Rapamycin and its analogs are clinically important macrolide compounds produced by Streptomyces hygroscopicus. They exhibit antifungal, immunosuppressive, antitumor, neuroprotective and antiaging activities. The core macrolactone ring of rapamycin is biosynthesized by hybrid type I modular polyketide synthase (PKS)/nonribosomal peptide synthetase systems primed with 4,5-dihydrocyclohex-1-ene-carboxylic acid. The linear polyketide chain is condensed with pipecolate by peptide synthetase, followed by cyclization to form the macrolide ring and modified by a series of post-PKS tailoring steps. The aim of this review was to outline past and recent advances in the biosynthesis and regulation of rapamycin, with an emphasis on the distinguished contributions of Professor Demain to the study of rapamycin. In addition, this article describes the biological activities as well as mechanism of action of rapamycin and its derivatives. Recent attempts to improve the productivity of rapamycin and generate diverse rapamycin analogs through mutasynthesis and mutagenesis are also introduced, along with some future perspectives.
Polyketides comprise one of the major families of natural products. They are found in a wide variety of bacteria, fungi, and plants and include a large number of medically important compounds. Polyketides are biosynthesized by polyketide synthases (PKSs). One of the major groups of polyketides are the macrolides, the activities of which are derived from the presence of a macrolactone ring to which one or more 6-deoxysugars are attached. The core macrocyclic ring is biosynthesized from acyl-CoA precursors by PKS. Genetic manipulation of PKS-encoding genes can result in predictable changes in the structure of the macrolactone component, many of which are not easily achieved through standard chemical derivatization or total synthesis. Furthermore, many of the changes, including post-PKS modifications such as glycosylation and oxidation, can be combined for further structural diversification. This review highlights the current state of novel macrolide production with a focus on the genetic engineering of PKS and post-PKS tailoring genes. Such engineering of the metabolic pathways for macrolide biosynthesis provides attractive alternatives for the production of diverse non-natural compounds. Other issues of importance, including the engineering of precursor pathways and heterologous expression of macrolide biosynthetic genes, are also considered.
Polycyclic aromatic hydrocarbons (PAHs) are commonly present xenobiotics in natural and contaminated soils. We studied three (phenanthrene, naphthalene, and biphenyl) xenobiotics, catabolism, and associated proteins in DJ77 by two-dimensional gel electrophoresis (2-DE) analysis. Comparative analysis of the growth-dependent 2-DE results revealed that the intensity of 10 protein spots changed identically upon exposure to the three xenobiotics. Among the upregulated proteins, five protein spots, which were putative dehydrogenase, dioxygenase, and hydrolase and involved in the catabolic pathway of xenobiotic degradation, were induced. Identification of these major multifunctional proteins allowed us to map the multiple catabolic pathway for phenanthrene, naphthalene, and biphenyl degradation. A part of the initial diverse catabolism was converged into the catechol degradation branch. Detection of intermediates from 2,3-dihydroxy-biphenyl degradation to pyruvate and acetyl-CoA production by LC/MS analysis showed that ring-cleavage products of PAHs entered the tricarboxylic acid cycle, and were mineralized in DJ77. These results suggest that DJ77 completely degrades a broad range of PAHs via a multiple catabolic pathway.
Due to the change in the naming convention of Sphingomonas chungbukensis DJ77 to Sphingobium chungbukense DJ77, the title of the article is updated to ''Identification of inducible proteins in the phenanthrene degrader Sphingobium chungbukense DJ77 by 2-dimensional electrophoresis and liquid chromatography/tandem mass spectrometry''.The online version of the original article can be found under
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