.,
RA Couturier C., Bacque E., Rhee K., Scarry S.M., Aube J., Yang G.,
RA Ouerfelli O., Schnappinger D., Ioerger T.R., Engelhart C.A.,
RA McConnell J.A., McAulay K., Fay A., Roubert C., Sacchettini J., Nathan C.;
RT "Opposing reactions in coenzyme A metabolism sensitize Mycobacterium
RT tuberculosis to enzyme inhibition.";
RL Science 364:0-0(2019).
CC -!- FUNCTION: Transfers the 4'-phosphopantetheine moiety from coenzyme A to
CC a Ser of acyl-carrier-protein (PubMed:9831524, PubMed:16709676,
CC PubMed:25785780, PubMed:28203522). Involved in post-translational
CC modification of various type-I polyketide synthases required for the
CC formation of both mycolic acids and lipid virulence factors
CC (PubMed:16709676). Acts on Pks13, Mas, PpsA, PpsB, PpsC and PpsD
CC (PubMed:16709676, PubMed:28203522). Also acts on AcpM, the meromycolate
CC extension acyl carrier protein (PubMed:25785780). In addition, is
CC involved in the activation of the acyl carrier protein MbtL and the
CC nonribosomal peptides synthases MbtB and MbtE, which are involved in
CC the biosynthesis of the siderophore mycobactin (PubMed:9831524,
CC PubMed:28203522). {ECO:0000269|PubMed:16709676,
CC ECO:0000269|PubMed:25785780, ECO:0000269|PubMed:28203522,
CC ECO:0000269|PubMed:9831524}.
CC -!- FUNCTION: Required for the replication and survival of Mycobacterium
CC during the acute and chronic phases of infection in mice.
CC {ECO:0000269|PubMed:23308068}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=apo-[ACP] + CoA = adenosine 3',5'-bisphosphate + H(+) + holo-
CC [ACP]; Xref=Rhea:RHEA:12068, Rhea:RHEA-COMP:9685, Rhea:RHEA-
CC COMP:9690, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:58343, ChEBI:CHEBI:64479; EC=2.7.8.7;
CC Evidence={ECO:0000269|PubMed:16709676, ECO:0000269|PubMed:25785780,
CC ECO:0000269|PubMed:28203522, ECO:0000269|PubMed:9831524};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:25785780};
CC -!- ACTIVITY REGULATION: Inhibited by the amidino-urea compound 1-[(2,6-
CC diethylphenyl)-3-N-ethylcarbamimodoyl]urea (compound 8918). It acts by
CC binding to the phosphopantetheine pocket in the active site. Inhibition
CC by compound 8918 kills M.tuberculosis. {ECO:0000269|PubMed:30705156}.
CC -!- MISCELLANEOUS: Identified as a drug target.
CC {ECO:0000269|PubMed:23308068}.
CC -!- SIMILARITY: Belongs to the P-Pant transferase superfamily.
CC {ECO:0000305}.
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DR EMBL; AL123456; CCP45593.1; -; Genomic_DNA.
DR RefSeq; NP_217310.1; NC_000962.3.
DR RefSeq; WP_003917055.1; NZ_NVQJ01000020.1.
DR PDB; 4QJK; X-ray; 1.59 A; A=1-227.
DR PDB; 4QVH; X-ray; 1.75 A; A/B=1-227.
DR PDB; 4U89; X-ray; 1.40 A; A=1-227.
DR PDB; 6CT5; X-ray; 1.76 A; A/B=1-227.
DR PDB; 7N8E; X-ray; 1.74 A; A/B=1-227.
DR PDB; 7N8L; X-ray; 2.26 A; A/B=1-227.
DR PDB; 7N8M; X-ray; 1.57 A; A/B=1-227.
DR PDBsum; 4QJK; -.
DR PDBsum; 4QVH; -.
DR PDBsum; 4U89; -.
DR PDBsum; 6CT5; -.
DR PDBsum; 7N8E; -.
DR PDBsum; 7N8L; -.
DR PDBsum; 7N8M; -.
DR AlphaFoldDB; O33336; -.
DR SMR; O33336; -.
DR STRING; 83332.Rv2794c; -.
DR PaxDb; O33336; -.
DR DNASU; 888226; -.
DR GeneID; 888226; -.
DR KEGG; mtu:Rv2794c; -.
DR PATRIC; fig|83332.111.peg.3107; -.
DR TubercuList; Rv2794c; -.
DR eggNOG; COG2977; Bacteria.
DR InParanoid; O33336; -.
DR OMA; GSLTHCD; -.
DR PhylomeDB; O33336; -.
DR BRENDA; 2.7.8.7; 3445.
DR PHI-base; PHI:2629; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0009366; C:enterobactin synthetase complex; IEA:InterPro.
DR GO; GO:0031226; C:intrinsic component of plasma membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR GO; GO:0008897; F:holo-[acyl-carrier-protein] synthase activity; IDA:MTBBASE.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0009239; P:enterobactin biosynthetic process; IEA:InterPro.
DR GO; GO:0019290; P:siderophore biosynthetic process; IDA:UniProtKB.
DR GO; GO:0009237; P:siderophore metabolic process; IBA:GO_Central.
DR InterPro; IPR008278; 4-PPantetheinyl_Trfase_dom.
DR InterPro; IPR037143; 4-PPantetheinyl_Trfase_dom_sf.
DR InterPro; IPR041354; 4PPT_N.
DR InterPro; IPR003542; Enbac_synth_compD-like.
DR PANTHER; PTHR38096; PTHR38096; 1.
DR Pfam; PF17837; 4PPT_N; 1.
DR Pfam; PF01648; ACPS; 1.
DR PRINTS; PR01399; ENTSNTHTASED.
DR SUPFAM; SSF56214; SSF56214; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Magnesium; Metal-binding; Reference proteome; Transferase.
FT CHAIN 1..227
FT /note="4'-phosphopantetheinyl transferase PptT"
FT /id="PRO_0000451441"
FT BINDING 48
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000269|PubMed:24963544,
FT ECO:0000269|PubMed:25450595, ECO:0000269|Ref.11"
FT BINDING 56
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000269|PubMed:24963544,
FT ECO:0000269|PubMed:25450595, ECO:0000269|Ref.11"
FT BINDING 75..78
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000269|PubMed:24963544,
FT ECO:0000269|PubMed:25450595, ECO:0000269|Ref.11"
FT BINDING 92..93
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000269|PubMed:24963544,
FT ECO:0000269|PubMed:25450595, ECO:0000269|Ref.11"
FT BINDING 114
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000269|PubMed:24963544,
FT ECO:0000269|PubMed:25450595"
FT BINDING 114
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:25450595,
FT ECO:0007744|PDB:4QVH"
FT BINDING 115
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:25450595,
FT ECO:0007744|PDB:4QVH"
FT BINDING 116
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:25450595,
FT ECO:0007744|PDB:4QVH"
FT BINDING 157
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000269|PubMed:24963544, ECO:0000269|Ref.11"
FT BINDING 161
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000269|PubMed:24963544,
FT ECO:0000269|PubMed:25450595, ECO:0000269|Ref.11"
FT BINDING 171
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000269|PubMed:24963544,
FT ECO:0000269|PubMed:25450595, ECO:0000269|Ref.11"
FT MUTAGEN 48
FT /note="R->A: 20-fold decrease in phosphopantetheinylation
FT activity."
FT /evidence="ECO:0000269|PubMed:24963544"
FT MUTAGEN 56
FT /note="R->A: 100-fold decrease in phosphopantetheinylation
FT activity."
FT /evidence="ECO:0000269|PubMed:24963544"
FT MUTAGEN 114
FT /note="D->N: Abolishes phosphopantetheinylation activity."
FT /evidence="ECO:0000269|PubMed:24963544"
FT MUTAGEN 116
FT /note="E->Q: 500-fold decrease in phosphopantetheinylation
FT activity."
FT /evidence="ECO:0000269|PubMed:24963544"
FT MUTAGEN 157
FT /note="E->Q: Abolishes phosphopantetheinylation activity."
FT /evidence="ECO:0000269|PubMed:24963544"
FT MUTAGEN 170
FT /note="W->L,S: Confers high-level resistance to compound
FT 8918."
FT /evidence="ECO:0000269|PubMed:30705156"
FT HELIX 6..10
FT /evidence="ECO:0007829|PDB:4U89"
FT HELIX 16..18
FT /evidence="ECO:0007829|PDB:4U89"
FT STRAND 19..26
FT /evidence="ECO:0007829|PDB:4U89"
FT TURN 35..37
FT /evidence="ECO:0007829|PDB:4U89"
FT HELIX 38..41
FT /evidence="ECO:0007829|PDB:4U89"
FT HELIX 46..65
FT /evidence="ECO:0007829|PDB:4U89"
FT HELIX 77..79
FT /evidence="ECO:0007829|PDB:4U89"
FT STRAND 87..94
FT /evidence="ECO:0007829|PDB:4U89"
FT STRAND 97..104
FT /evidence="ECO:0007829|PDB:4U89"
FT TURN 105..107
FT /evidence="ECO:0007829|PDB:4U89"
FT STRAND 109..118
FT /evidence="ECO:0007829|PDB:4U89"
FT HELIX 123..129
FT /evidence="ECO:0007829|PDB:4U89"
FT HELIX 132..141
FT /evidence="ECO:0007829|PDB:4U89"
FT HELIX 148..167
FT /evidence="ECO:0007829|PDB:4U89"
FT HELIX 173..175
FT /evidence="ECO:0007829|PDB:4U89"
FT STRAND 176..182
FT /evidence="ECO:0007829|PDB:4U89"
FT STRAND 186..195
FT /evidence="ECO:0007829|PDB:4U89"
FT STRAND 202..205
FT /evidence="ECO:0007829|PDB:4U89"
FT STRAND 209..217
FT /evidence="ECO:0007829|PDB:4U89"
FT STRAND 220..227
FT /evidence="ECO:0007829|PDB:4U89"
SQ SEQUENCE 227 AA; 24709 MW; 60C988873EE28472 CRC64;
MTVGTLVASV LPATVFEDLA YAELYSDPPG LTPLPEEAPL IARSVAKRRN EFITVRHCAR
IALDQLGVPP APILKGDKGE PCWPDGMVGS LTHCAGYRGA VVGRRDAVRS VGIDAEPHDV
LPNGVLDAIS LPAERADMPR TMPAALHWDR ILFCAKEATY KAWFPLTKRW LGFEDAHITF
ETDSTGWTGR FVSRILIDGS TLSGPPLTTL RGRWSVERGL VLTAIVL
