The Biosynthesis of Aliphatic Polyketides

Abstract

Aliphatic polyketides are a large family of natural products which exhibit an impressive range of biological activities. They are synthesised by a common pathway in which units derived from acetate, propionate and butyrate are condensed onto a growing chain, which is initiated from a range of structurally varied carboxylic acid starter units, in a process closely resembling fatty acid biosynthesis. The intermediates remain bound to the polyketide synthase (PKS) throughout multiple rounds of chain extension, and to a variable degree, reduction of the newly formed b-keto functionality. It is the manner in which each different PKS controls the number and type of extender units added, and the extent and stereochemistry of reduction at each cycle which gives rise to the diverse structural variation seen in this family of natural products. Furthermore, the aglycone product of the PKS may be modified by post-PKS enzymes, including glycosidases, methyltransferases, acylases and oxidative enzymes, to produce still greater diversity. In this article the development of the field will be exemplified by a detailed discussion of the archetypal example of erythromycin A biosynthesis. This will then be followed by further discussion of other relevant areas of research in this field.

Structural elucidation studies of erythromycins by electrospray tandem mass spectrometry II

“…[1][2][3][4] These are usually characterised by nuclear magnetic resonance (NMR) spectroscopy, a process that requires the growth of large quantities of bacterial culture and purification of milligram quantities of analyte. The large number of samples that may be expected from combinatorial experiments will require a faster, more sensitive analysis for preliminary screening and structure determination.…”

Biogenesis of 3‐Alkylpyridine Alkaloids in the Marine Mollusc Haminoea Orbignyana

“…This hypothesis is, however, not groundless if one considers the many examples of similar molecules that can be loaded by polyketide synthases of bacteria and fungi. [8] The short life-cycle of H. orbignyana (only 5-6 weeks) strongly limited our possibility of performing other feeding experiments (for example, with doubly labeled acetate) to shed light on these unresolved aspects.…”

Structural elucidation studies on 14- and 16-membered macrolide aglycones by accurate-mass electrospray sequential mass spectrometry

“…Therefore, it appears likely that the loss is from the same unit of the molecule in each case and that this unit contains the starter unit and does not contain the 6-OH or "stuttered" unit. Thus, a possible structure is presented in Scheme 4, which shows the fragmentation reactions that are observed for all of the analogs (the only exception was that fragment b 4 was not observed in experiments on stutt-6-dEB). This scheme illustrates the high degree of similarity between the fragmentation pathways of all of the analogs.…”

“…Although the post-PKS steps are required to produce active antibiotics, most academic research activity has focused upon the operations of the PKS. This is because the structure of the PKS products are programmed specifically in the genes encoding the PKS enzymes, allowing the biosynthetic process to be manipulated at the genetic level to produce specific structural modifications [1][2][3][4]. Particular interest is focused upon producing polyketide libraries through combinatorial genetic manipulation.…”