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Information on EC 2.7.8.7 - holo-[acyl-carrier-protein] synthase and Organism(s) Homo sapiens

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EC Tree
IUBMB Comments
Requires Mg2+. All polyketide synthases, fatty-acid synthases and non-ribosomal peptide synthases require post-translational modification of their constituent acyl-carrier-protein (ACP) domains to become catalytically active. The inactive apo-proteins are converted into their active holo-forms by transfer of the 4'-phosphopantetheinyl moiety of CoA to the sidechain hydroxy group of a conserved serine residue in each ACP domain . The enzyme from human can activate both the ACP domain of the human cytosolic multifunctional fatty-acid synthase system (EC 2.3.1.85) and that associated with human mitochondria as well as peptidyl-carrier and acyl-carrier-proteins from prokaryotes . Removal of the 4-phosphopantetheinyl moiety from holo-ACP is carried out by EC 3.1.4.14, [acyl-carrier-protein] phosphodiesterase.
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Homo sapiens
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
pptase, phosphopantetheinyl transferase, surfactin synthetase, 4'-phosphopantetheinyl transferase, mtppt, type ii fatty acid synthase system, sfp-type pptase, holo-acyl carrier protein synthase, schppt, mtacps, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
4'-phosphopantetheinyl transferase
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acyl carrier protein holoprotein (holo-ACP) synthetase
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acyl carrier protein synthetase
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acyl carrier protein-specific 4'-phosphopantetheinyl transferase
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coenzyme A:fatty acid synthetase apoenzyme 4'-phosphopantetheine transferase
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holo ACP synthase
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holo-ACP synthase
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holo-ACP synthetase
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holosynthase
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human PPTase
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L-aminoadipate-semialdehyde dehydrogenase-phosphopantetheinyl transferase
UniProt
phosphopantetheinyl transferase
Sfp-PPTase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
CoA-[4'-phosphopantetheine] + an apo-[acyl-carrier protein] = adenosine 3',5'-bisphosphate + an [acyl-carrier protein]
show the reaction diagram
sequential binding mechanism: initial CoA- and Mg2+-binding followed by binding of acyl-carrier protein (ACP), nucleophilic attack of ACP-serine-hydroxylate on beta-phosphate of CoA followed by charge migration, Lys185-protonation, diphosphate-cleavage, and product dissociation, rate limiting step: release of 3',5'-ADP, key acid/base catalysts: residues E181 (CoA-binding) and K185 (Mg2+-binding)
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
substituted phospho group transfer
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PATHWAY SOURCE
PATHWAYS
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-, -, -, -
SYSTEMATIC NAME
IUBMB Comments
CoA-[4'-phosphopantetheine]:apo-[acyl-carrier protein] 4'-pantetheinephosphotransferase
Requires Mg2+. All polyketide synthases, fatty-acid synthases and non-ribosomal peptide synthases require post-translational modification of their constituent acyl-carrier-protein (ACP) domains to become catalytically active. The inactive apo-proteins are converted into their active holo-forms by transfer of the 4'-phosphopantetheinyl moiety of CoA to the sidechain hydroxy group of a conserved serine residue in each ACP domain [3]. The enzyme from human can activate both the ACP domain of the human cytosolic multifunctional fatty-acid synthase system (EC 2.3.1.85) and that associated with human mitochondria as well as peptidyl-carrier and acyl-carrier-proteins from prokaryotes [6]. Removal of the 4-phosphopantetheinyl moiety from holo-ACP is carried out by EC 3.1.4.14, [acyl-carrier-protein] phosphodiesterase.
CAS REGISTRY NUMBER
COMMENTARY hide
37278-30-1
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SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
apo-[acyl-carrier protein] + acetyl-CoA
CoA + acetyl-[acyl-carrier protein]
show the reaction diagram
pH 7, 37°C
reaction stop by 10% trichloroacetic acid, limited release of 3’,5’-ADP by interactions with guanidinium moieties of R74 and R86
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?
CoA + apo-[acyl-carrier protein]
adenosine 3',5'-bisphosphate + holo-[acyl-carrier protein]
show the reaction diagram
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r
CoA + apo-[alpha-aminoadipate semialdehyde dehydrogenase]
adenosine 3',5'-bisphosphate + holo-[alpha-aminoadipate semialdehyde dehydrogenase]
show the reaction diagram
CoA + apo-[peptidyl carrier protein]
adenosine 3',5'-bisphosphate + holo-[peptidyl-carrier protein]
show the reaction diagram
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-
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r
CoA-[4'-phosphopantetheine] + apo-[acyl-carrier protein]
adenosine 3',5'-bisphosphate + holo-[acyl-carrier protein]
show the reaction diagram
CoA-[4'-phosphopantetheine] + apo-[FDH protein]
adenosine 3',5'-bisphosphate + holo-[FDH protein]
show the reaction diagram
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the enzyme modifies the apo-FDH protein at serine 354 and activates its catalysis
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-
?
additional information
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
CoA + apo-[acyl-carrier protein]
adenosine 3',5'-bisphosphate + holo-[acyl-carrier protein]
show the reaction diagram
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-
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r
CoA + apo-[alpha-aminoadipate semialdehyde dehydrogenase]
adenosine 3',5'-bisphosphate + holo-[alpha-aminoadipate semialdehyde dehydrogenase]
show the reaction diagram
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phosphopantetheinylation of the enzyme involved in lysine catabolism
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r
CoA-[4'-phosphopantetheine] + apo-[acyl-carrier protein]
adenosine 3',5'-bisphosphate + holo-[acyl-carrier protein]
show the reaction diagram
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
4'-phosphopantetheine
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0247 - 0.399
acetyl-CoA
0.021
apo-ACP
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pH 7.0, 37°C, Bacillus subtilis acyl carrier protein-A as substrate
0.0031 - 0.0075
apo-acyl-carrier protein
0.0064
apo-peptidyl carrier protein
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pH 7.0, 37°C
0.44 - 104.1
Mg2+
additional information
acetyl-CoA
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.000098 - 0.973
acetyl-CoA
0.0003 - 1.2
Mg2+
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.7
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
assay at
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
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enzyme silencing by small interfering RNA in A-549 cells prevents FDH modification. Enzyme-silenced cells demonstrate significantly reduced proliferation and undergo strong G1 arrest
physiological function
phosphopantetheinyl transferase activates biosynthetic pathways that synthesize both primary and secondary metabolites in bacteria
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
ADPPT_HUMAN
309
0
35776
Swiss-Prot
Mitochondrion (Reliability: 5)
E9PNF3_HUMAN
160
0
18696
TrEMBL
Mitochondrion (Reliability: 5)
E9PLW6_HUMAN
190
0
22241
TrEMBL
Mitochondrion (Reliability: 5)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
35000
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x * 35000, recombinant His-tagged enzyme, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
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x * 35000, recombinant His-tagged enzyme, SDS-PAGE
monomer
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
apo-PPT (PDB: 2BYD) or in complex with coenzyme A (CoA, 5 mM) and Mg2+ (20 mM) (PDB: 2C43) or coenzyme A (2.5 mM) and acyl-carrier protein (S2156A mutant of ACP domain of fatty acid synthase) (PDB: 2CG5), precipitant: 14% PEG3350 and 0.05 M H3Cit/Na3Cit pH 5.7 or 2 M NaCl and 10% PEG6000 (complexes), apo-PPT: space group: P2(1)2(1)2(1), unit cell parameters: a: 63.78, b: 69.95, c: 71.24, alpha/beta fold with pseudo 2fold symmetry, N-terminal beta sheet (residues 91-116) connected to C-terminal beta sheet (residues 207-239) by a one residue linker and unique N-terminal and C-terminal extensions of 13 and 52 amino acids, respectively, PPT-CoA complex: space group: P2(1)2(1)2(1), unit cell parameters: a: 65.59, b: 68.96, c: 70.75, CoA-binding at the interface of N- and C-terminal domain mediated by PPT residues 47, 86, 110, 111, 185 (hydrophobic interactions, hydrogen bonds and salt bridges), and independent of Mg2+, Mg2+ bound through PPT residues 181 and 129 and coordinated by a water molecule, PPT-CoA-ACP complex: space group: P3(2)21, unit cell parameters: a, b: 69.36, c: 184.7, ACP-binding in the cleft between N- and C-terminal domain causes their rotation and slight closure, and is facilitated predominantly by hydrophobic interactions with PPT residues 51-54, 191, 144-148, 173, and 177 and a few polar interactions, disorder of C-terminal coil (residues 290-305), lack of Mg2+
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D129A
reduced Mg2+ affinity and catalytic efficiency, D129 plays a role in Mg2+-coordination
E181A
significant loss in enzyme activity, reduced Mg2+ affinity and catalytic efficiency
E181Q
significant loss in enzyme activity, reduced Mg2+ affinity (20fold) and catalytic efficiency (300fold)
K185
significant loss in enzyme activity, reduced catalytic efficiency
Q112E
slightly reduced catalytic efficiency
Q112E, E181Q
double mutant, reduced Mg2+ affinity (200fold) and catalytic efficiency
R47A
reduced coenzymeA and Mg2+ affinity, increased catalytic efficiency
R86A
reduced coenzymeA and Mg2+ affinity, increased catalytic efficiency
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
from bacterial lysate by immobilized metal affinity chromatography followed by gel filtration chromatography on Superdex200 HiLoad 26/60 column and concentration to 20 mg/ml or anion exchange chromatography and dialysis
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cloned and expressed in Sf9 insect cells
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expressed in Escherichia coli BL21(DE3)-codon plus cells
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gene AASDHPPT, recombinant expression of the Sfp-PPTase from plasmid pET29b in Escherichia coli strain BL21(DE3)
in pCOEX1 for expression with TEV protease-cleavable N-terminal hexa-His-tag in Escherichia coli BL21(DE3)-R3
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
molecular biology
insights in molecular architecture and reaction mechanism of group II PPTs in contrast to group I PPTs (bacterial) enable screening for antibacterial agents which specifically inhibit bacterial PPTs
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Joshi, A.K.; Zhang, L.; Rangan, V.S.; Smith, S.
Cloning, expression, and characterization of a human 4'-phosphopantetheinyl transferase with broad substrate specificity
J. Biol. Chem.
278
33142-33149
2003
Homo sapiens
Manually annotated by BRENDA team
Bunkoczi, G.; Pasta, S.; Joshi, A.; Wu, X.; Kavanagh, K.L.; Smith, S.; Oppermann, U.
Mechanism and substrate recognition of human holo ACP synthase
Chem. Biol.
14
1243-1253
2007
Homo sapiens (Q9NRN7), Homo sapiens
Manually annotated by BRENDA team
Strickland, K.C.; Hoeferlin, L.A.; Oleinik, N.V.; Krupenko, N.I.; Krupenko, S.A.
Acyl carrier protein-specific 4-phosphopantetheinyl transferase activates 10-formyltetrahydrofolate dehydrogenase
J. Biol. Chem.
285
1627-1633
2010
Homo sapiens
Manually annotated by BRENDA team
Kosa, N.M.; Foley, T.L.; Burkart, M.D.
Fluorescent techniques for discovery and characterization of phosphopantetheinyl transferase inhibitors
J. Antibiot.
67
113-120
2014
Homo sapiens (Q9NRN7), Homo sapiens
Manually annotated by BRENDA team