PKS and NRPS release mechanisms

Abstract

This review covers the recent literature on the release mechanisms for polyketides and nonribosomal peptides produced by microorganisms. The emphasis is on the novel enzymology and mechanistic insights revealed by the biosynthetic studies of new natural products.

Characterization of the Biosynthesis Gene Cluster for the Pyrrole Polyether Antibiotic Calcimycin (A23187) in Streptomyces chartreusis NRRL 3882

“…A variety of termination strategies for PKS assembly lines are known (9). Most often, a C-terminal PKS TE domain catalyzes the release of the mature polyketide chain.…”

“…The pyrrole-2-carboxylic acid starter unit is transferred from CalN3 to the active-site cysteine residue of the KS domain of module 1 to prime the biosynthesis of the polyketide chain. Finally, CalG resembles type II thioesterases (TEs) and probably releases the completed polyketide from the PKS, and it may also serve as an editing enzyme by cleaving miscognate chains from the ACP domains (9,13,16,38).…”

Directed evolution of the tryptophan synthase β-subunit for stand-alone function recapitulates allosteric activation

“…protein engineering | allostery | noncanonical amino acid | PLP H eteromeric enzyme complexes catalyzing a rich array of useful reactions are often allosterically regulated by their protein partners, such that the catalytic subunits are much less active when isolated (1)(2)(3). Utilization of isolated enzyme subunits, however, is desirable for biosynthetic applications, where expressing large complexes increases the metabolic load on the host cell and complicates efforts to engineer activity, substrate specificity, stability, and other properties.…”

Fungal cyclooligomerdepsipeptides: From classical biochemistry to combinatorial biosynthesis

“…7 The tremendous structural variety of nonribosomal peptides is based on the flexibility of the biosynthetic programming of the NRPS: the utilization of non-proteinogenic amino acid precursors (more than 300 described); the formation of main-chain heterocycles (thiazole, oxazole and their derivatives); and the construction of linear, macrocyclic or branched macrocyclic structures with amide, ester or even thioester or imino ring closures. 4,8 In the scaffold of the nonribosomal depsipeptides, at least one bond of the peptide backbone is replaced by an ester bond: these connect carboxy groups of amino acids with a 2-hydroxycarboxylic acid, or provide alternative routing of the chain via side chain hydroxy groups of amino acids and the Cterminus of the peptide. The structural complexity of nonribosomal (depsi)peptides is further enhanced by the installation of N-terminal aryl or alkyl caps, lipid or glycosyl side chains, and the formation of intramolecular bridges (disulfide bridges, oxidative coupling between side chains), as catalyzed by ''decorating'' enzymes.…”