2002
DOI: 10.1073/pnas.082590499
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Expanding the biosynthetic repertoire of plant type III polyketide synthases by altering starter molecule specificity

Abstract: Type III polyketide synthases (PKS) generate an array of natural products by condensing multiple acetyl units derived from malonyl-CoA to thioester-linked starter molecules covalently bound in the PKS active site. One strategy adopted by Nature for increasing the functional diversity of these biosynthetic enzymes involves modifying polyketide assembly by altering the preference for starter molecules. Chalcone synthase (CHS) is a ubiquitous plant PKS and the first type III PKS described functionally and structu… Show more

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Cited by 133 publications
(101 citation statements)
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“…Type III PKSs are promiscuous enzymes that have a broad tolerance for diverse substrates and are able to catalyze multiple reactions [84,85]. Type III PKSs that use cyclic nitrogen-containing substrates have been previously characterized for their roles in alkaloid production [86][87][88]. However, unlike these previous studies the predicted substrate in TA metabolism, N-methyl-∆ 1 -pyrrolinium cation (19) [81].…”
Section: Tropane Alkaloid Biosynthesiscontrasting
confidence: 43%
“…Type III PKSs are promiscuous enzymes that have a broad tolerance for diverse substrates and are able to catalyze multiple reactions [84,85]. Type III PKSs that use cyclic nitrogen-containing substrates have been previously characterized for their roles in alkaloid production [86][87][88]. However, unlike these previous studies the predicted substrate in TA metabolism, N-methyl-∆ 1 -pyrrolinium cation (19) [81].…”
Section: Tropane Alkaloid Biosynthesiscontrasting
confidence: 43%
“…The 'gatekeeper' Phe215 is generally conserved in most type III PKSs and is located between the CoA-binding tunnel and the entrance of the active site cavity. Despite having a lower malonyl-CoA decarboxylation activity compared to wild-type alfalfa CHS, the F215S mutant is able to utilize p-coumaroyl-CoA, phenylacetyl-CoA, benzoyl-CoA, and C5-C8 acyl-CoAs with less than 3% the catalytic efficiency of the wild-type enzyme to produce tetraketide lactones [100]. Intriguingly, although N-methylanthraniloyl-CoA is not normally utilized by the wild type CHS, the F215S mutant was found to accept the bulky starter with a comparable k cat /K m to R. graveolens acridone synthase (ACS), to form a tetraketide N-methylanthraniloyltriacetic acid lactone (31).…”
Section: Structure-based Engineering and The Versatility Of Type III mentioning
confidence: 99%
“…Simultaneous mutation of the neighbouring Phe66 residue to leucine resulted in an OKS double mutant that is capable of synthesizing an unnatural dodecaketide naphthophenone TW95a (70) by the successive decarboxylative condensations of 12 units of malonyl-CoA, making it one of the longest polyketide synthesized by the structurally simple type III PKS (Scheme 24C) [104]. having a lower malonyl-CoA decarboxylation activity compared to wild-type alfalfa CHS, the F215S mutant is able to utilize p-coumaroyl-CoA, phenylacetyl-CoA, benzoyl-CoA, and C5-C8 acyl-CoAs with less than 3% the catalytic efficiency of the wild-type enzyme to produce tetraketide lactones [100]. Intriguingly, although N-methylanthraniloyl-CoA is not normally utilized by the wild type CHS, the F215S mutant was found to accept the bulky starter with a comparable kcat/Km to R. graveolens acridone synthase (ACS), to form a tetraketide N-methylanthraniloyltriacetic acid lactone (31).…”
Section: Structure-based Engineering and The Versatility Of Type III mentioning
confidence: 99%
“…CHS and STS are the most investigated members at both the biochemical and the molecular levels (Flores-Sanchez & Verpoorte 2009). Despite the functional diversity, plantspecific PKS proteins have in common to be dimeric proteins of approximately 42 kDa with a catalytic triad Cys-His-Asn in the active centre (Jez et al 2002). This facilitates the isolation of new genes coding for PKS family proteins based on homology-based techniques, such as using degenerate oligonucleotide primers.…”
Section: Introductionmentioning
confidence: 99%