Carrier protein (CP) domains are crucial components involved in the transfer
of thiol ester-bound intermediates during the biosynthesis of primary and
secondary metabolites such as fatty acids, polyketides, and nonribosomal
peptides. CP domains, also referred to as thiolation domains, are responsible
for transporting the substrate and chain intermediates to the catalytic
centers of the polyketide synthase (PKS), nonribosomal peptide synthetase
(NRPS), and fatty acid synthase (FAS) assembly lines. The biosynthetic chain
intermediates are tethered as thioesters on the terminal thiol of a
phosphopantetheine (or pantetheine 4' phosphate) (Ppant) prosthetic group that
is covalently attached to an invariant serine residue of the CP domain. CP
domains, typically consisting of 70–100 residues, are either freestanding or
embedded in these multifunctional proteins and exist as three variants: an
acyl carrier protein (ACP) found in PKSs and FASs, a peptidyl carrier protein
(PCP) found in NRPS systems, and an aryl carrier protein (ArCP) commonly found
in siderophore NRPS synthetases [1,2,3]. CP domains have been found in various
enzyme systems which are listed below:
Fatty acid synthase (FAS), which catalyzes the formation of long-chain
fatty acids from acetyl-CoA, malonyl-CoA and NADPH. Bacterial and plant
chloroplast FAS are composed of eight separate subunits which correspond to
the different enzymatic activities; CP is one of these polypeptides. Fungal
FAS consists of two multifunctional proteins, FAS1 and FAS2; the CP domain
is located in the N-terminal section of FAS2. Vertebrate FAS consists of a
single multifunctional enzyme; the CP domain is located between the β-
ketoacyl reductase domain and the C-terminal thioesterase domain .
Polyketide antibiotics synthase enzyme systems. Polyketides are secondary
metabolites produced from simple fatty acids, by microorganisms and plants.
CP is one of the polypeptidic components involved in the biosynthesis of
Streptomyces polyketide antibiotics actinorhodin, curamycin, granatacin,
monensin, oxytetracycline and tetracenomycin C.
Bacillus subtilis putative polyketide synthases pksK, pksL and pksM which
respectively contain three, five and one CP domains.
The multifunctional 6-methysalicylic acid synthase (MSAS) from Penicillium
patulum. This is a multifunctional enzyme involved in the biosynthesis of a
polyketide antibiotic and which contains a CP domain in the C-terminal
Multifunctional mycocerosic acid synthase (gene mas) from Mycobacterium
Gramicidin S synthase I (gene grsA) from Bacillus brevis. This enzyme
catalyzes the first step in the biosynthesis of the cyclic antibiotic
Tyrocidine synthase I (gene tycA) from Bacillus brevis. The reaction
carried out by tycA is identical to that catalyzed by grsA.
Gramicidin S synthase II (gene grsB) from Bacillus brevis. This enzyme is a
multifunctional protein that activates and polymerizes proline, valine,
ornithine and leucine. GrsB contains four CP domains.
Erythronolide synthase proteins 1, 2 and 3 from Saccharopolyspora erythraea
which is involved in the biosynthesis of the polyketide antibiotic
erythromicin. Each of these proteins contains two CP domains.
Conidial green pigment synthase from Aspergillus nidulans.
ACV synthase from various fungi. This enzyme catalyzes the first step in
the biosynthesis of penicillin and cephalosporin. It contains three CP
Enterobactin synthase component F (gene entF) from Escherichia coli. This
enzyme is involved in the ATP-dependent activation of serine during
enterobactin (enterochelin) biosynthesis.
Cyclic peptide antibiotic surfactin synthase subunits 1, 2 and 3 from
Bacillus subtilis. Subunits 1 and 2 contain three related domains while
subunit 3 only contains a single domain.
HC-toxin synthase (gene HTS1) from Cochliobolus carbonum. This enzyme
synthesizes HC-toxin, a cyclic tetrapeptide. HTS1 contains four CP domains.
Fungal mitochondrial ACP, which is part of the respiratory chain NADH
dehydrogenase (complex I).
Rhizobium nodulation protein nodF, which probably acts as an CP in the
synthesis of the nodulation Nod factor fatty acyl chain.
The CP domain fold is variably referred to as a 3- or 4-helix bundle and
typically consists of 3 major α helices, with helix I being antiparallel
to helices II and IV, plus a short 3(10) or α-helical segment (helix III)
linking helices II and IV (see <PDB:1ACP>) .
The sequence around the phosphopantetheine attachment site is conserved in all
these proteins and can be used as a signature pattern. A profile was also
developed that spans the complete CP domain.
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