Lovastatin biosynthesis in Aspergillus terreus: Characterization of blocked mutants, enzyme activities and a multifunctional polyketide synthase gene

Hendrickson, Lee E.; Davis, Carol; Roach, Claudia; Nguyen, Di Kim; Aldrich, Teri L.; McAda, P C; Reeves, Christopher D.

doi:10.1016/s1074-5521(99)80061-1

Cited by 196 publications

(130 citation statements)

References 25 publications

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“…The deduced amino acid sequence of our gene is most similar to PKS proteins involved in the biosynthesis of mycotoxins and other bioactive compounds. For example, the PKS proteins with the highest degree of similarity to the A. ochraceus PKS were from C. heterostrophus (T-toxin) (Yang et al, 1996), A. terreus (lovastatin) (Hendrickson et al, 1999), G. moniliformis (fumonisin biosynthesis) (Proctor et al, 2003) and Penicillium citrinum (compactin) (Abe et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

A polyketide synthase gene required for ochratoxin A biosynthesis in Aspergillus ochraceus

2003

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Ochratoxin A is an important nephrotoxic and nephrocarcinogenic mycotoxin, produced by Aspergillus ochraceus as a polyketide-derived secondary metabolite. A portion of a putative polyketide synthase gene ( pks) involved in the biosynthesis of this mycotoxin was cloned by using a suppression subtractive hybridization PCR-based approach. The predicted amino acid sequence of the 1?4 kb clone shared 28-35 % identity to acyl transferase regions from fungal polyketide synthases found in the databases. Based on reverse transcription PCR studies, the pks gene is expressed only under ochratoxin A permissive conditions and only during the early stages of the mycotoxin synthesis. A mutant in which the pks gene has been interrupted cannot synthesize ochratoxin A. This report is the first of the cloning and characterization of a gene involved in ochratoxin A biosynthesis.

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Section: Discussionmentioning

confidence: 99%

A polyketide synthase gene required for ochratoxin A biosynthesis in Aspergillus ochraceus

2003

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“…LNKS carries the same PKS domains as Ace1 (KS, AT, DH, MT, KR, and ACP) and displays at its C terminus a sequence with similarity to NRPS condensation domains (C-domains; Hendrickson et al, 1999). In contrast with Ace1, the KR domain from LNKS is functional (Hutchinson et al, 2000), but the C-domain from the LNKS NRPS module lacks the second essential His of the core 3 motif HHxxxDG (Table 2; Marahiel et al, 1997) and is therefore unlikely to be functional.…”

Section: Ace1 Belongs To a Family Of Fungal Pks/nrpsmentioning

confidence: 99%

A Putative Polyketide Synthase/Peptide Synthetase fromMagnaporthe griseaSignals Pathogen Attack to Resistant Rice[W]

et al. 2004

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Isolates of the rice blast fungus Magnaporthe grisea that carry the gene encoding Avirulence Conferring Enzyme1 (ACE1) are specifically recognized by rice (Oryza sativa) cultivars carrying the resistance gene Pi33. This recognition enables resistant plants to activate a defense response. ACE1 was isolated by map-based cloning and encodes a putative hybrid between a polyketide synthase and a nonribosomal peptide synthetase, enzymes involved in microbial secondary metabolism. ACE1 is expressed exclusively during fungal penetration of host leaves, the time point at which plant defense reactions are triggered. Ace1 appears to be localized in the cytoplasm of the appressorium. Mutation of the putative catalytic site of the b-ketoacyl synthase domain of Ace1 abolishes recognition of the fungus by resistant rice. This suggests that Ace1 biosynthetic activity is required for avirulence. Our results are consistent with the hypothesis that the fungal signal recognized by resistant rice plants is the secondary metabolite whose synthesis depends on Ace1.

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“…Fungal PKSs can also have a variety of other catalytic domains, and cryptically encoded in their structure is a "program" for using (or skipping) specific catalytic activities after each condensation cycle (6,16). Examples of R-PKSs include the two PKSs for lovastatin biosynthesis in Aspergillus terreus (12,17) and one of the two PKSs for T-toxin biosynthesis in Cochliobolus heterostrophus (42). The mechanisms of fungal PKS programming are unknown and present a fascinating challenge to workers interested in engineering the production of novel polyketides.…”

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confidence: 99%

Genes for the Biosynthesis of the Fungal Polyketides Hypothemycin from Hypomyces subiculosus and Radicicol from Pochonia chlamydosporia

Reeves¹,

Hu²,

Reid³

et al. 2008

Appl Environ Microbiol

129

141

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Gene clusters for biosynthesis of the fungal polyketides hypothemycin and radicicol from Hypomyces subiculosus and Pochonia chlamydosporia, respectively, were sequenced. Both clusters encode a reducing polyketide synthase (PKS) and a nonreducing PKS like those in the zearalenone cluster of Gibberella zeae, plus enzymes with putative post-PKS functions. Introduction of an O-methyltransferase (OMT) knockout construct into H. subiculosus resulted in a strain with increased production of 4-O-desmethylhypothemycin, but because transformation of H. subiculosus was very difficult, we opted to characterize hypothemycin biosynthesis using heterologous gene expression. In vitro, the OMT could methylate various substrates lacking a 4-O-methyl group, and the flavin-dependent monooxygenase (FMO) could epoxidate substrates with a 1,2 double bond. The glutathione S-transferase catalyzed cis-trans isomerization of the 7,8 double bond of hypothemycin. Expression of both hypothemycin PKS genes (but neither gene alone) in yeast resulted in production of trans-7,8-dehydrozearalenol (DHZ). Adding expression of OMT, expression of FMO, and expression of cytochrome P450 to the strain resulted in methylation, 1,2-epoxidation, and hydroxylation of DHZ, respectively. The radicicol gene cluster encodes halogenase and cytochrome P450 homologues that are presumed to catalyze chlorination and epoxidation, respectively. Schemes for biosynthesis of hypothemycin and radicicol are proposed. The PKSs encoded by the two clusters described above and those encoded by the zearalenone cluster all synthesize different products, yet they have significant sequence identity. These PKSs may provide a useful system for probing the mechanisms of fungal PKS programming.Hypothemycin and structurally related compounds are resorcylic acid lactones (RALs) that are produced by Hypomyces subiculosus and other fungi (1,7, 14,25,26,28,43). The structures of some naturally occurring RALs are shown in Fig.

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Lovastatin biosynthesis in Aspergillus terreus: Characterization of blocked mutants, enzyme activities and a multifunctional polyketide synthase gene

Cited by 196 publications

References 25 publications

A polyketide synthase gene required for ochratoxin A biosynthesis in Aspergillus ochraceus

A polyketide synthase gene required for ochratoxin A biosynthesis in Aspergillus ochraceus

A Putative Polyketide Synthase/Peptide Synthetase fromMagnaporthe griseaSignals Pathogen Attack to Resistant Rice[W]

Genes for the Biosynthesis of the Fungal Polyketides Hypothemycin from Hypomyces subiculosus and Radicicol from Pochonia chlamydosporia

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