The incorporation and removal of ″auxiliary″ building blocks and their functions in the biosynthesis of polyketides and non-ribosomal polypeptides

Abstract

Natural products that produced by animals, plants or microorganisms, especially polyketides (PKs), non-ribosomal peptides (NRPs) and their hybrids, exhibit an extremely wide range of biological activities, include antibacterial, antifungal, antitumor, antiviral and immunosuppressive activities, which underlie the critical roles of natural products in medical industry as various drugs. The biosynthetic pathways of PKs, NRPs and their hybrids share a templated multifunctional enzymology for skeleton assembly. Polyketide synthases (PKSs) usually catalyze C−C bond formation using short carboxylic acid as monomers, whereas non-ribosomal peptide synthetases (NRPSs) incorporate amino acids through C−N bond formation. Consistent with their catalytic cycles, both PKSs and NRPSs are often giant enzymes organized into modules, which each contains a common thiolation (T) domain for loading building blocks. A prototype of a PKS module consists of an acyltransferase (AT), a T domain and a β-ketoacyl synthase (KS) domain. A minimum NRPS module contains an adenylation (A) domain, a T domain and a condensation (C) domain. AT or A domain is responsible for recognition and activation of building blocks, while KS or C domain catalyzes the elongation of the growing skeleton. In general, modular PKSs or NRPSs appear to function as assembly lines, which program monomer polymerization/modification and chain tailoring/termination following a non-iteratively ″one domain, one function″ like co-linearity rule. Thus, the domain composition of each module and the number of modules can be used to predict the structure of skeleton. However, there are exceptions reported in recent years, as modules are now known to be both skipped and iterated during the normal biosynthetic processes. In addition, another origin for a lack of correlation between domain composition of the multienzyme complex and the final product structure has been identified recently. In this case, the missing building blocks are normally incorporated on the assembly lines, but they will be removed by the post-assembly modifications. These kind of building blocks which would not appear in the final products seem ″unnecessary″, but they are essential in the biosynthetic pathways exactly. In this review, we summarize these ″auxiliary″ building blocks, focus on the chemical mechanisms of the incorporation and removal of them and discuss their biological functions that have been reported since 2000. The related building blocks here include fatty acyls, amino acids, unnatural amino acids and fatty acyl-amino acids. Some of these ″auxiliary″ build blocks are involved in the biosynthesis of natural products with specific structures, such as 2,2′-bipyridine cores, tetrahydroisoquinoline alkaloids, β-lactam and macrocyclic lactam antibiotics. In this case, building blocks are incorporated by the PKSs, NRPSs or their hybrids assembly lines, but the chemical mechanisms are unusual. The biological functions of these kind of building blocks are considered to be strategies for protection of the reactive groups and mediation of molecular assembly and modifications. On the other hand, some of the ″auxiliary″ building blocks are present in biosynthesis of natural products which are structurally different from each other, however, the ″unnecessary″ building blocks are almost same and their chemical mechanisms of incorporation and removal are similar. These kind of building blocks are proposed to be very important for protection the chemical producers by prodrug generation. In summary, the molecules mentioned in this review could increase the knowledge regarding the ″auxiliary″ building blocks, add another layer of complexity to natural product biosynthesis, help to hypothesize biosynthetic pathways of other natural products with specific structures and assist the association of molecules and their gene clusters.