Type I polyketide synthase requiring a discrete acyltransferase for polyketide biosynthesis

C, Yi; Tang, Gong Li; Shen, Ben

doi:10.1073/pnas.0537286100

Cited by 250 publications

(266 citation statements)

References 32 publications

Supporting

Mentioning

262

Contrasting

Unclassified

Order By: Relevance

“…Unlike NRPS-like enzymes (37,38), these type IIlike NRPS clusters have a complete core domain set, such as the identified putative brucebactin gene clusters that contain one fully dissociated NRPS module. Previously, reclassification of PKSs had been proposed (39), due to the discoveries of transition states between type I and II PKSs, the trans-AT PKS systems (25), and that between type II and III PKSs shown to be independent of the acyl carrier protein (40). The type II-like PKS clusters found in this study also appeared as transition states between type I and type II PKSs.…”

Section: Discussionmentioning

confidence: 53%

“…S3). For example, a total of 113 bacterial gene clusters were found with free-standing acyltransferases (AT), which iteratively load the monomers in trans for other modular PKSs lacking an AT domain (25). They are almost all the hybrid type, illustrated by the fact that their docking and dehydratase domains are entirely from hybrid clusters (Fig.…”

Section: Gene-cluster Composition Reveals High Diversity Of Nrps and Pksmentioning

confidence: 99%

See 1 more Smart Citation

Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes

Wang¹,

Fewer²,

Holm

et al. 2014

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

303

263

View full text Add to dashboard Cite

Nonribosomal peptides and polyketides are a diverse group of natural products with complex chemical structures and enormous pharmaceutical potential. They are synthesized on modular nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) enzyme complexes by a conserved thiotemplate mechanism. Here, we report the widespread occurrence of NRPS and PKS genetic machinery across the three domains of life with the discovery of 3,339 gene clusters from 991 organisms, by examining a total of 2,699 genomes. These gene clusters display extraordinarily diverse organizations, and a total of 1,147 hybrid NRPS/PKS clusters were found. Surprisingly, 10% of bacterial gene clusters lacked modular organization, and instead catalytic domains were mostly encoded as separate proteins. The finding of common occurrence of nonmodular NRPS differs substantially from the current classification. Sequence analysis indicates that the evolution of NRPS machineries was driven by a combination of common descent and horizontal gene transfer. We identified related siderophore NRPS gene clusters that encoded modular and nonmodular NRPS enzymes organized in a gradient. A higher frequency of the NRPS and PKS gene clusters was detected from bacteria compared with archaea or eukarya. They commonly occurred in the phyla of Proteobacteria, Actinobacteria, Firmicutes, and Cyanobacteria in bacteria and the phylum of Ascomycota in fungi. The majority of these NRPS and PKS gene clusters have unknown end products highlighting the power of genome mining in identifying novel genetic machinery for the biosynthesis of secondary metabolites.biosynthetic gene cluster | data mining | distribution | bioactive compound

show abstract

Section: Discussionmentioning

confidence: 53%

Section: Gene-cluster Composition Reveals High Diversity Of Nrps and Pksmentioning

confidence: 99%

Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes

Wang¹,

Fewer²,

Holm

et al. 2014

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

303

263

View full text Add to dashboard Cite

show abstract

“…The use of a tailoring enzyme in trans for the formation of the naphthalene ring during polyketide chain extension is unprecedented in polyketide biosynthesis. To date, a number of unusual examples have been reported in PKS systems, in which the acyltransferase domain is located outside the PKS modules and functions in trans with the modular enzymes (Cheng et al, 2003;Piel, 2002). However, there are no examples of an oxidation reaction that takes place during polyketide chain assembly nor of an oxidation domain located within a modular PKS system.…”

Section: Discussionmentioning

confidence: 99%

Identification of tailoring genes involved in the modification of the polyketide backbone of rifamycin B by Amycolatopsis mediterranei S699

et al. 2005

View full text Add to dashboard Cite

Rifamycin B biosynthesis by Amycolatopsis mediterranei S699 involves a number of unusual modification reactions in the formation of the unique polyketide backbone and decoration of the molecule. A number of genes believed to be involved in the tailoring of rifamycin B were investigated and the results confirmed that the formation of the naphthalene ring moiety of rifamycin takes place during the polyketide chain extension and is catalysed by Rif-Orf19, a 3-(3-hydroxyphenyl)propionate hydroxylase-like protein. The cytochrome P450-dependent monooxygenase encoded by rif-orf5 is required for the conversion of the D12, 29 olefinic bond in the polyketide backbone of rifamycin W into the ketal moiety of rifamycin B. Furthermore, Rif-Orf3 may be involved in the regulation of rifamycin B production, as its knock-out mutant produced about 40 % more rifamycin B than the wild-type. The work also revealed that many of the genes located in the cluster are not involved in rifamycin biosynthesis, but might be evolutionary remnants carried over from an ancestral lineage. INTRODUCTIONRifamycin continues to play a significant role in clinical medicine. Synthetically modified derivatives, such as rifampicin, rifabutin and rifapentine, remain the principal chemotherapeutic agents used for combating tuberculosis, leprosy and AIDS-related mycobacterial infections (Maggi et al., 1966;Ramos-e-Silva & Rebello, 2001;Sepkowitz et al., 1995). The potent antibacterial activity of this class of antibiotics is due to their specific inhibition of bacterial DNA-dependent RNA polymerases (Campbell et al., 2001;Wehrli & Staehelin, 1969). At the same time, they have relatively low if any activity against eukaryotic RNA polymerases. Due to their high selectivity for their molecular target, the rifamycins have become a safe and effective medication. Unfortunately, as with many other antibiotics, the incidence of resistance of Mycobacterium tuberculosis, the causative agent of tuberculosis, to rifamycins is continuing to increase over time, due largely to mutational alterations of the target molecule, the b subunit of RNA polymerase (Kirschbaum & Gotte, 1993;Suzuki et al., 1995). This high-level resistance has contributed to the recent reemergence of tuberculosis as a major health problem and the consequent increase in the death toll among world populations (Dye et al., 2002). Therefore, new drug discovery and continued development of the existing drugs to combat tuberculosis is indispensable.Despite the preparation of a large number of rifamycin derivatives by semi-synthetic approaches, the structural modifications have been limited primarily to one region of the molecule, the C-3 or C-4 positions of the aromatic core unit (Cricchio et al., 1974(Cricchio et al., , 1975Maggi et al., 1965; Wehrli et al., 1987). Alterations at other locations are difficult to accomplish chemically due to the complexity of the molecule, and require the implementation of alternative methodology, including combinatorial biosynthesis or mutasynthesis, to achieve additional...

show abstract

“…Iterative type III PKS, also called chalcone synthases, are ACP-independent consisting of a single KS protein catalyzing multiple decarboxylative condensations (20). Rather recently, several bacterial PKS have been found that do not fit these model systems (21)(22)(23)(24)(25). For example, several iterative PKS have been discovered that contain one module located on a single protein analogous to fungal PKSs, and many of these PKS have been functionally characterized in heterologous hosts (26)(27)(28)(29).…”

mentioning

confidence: 99%

A phosphopantetheinylating polyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis

Zhang¹,

Lanen

et al. 2008

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

Self Cite

136

View full text Add to dashboard Cite

The enediynes, unified by their unique molecular architecture and mode of action, represent some of the most potent anticancer drugs ever discovered. The biosynthesis of the enediyne core has been predicted to be initiated by a polyketide synthase (PKS) that is distinct from all known PKSs. Characterization of the enediyne PKS involved in C-1027 (SgcE) and neocarzinostatin (NcsE) biosynthesis has now revealed that (i) the PKSs contain a central acyl carrier protein domain and C-terminal phosphopantetheinyl transferase domain; (ii) the PKSs are functional in heterologous hosts, and coexpression with an enediyne thioesterase gene produces the first isolable compound, 1,3,5,7,9,11,13-pentadecaheptaene, in enediyne core biosynthesis; and (iii) the findings for SgcE and NcsE are likely shared among all nine-membered enediynes, thereby supporting a common mechanism to initiate enediyne biosynthesis.C-1027 ͉ neocarzinostatin ͉ phosphopantetheinyl transferase

show abstract

Type I polyketide synthase requiring a discrete acyltransferase for polyketide biosynthesis

Cited by 250 publications

References 32 publications

Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes

Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes

Identification of tailoring genes involved in the modification of the polyketide backbone of rifamycin B by Amycolatopsis mediterranei S699

A phosphopantetheinylating polyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis

Contact Info

Product

Resources

About