David E. Cane

Bio: David E. Cane is an academic researcher from Brown University. The author has contributed to research in topics: Polyketide & Polyketide synthase. The author has an hindex of 75, co-authored 346 publications receiving 20099 citations. Previous affiliations of David E. Cane include Kosan Biosciences & University of California, San Francisco.

Biosynthesis of Complex Polyketides in a Metabolically Engineered Strain of E. coli

Abstract: The macrocyclic core of the antibiotic erythromycin, 6-deoxyerythronolide B (6dEB), is a complex natural product synthesized by the soil bacterium Saccharopolyspora erythraea through the action of a multifunctional polyketide synthase (PKS). The engineering potential of modular PKSs is hampered by the limited capabilities for molecular biological manipulation of organisms (principally actinomycetes) in which complex polyketides have thus far been produced. To address this problem, a derivative of Escherichia coli has been genetically engineered. The resulting cellular catalyst converts exogenous propionate into 6dEB with a specific productivity that compares well with a high-producing mutant of S. erythraea that has been incrementally enhanced over decades for the industrial production of erythromycin.

Harnessing the Biosynthetic Code: Combinations, Permutations, and Mutations

Abstract: Polyketides and non-ribosomal peptides are two large families of complex natural products that are built from simple carboxylic acid or amino acid monomers, respectively, and that have important medicinal or agrochemical properties. Despite the substantial differences between these two classes of natural products, each is synthesized biologically under the control of exceptionally large, multifunctional proteins termed polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) that contain repeated, coordinated groups of active sites called modules, in which each module is responsible for catalysis of one complete cycle of polyketide or polypeptide chain elongation and associated functional group modifications. It has recently become possible to use molecular genetic methodology to alter the number, content, and order of such modules and, in so doing, to alter rationally the structure of the resultant products. This review considers the promise and challenges inherent in the combinatorial manipulation of PKS and NRPS structure in order to generate entirely "unnatural" products.

Genome-minimized Streptomyces host for the heterologous expression of secondary metabolism

Abstract: To construct a versatile model host for heterologous expression of genes encoding secondary metabolite biosynthesis, the genome of the industrial microorganism Streptomyces avermitilis was systematically deleted to remove nonessential genes. A region of more than 1.4 Mb was deleted stepwise from the 9.02-Mb S. avermitilis linear chromosome to generate a series of defined deletion mutants, corresponding to 83.12-81.46% of the wild-type chromosome, that did not produce any of the major endogenous secondary metabolites found in the parent strain. The suitability of the mutants as hosts for efficient production of foreign metabolites was shown by heterologous expression of three different exogenous biosynthetic gene clusters encoding the biosynthesis of streptomycin (from S. griseus Institute for Fermentation, Osaka [IFO] 13350), cephamycin C (from S. clavuligerus American type culture collection (ATCC) 27064), and pladienolide (from S. platensis Mer-11107). Both streptomycin and cephamycin C were efficiently produced by individual transformants at levels higher than those of the native-producing species. Although pladienolide was not produced by a deletion mutant transformed with the corresponding intact biosynthetic gene cluster, production of the macrolide was enabled by introduction of an extra copy of the regulatory gene pldR expressed under control of an alternative promoter. Another mutant optimized for terpenoid production efficiently produced the plant terpenoid intermediate, amorpha-4,11-diene, by introduction of a synthetic gene optimized for Streptomyces codon usage. These findings highlight the strength and flexibility of engineered S. avermitilis as a model host for heterologous gene expression, resulting in the production of exogenous natural and unnatural metabolites.

Crystal structure of pentalenene synthase: Mechanistic insights on terpenoid cyclization reactions in biology

Abstract: The crystal structure of pentalenene synthase at 2.6 angstrom resolution reveals critical active site features responsible for the cyclization of farnesyl diphosphate into the tricyclic hydrocarbon pentalenene. Metal-triggered substrate ionization initiates catalysis, and the α-barrel active site serves as a template to channel and stabilize the conformations of reactive carbocation intermediates through a complex cyclization cascade. The core active site structure of the enzyme may be preserved among the greater family of terpenoid synthases, possibly implying divergence from a common ancestral synthase to satisfy biological requirements for increasingly diverse natural products.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Methods in Enzymology.

Abstract: I read this book the same weekend that the Packers took on the Rams, and the experience of the latter event, obviously, colored my judgment. Although I abhor anything that smacks of being a handbook (like, \"How to Earn a Merit Badge in Neurosurgery\") because too many volumes in biomedical science already evince a boyscout-like approach, I must confess that parts of this volume are fast, scholarly, and significant, with certain reservations. I like parts of this well-illustrated book because Dr. Sj6strand, without so stating, develops certain subjects on technique in relation to the acquisition of judgment and sophistication. And this is important! So, given that the author (like all of us) is somewhat deficient in some areas, and biased in others, the book is still valuable if the uninitiated reader swallows it in a general fashion, realizing full well that what will be required from the reader is a modulation to fit his vision, propreception, adaptation and response, and the kind of problem he is undertaking. A major deficiency of this book is revealed by comparison of its use of physics and of chemistry to provide understanding and background for the application of high resolution electron microscopy to problems in biology. Since the volume is keyed to high resolution electron microscopy, which is a sophisticated form of structural analysis, but really morphology in a modern guise, the physical and mechanical background of The instrument and its ancillary tools are simply and well presented. The potential use of chemical or cytochemical information as it relates to biological fine structure , however, is quite deficient. I wonder when even sophisticated morphol-ogists will consider fixation a reaction and not a technique; only then will the fundamentals become self-evident and predictable and this sine qua flon will become less mystical. Staining reactions (the most inadequate chapter) ought to be something more than a technique to selectively enhance contrast of morphological elements; it ought to give the structural addresses of some of the chemical residents of cell components. Is it pertinent that auto-radiography gets singled out for more complete coverage than other significant aspects of cytochemistry by a high resolution microscopist, when it has a built-in minimal error of 1,000 A in standard practice? I don't mean to blind-side (in strict football terminology) Dr. Sj6strand's efforts for what is \"routinely used in our laboratory\"; what is done is usually well done. It's just that …

C-H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals

Abstract: The direct functionalization of C-H bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon-carbon and carbon-heteroatom bonds. This Review provides an overview of C-H bond functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets.

Cascade reactions in total synthesis.

Abstract: The design and implementation of cascade reactions is a challenging facet of organic chemistry, yet one that can impart striking novelty, elegance, and efficiency to synthetic strategies. The application of cascade reactions to natural products synthesis represents a particularly demanding task, but the results can be both stunning and instructive. This Review highlights selected examples of cascade reactions in total synthesis, with particular emphasis on recent applications therein. The examples discussed herein illustrate the power of these processes in the construction of complex molecules and underscore their future potential in chemical synthesis.

Biogenic Volatile Organic Compounds (VOC): An Overview on Emission, Physiology and Ecology

Abstract: This overview compiles the actual knowledge of the biogenic emissions of some volatile organic compounds (VOCs), i.e., isoprene, terpenes, alkanes, alkenes, alcohols, esters, carbonyls, and acids. We discuss VOC biosynthesis, emission inventories, relations between emission and plant physiology as well as temperature and radiation, and ecophysiological functions. For isoprene and monoterpenes, an extended summary of standard emission factors, with data related to the plant genus and species, is included. The data compilation shows that we have quite a substantial knowledge of the emission of isoprene and monoterpenes, including emission rates, emission regulation, and biosynthesis. The situation is worse in the case of numerous other compounds (other VOCs or OVOCs) being emitted by the biosphere. This is reflected in the insufficient knowledge of emission rates and biological functions. Except for the terpenoids, only a limited number of studies of OVOCs are available; data are summarized for alkanes, alkenes, carbonyls, alcohols, acids, and esters. In addition to closing these gaps of knowledge, one of the major objectives for future VOC research is improving our knowledge of the fate of organic carbon in the atmosphere, ending up in oxidation products and/or as aerosol particles.