Browse
Submit Data
Databases
API
Help

Dataset Information

24 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identification of the Polyketide Biosynthetic Machinery for the Indolizidine Alkaloid Cyclizidine.

ABSTRACT: The cyclizidine biosynthetic gene cluster was identified from Streptomyces NCIB 11649, which revealed the polyketide biosynthetic machinery for cyclizidine alkaloid biosynthesis. Both in vivo mutagenesis study and in vitro biochemical analysis provided insight into the timing and mechanism of the biosynthetic enzymes that produce cyclizidine-type indolizidine alkaloids.

SUBMITTER: Huang W

PROVIDER: S-EPMC4646845 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Identification of the Polyketide Biosynthetic Machinery for the Indolizidine Alkaloid Cyclizidine.

Huang Wei W Kim Seong Jong SJ Liu Joyce J Zhang Wenjun W

Organic letters 20151016 21

The cyclizidine biosynthetic gene cluster was identified from Streptomyces NCIB 11649, which revealed the polyketide biosynthetic machinery for cyclizidine alkaloid biosynthesis. Both in vivo mutagenesis study and in vitro biochemical analysis provided insight into the timing and mechanism of the biosynthetic enzymes that produce cyclizidine-type indolizidine alkaloids. ...[more]

PMID: 26473429

Similar Datasets

Total synthesis of the indolizidine alkaloid tashiromine.

Project description:BackgroundTashiromine 1 is a naturally occurring indolizidine alkaloid. It has been the subject of thirteen successful total syntheses to date. Our own approach centres on the stereoselective construction of the indolizidine core by capture of an electrophilic acyliminium species by a pendant allylsilane. The key cyclisation precursor is constructed using olefin cross-metathesis chemistry, which has the potential to facilitate both racemic and asymmetric approaches, depending upon the choice of the allylsilane metathesis partner.ResultsThe use of the allyltrimethylsilane cross-metathesis approach enables the rapid construction of the key cyclisation precursor 3 (3 steps from commercial materials), which undergoes acid-induced cyclisation to give the desired bicyclic indolizidine skeleton as a 96:4 mixture of diastereomers. Simple functional group interconversions allowed the completion of the total synthesis of racemic tashiromine in six steps (19% overall yield). Three chiral alpha-alkoxyallylsilanes (12,14 and 15) were prepared in enantioenriched form and their cross-metathesis reactions studied as part of a putative asymmetric approach to tashiromine. In the event, alpha-hydroxysilane 12 underwent isomerisation under the reaction conditions to acylsilane 17, while silanes 14 and 15 were unreactive towards metathesis.ConclusionA concise, stereoselective total synthesis of racemic tashiromine has been developed. Attempts to translate this into an asymmetric synthesis have thus far been unsuccessful.

| S-EPMC2241604 | biostudies-literature

Synthesis of the benzo-fused indolizidine alkaloid mimics.

Project description:A general synthesis of various benzo-fused indolizidine alkaloid mimics has been developed. The indolizidine derivatives 8 were prepared via heteroaryl Grignard addition to N-acylpyridinium salts followed by an intramolecular Heck cyclization. Further substitution reactions were developed to demonstrate that heterocycles 8 are good scaffolds for chemical library preparation.

| S-EPMC2200666 | biostudies-literature

Convergence of isoprene and polyketide biosynthetic machinery: isoprenyl-S-carrier proteins in the pksX pathway of Bacillus subtilis.

Project description:The pksX gene cluster from Bacillus subtilis is predicted to encode the biosynthesis of an as yet uncharacterized hybrid nonribosomal peptide/polyketide secondary metabolite. We used a combination of biochemical and mass spectrometric techniques to assign functional roles to the proteins AcpK, PksC, PksL, PksF, PksG, PksH, and PksI, and we conclude that they act to incorporate an acetate-derived beta-methyl branch on an acetoacetyl-S-carrier protein and ultimately generate a Delta(2)-isoprenyl-S-carrier protein. This work highlights the power of mass spectrometry to elucidate the functions of orphan biosynthetic enzymes, and it details a mechanism by which single-carbon beta-branches can be inserted into polyketide-like structures. This pathway represents a noncanonical route to the construction of prenyl units and serves as a prototype for the intersection of isoprenoid and polyketide biosynthetic manifolds in other natural product biosynthetic pathways.

| S-EPMC1482551 | biostudies-literature

Identification of a novel sesquiterpene biosynthetic machinery involved in astellolide biosynthesis.

Project description:Esterified drimane-type sesquiterpene lactones such as astellolides display various biological activities and are widely produced by plants and fungi. Given their low homology to known sesquiterpene cyclases, the genes responsible for their biosynthesis have not been uncovered yet. Here, we identified the astellolide gene cluster from Aspergillus oryzae and discovered a novel sesquiterpene biosynthetic machinery consisting of AstC, AstI, and AstK. All these enzymes are annotated as haloacid dehalogenase-like hydrolases, whereas AstC also contains a DxDTT motif conserved in class II diterpene cyclases. Based on enzyme reaction analyses, we found that AstC catalysed the protonation-initiated cyclisation of farnesyl pyrophosphate into drimanyl pyrophosphate. This was successively dephosphorylated by AstI and AstK to produce drim-8-ene-11-ol. Moreover, we also identified and characterised a unique non-ribosomal peptide synthetase, AstA, responsible for esterifying aryl acids to drimane-type sesquiterpene lactones. In this study, we highlight a new biosynthetic route for producing sesquiterpene and its esterified derivative. Our findings shed light on the identification of novel sesquiterpenes via genome mining.

| S-EPMC5024094 | biostudies-literature

A combination of polyunsaturated fatty acid, nonribosomal peptide and polyketide biosynthetic machinery is used to assemble the zeamine antibiotics.

Project description:The zeamines are a unique group of antibiotics produced by Serratia plymuthica RVH1 that contain variable hybrid peptide-polyketide moieties connected to a common pentaamino-hydroxyalkyl chain. They exhibit potent activity against a broad spectrum of Gram-positive and Gram-negative bacteria. Here we report a combination of targeted gene deletions, high resolution LC-MS(/MS) analyses, in vitro biochemical assays and feeding studies that define the functions of several key zeamine biosynthetic enzymes. The pentaamino-hydroxyalkyl chain is assembled by an iterative multienzyme complex (Zmn10-13) that bears a close resemblance to polyunsaturated fatty acid synthases. Zmn14 was shown to function as an NADH-dependent thioester reductase and is proposed to release a tetraamino-hydroxyalkyl thioester from the acyl carrier protein domain of Zmn10 as an aldehyde. Despite the intrinsic ability of Zmn14 to catalyze further reduction of aldehydes to alcohols, the initially-formed aldehyde intermediate is proposed to undergo preferential transamination to produce zeamine II. In a parallel pathway, hexapeptide-monoketide and hexapeptide-diketide thioesters are generated by a hybrid nonribosomal peptide synthetase-polyketide synthase multienzyme complex (Zmn16-18) and subsequently conjugated to zeamine II by a stand-alone condensing enzyme (Zmn19). Structures for the resulting prezeamines were elucidated using a combination of high resolution LC-MS/MS and 1- and 2-D NMR spectroscopic analyses. The prezeamines are hypothesized to be precursors of the previously-identified zeamines, which are generated by the action of Zmn22, an acylpeptide hydrolase that specifically cleaves the N-terminal pentapeptide of the prezeamines in a post-assembly processing step. Thus, the zeamine antibiotics are assembled by a unique combination of nonribosomal peptide synthetase, type I modular polyketide synthase and polyunsaturated fatty acid synthase-like biosynthetic machinery.

| S-EPMC5811116 | biostudies-literature

Inhibition of lysosomal alpha-mannosidase by swainsonine, an indolizidine alkaloid isolated from Swainsona canescens.

Project description:An indolizidine alkaloid (swainsonine) was isolated from the plant Swainsona canescens. Swainsonine is a specific and potent inhibitor of alpha-mannosidase (EC 3.2.1.24) and when administered to animals produces a phenocopy of the genetically based lysosomal storage disease, mannosidosis. Evidence is presented to suggest that swainsonine is a reversible active site-directed inhibitor of lysosomal alpha-mannosidase.

| S-EPMC1162258 | biostudies-other

Identification and developmental expression profiling of putative alkaloid biosynthetic genes in Corydalis yanhusuo bulbs.

Project description:Alkaloids in bulbs of Corydalis (C.) yanhusuo are the major pharmacologically active compounds in treatment of blood vessel diseases, tumors and various pains. However, due to the absence of gene sequences in C. yanhusuo, the genes involved in alkaloid biosynthesis and their expression during bulb development remain unknown. We therefore established the first transcriptome database of C. yanhusuo via Illumina mRNA-Sequencing of a RNA composite sample collected at Bulb initiation (Day 0), early enlargement (Day 10) and maturation (Day 30). 25,013,630 clean 90?bp paired-end reads were de novo assembled into 47,081 unigenes with an average length of 489?bp, among which 30,868 unigenes (65.56%) were annotated in four protein databases. Of 526 putative unigenes involved in biosynthesis o f various alkaloids, 187 were identified as the candidate genes involved in the biosynthesis of benzylisoquinoline alkaloids (BIAs), the only alkaloid type reported in C. yanhusuo untill now. BIAs biosynthetic genes were highly upregulated in the overall pathway during bulb development. Identification of alkaloid biosynthetic genes in C. yanhusuo provide insights on pathways and molecular regulation of alkaloid biosynthesis, to initiate metabolic engineering in order to improve the yield of interesting alkaloids and to identify potentially new alkaloids predicted from the transcriptomic information.

| S-EPMC4726099 | biostudies-literature

Cycloheximide and actiphenol production in Streptomyces sp. YIM56141 governed by single biosynthetic machinery featuring an acyltransferase-less type I polyketide synthase.

Project description:Cycloheximide (1) and actiphenol (2) have been isolated from numerous Streptomyces species. Cloning, sequencing, and characterization of a gene cluster from Streptomyces sp. YIM65141 now establish that 1 and 2 production is governed by single biosynthetic machinery. Biosynthesis of 1 features an acyltransferase-less type I polyketide synthase to construct its carbon backbone but may proceed via 2 as a key intermediate, invoking a provocative reduction of a phenol to a cyclohexanone moiety in natural product biosynthesis.

| S-EPMC4051428 | biostudies-literature

Identification and reconstitution of the rubber biosynthetic machinery on rubber particles from Hevea brasiliensis.

Project description:Natural rubber (NR) is stored in latex as rubber particles (RPs), rubber molecules surrounded by a lipid monolayer. Rubber transferase (RTase), the enzyme responsible for NR biosynthesis, is believed to be a member of the cis-prenyltransferase (cPT) family. However, none of the recombinant cPTs have shown RTase activity independently. We show that HRT1, a cPT from Heveabrasiliensis, exhibits distinct RTase activity in vitro only when it is introduced on detergent-washed HeveaRPs (WRPs) by a cell-free translation-coupled system. Using this system, a heterologous cPT from Lactucasativa also exhibited RTase activity, indicating proper introduction of cPT on RP is the key to reconstitute active RTase. RP proteomics and interaction network analyses revealed the formation of the protein complex consisting of HRT1, rubber elongation factor (REF) and HRT1-REF BRIDGING PROTEIN. The RTase activity enhancement observed for the complex assembled on WRPs indicates the HRT1-containing complex functions as the NR biosynthetic machinery.

| S-EPMC5110245 | biostudies-literature

Synthesis of unnatural alkaloid scaffolds by exploiting plant polyketide synthase.

Project description:HsPKS1 from Huperzia serrata is a type III polyketide synthase (PKS) with remarkable substrate tolerance and catalytic potential. Here we present the synthesis of unnatural unique polyketide-alkaloid hybrid molecules by exploiting the enzyme reaction using precursor-directed and structure-based approaches. HsPKS1 produced novel pyridoisoindole (or benzopyridoisoindole) with the 6.5.6-fused (or 6.6.5.6-fused) ring system by the condensation of 2-carbamoylbenzoyl-CoA (or 3-carbamoyl-2-naphthoyl-CoA), a synthetic nitrogen-containing nonphysiological starter substrate, with two molecules of malonyl-CoA. The structure-based S348G mutant not only extended the product chain length but also altered the cyclization mechanism to produce a biologically active, ring-expanded 6.7.6-fused dibenzoazepine, by the condensation of 2-carbamoylbenzoyl-CoA with three malonyl-CoAs. Thus, the basic nitrogen atom and the structure-based mutagenesis enabled additional C?C and C?N bond formation to generate the novel polyketide-alkaloid scaffold.

| S-EPMC3158201 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data