Type I polyketide biosynthesis in bacteria (Part B) (1995 to mid-2000)

Rawlings, Bernard J.

doi:10.1039/b100191o

Cited by 94 publications

(54 citation statements)

References 167 publications

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“…For example, many Streptomyces species couple antibiotic biosynthesis with developmental pathways of aerial growth and sporulation through complex regulatory circuits (17). In some cases, antibiotic biosynthesis is activated by pathway-specific regulatory genes that may be directed by developmental regulators (69). When no pathway-specific regulatory proteins are present, identifying the specific determinants of activation requires understanding the developmental control networks of the organism.…”

Section: Discussionmentioning

confidence: 99%

Bacterial Competition Reveals Differential Regulation of the pks Genes by Bacillus subtilis

2014

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Section: Discussionmentioning

confidence: 99%

Bacterial Competition Reveals Differential Regulation of the pks Genes by Bacillus subtilis

2014

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“…However, the function of these elements in pedI has been unclear, because they do not correspond to any structural counterpart of pederin (18). They are therefore most likely an inactive evolutionary remnant, a feature that has been reported in several other PKS systems (13). Another presumably nonfunctional domain is the additional acyl carrier protein (ACP)-like region in module 3 of onnB, which lacks the strictly conserved serine residue necessary for polyketide biosynthesis (22).…”

Section: Onnamide͞theopederin Biosynthesis Genes Belong To a Symbioticmentioning

confidence: 99%

“…2 A), which is a rare exception for bacterial secondary metabolites. Bacterial modular PKSs are giant enzymes containing a large number of variable catalytic domains that are organized into repeated sets of modules (13). Because each module usually incorporates one building block into the growing polyketide chain, the domain architecture of PKSs in most cases closely mirrors the structure of the assembled metabolite.…”

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confidence: 99%

Antitumor polyketide biosynthesis by an uncultivated bacterial symbiont of the marine sponge Theonella swinhoei

Piel

Hui

Wen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

507

405

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Bacterial symbionts have long been suspected to be the true producers of many drug candidates isolated from marine invertebrates. Sponges, the most important marine source of biologically active natural products, have been frequently hypothesized to contain compounds of bacterial origin. This symbiont hypothesis, however, remained unproven because of a general inability to cultivate the suspected producers. However, we have recently identified an uncultured Pseudomonas sp. symbiont as the most likely producer of the defensive antitumor polyketide pederin in Paederus fuscipes beetles by cloning the putative biosynthesis genes. Here we report closely related genes isolated from the highly complex metagenome of the marine sponge Theonella swinhoei, which is the source of the onnamides and theopederins, a group of polyketides that structurally resemble pederin. Sequence features of the isolated genes clearly indicate that it belongs to a prokaryotic genome and should be responsible for the biosynthesis of almost the entire portion of the polyketide structure that is correlated with antitumor activity. Besides providing further proof for the role of the related beetle symbiont-derived genes, these findings raise intriguing ecological and evolutionary questions and have important general implications for the sustainable production of otherwise inaccessible marine drugs by using biotechnological strategies. F or almost 30 years, symbiotic bacteria have been discussed as the likely true producers of numerous natural products isolated from marine invertebrates (1). Particularly suggestive of a bacterial origin is the similarity of many compounds from sponges, tunicates, or bryozoans to complex polyketides and nonribosomal peptides, two groups of metabolites that are otherwise known exclusively from microorganisms (2, 3). Into these structural families fall some of today's most promising drug candidates, such as discodermolide, bryostatin 1, aplidine, and ET-743 (4). The existence of producing symbionts could have far reaching consequences for the development of sustainable, fermentation-based sources of invertebrate-derived drug candidates, almost all of which are currently inaccessible in large amounts. Several studies have tried to pinpoint the producers by using cultivation (5), cell separation (6), immunolocalization (7), or in situ hybridization (8) approaches. However, as none of these methods have so far provided unambiguous results, the true origin of the compounds still remains an enigma. We have recently used a genetic strategy to provide insights into natural product symbiosis in terrestrial insects (9). Rove beetles of the genera Paederus and Paederidus are the source of the highly active antitumor polyketide pederin (Fig. 1), which they use as chemical defense (10). We isolated a set of putative pederin biosynthesis genes (9, 11) from the metagenome of Paederus fuscipes beetles and traced them to a bacterial symbiont with the closest relationship to Pseudomonas aeruginosa (12). The genes encode a mixed modul...

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“…Type I PKSs, the so-called modular PKSs, are multifunctional enzymes and catalyze the synthesis of polyketide in a modular fashion (7)(8)(9)(10)(11). Type II PKSs, on the other hand, are multienzyme complexes with each domain located on a single protein (12,13).…”

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confidence: 99%

Characterization of the Substrate Specificity of PhlD, a Type III Polyketide Synthase fromPseudomonas fluorescens

Zha

Rubin-Pitel

Zhao³

2006

J. Biol. Chem.

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PhlD, a type III polyketide synthase from Pseudomonas fluorescens, catalyzes the synthesis of phloroglucinol from three molecules of malonyl-CoA. Kinetic analysis by direct measurement of the appearance of the CoASH product (k cat ‫؍‬ 24 ؎ 4 min ؊1 and K m ‫؍‬ 13 ؎ 1 M) gave a k cat value more than an order of magnitude higher than that of any other known type III polyketide synthase. PhlD exhibits broad substrate specificity, accepting C 4 -C 12 aliphatic acyl-CoAs and phenylacetyl-CoA as the starters to form C6-polyoxoalkylated ␣-pyrones from sequential condensation with malonyl-CoA. Interestingly, when primed with long chain acyl-CoAs, PhlD catalyzed extra polyketide elongation to form up to heptaketide products. A homology structural model of PhlD showed the presence of a buried tunnel extending out from the active site to assist the binding of long chain acyl-CoAs. To probe the structural basis for the unusual ability of PhlD to accept long chain acyl-CoAs, both site-directed mutagenesis and saturation mutagenesis were carried out on key residues lining the tunnel. Three mutations, M21I, H24V, and L59M, were found to significantly reduce the reactivity of PhlD with lauroyl-CoA while still retaining its physiological activity to synthesize phloroglucinol. Our homology modeling and mutational studies indicated that even subtle changes in the tunnel volume could affect the ability of PhlD to accept long chain acyl-CoAs. This suggested novel strategies for combinatorial biosynthesis of unnatural pharmaceutically important polyketides.

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Type I polyketide biosynthesis in bacteria (Part B) (1995 to mid-2000)

Cited by 94 publications

References 167 publications

Bacterial Competition Reveals Differential Regulation of the pks Genes by Bacillus subtilis

Bacterial Competition Reveals Differential Regulation of the pks Genes by Bacillus subtilis

Antitumor polyketide biosynthesis by an uncultivated bacterial symbiont of the marine sponge Theonella swinhoei

Characterization of the Substrate Specificity of PhlD, a Type III Polyketide Synthase fromPseudomonas fluorescens

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