Nonribosomal peptide synthetases serve as multidomain protein templates
for producing a wealth of pharmaceutically important natural products.
For the correct assembly of the desired natural product the interactions
between the different catalytic centres and the reaction intermediates bound
to the peptidyl carrier protein must be precisely controlled at spatial and
Aspergillus fumigatusis an important human fungal pathogen. The Asper-gillus fumigatus genome contains 14 nonribosomal peptide synthetase
genes, potentially responsible for generating metabolites that contribute to
organismal virulence. Differential expression of the nonribosomal peptide
synthetase gene,pes1, in four strains of Aspergillus fumigatuswas observed.
Recent studies on type II thioesterases (TEIIs) involved in
microbial secondary metabolism described a role for these
enzymes in the removal of short acyl-S- phosphopantetheine
intermediates from misprimed holo-(acyl carrier proteins)
and holo-(peptidyl carrier proteins) of polyketide synthases
and nonribosomal peptide synthetases.
This work presents a computational analysis of the molecular characteris-tics shared by the adenylation domains from traditional nonribosomal pep-tide synthetases (NRPSs) and the group of the freestanding homologous
enzymes: a-aminoadipate semialdehyde dehydrogenase, a-aminoadipate
reductase and the protein Ebony. The results of systematic sequence com-parisons allow us to conclude that a specificity-conferring code, similar to
that described for the NRPSs, can be recognized in such enzymes.
Many pharmacologically important agents are assembled on multimodular
nonribosomal peptide synthetases (NRPSs) whose modules comprise a set
of core domains with all essential catalytic functions necessary for the
incorporation and modification of one building block. Very often, d-amino
acids are found in such products which, with few exceptions, are generated
by the action of NRPS integrated epimerization (E) domains that alter the
stereochemistry of the corresponding peptidyl carrier protein (PCP) bound
The initial condensation event in the nonribosomal biosyn-thesisof thepeptideantibioticsgramicidinSandtyrocidineA
takes place between a phenylalanine activating racemase
GrsA/TycAand the ®rst proline-activatingmodule ofGrsB/
TycB. Recently we established a minimalin vitro model
system for NRPS with recombinant His6-tagged GrsA
Phe-ATE; 127 kDa) and TycB1 (TycB1Pro-CAT;
120 kDa) and demonstrated the catalytic function of the
C-domaininTycB1Pro-CAT to form a peptide bond
between phenylalanine and proline during diketopiperazine
formation (DKP). ...
The class of nonribosomally assembled siderophores encompasses a multi-tude of structurally diverse natural products. The genome of the erythro-mycin-producing strainSaccharopolyspora erythraeacontains 25 secondary
metabolite gene clusters that are mostly considered to be orphan, including
two that are responsible for siderophore assembly.
Despite the unique phenotypic properties and clinical importance ofPeni-cillium marneffei, the polyketide synthase genes in its genome have never
been characterized. Twenty-three putative polyketide synthase genes and
two putative polyketide synthase nonribosomal peptide-synthase hybrid
genes were identified in theP.
Ribosome subunit assembly in bacteria is a fast and efficient process.
Among the nonribosomal proteins involved in ribosome biogenesis are
RNA helicases. We describe ribosome biogenesis inEscherichia colistrains
lacking RNA helicase DeaD (CsdA) or DbpA.
Microorganisms produce a large number of pharmaco-logically and biotechnologically important peptides by
using nonribosomal peptide synthetases (NRPSs). Due to
their modular arrangement and their domain organization
NRPSs are particularly suitable for engineering recom-binant proteins for the production of novel peptides with
The family of chromodepsipeptides constitutes a class of structurally
related pseudosymmetrical peptidolactones and peptidothiolactones synthe-sized by nonribosomal peptide synthetases. The chromodepsipeptides,
which are analogous to the extensively characterized echinomycin, attain
their DNA-bisintercalating properties from chromophore moieties attached
to the N-termini of the oligopeptide chain.
Daptomycin and A21987C antibiotics are branched, cyclic, nonribosomally
assembled acidic lipodepsipeptides produced byStreptomyces roseosporus.
The antibacterial activity of daptomycin against Gram-positive bacteria
strongly depends on the nature of the N-terminal fatty acid moiety.
The elongation phase of mRNA translation is the stage
at which the polypeptide is assembled and requires a
substantial amount of metabolic energy. Translation
elongation in mammals requires a set of nonribosomal
proteins called eukaryotic elongation actors or eEFs.
Several of these proteins are subject to phosphorylation
in mammalian cells, including the factors eEF1A and
eEF1B that are involved in recruitment of amino acyl-tRNAs to the ribosome.