Details
| Original language | English |
|---|---|
| Pages (from-to) | 8478-8489 |
| Number of pages | 12 |
| Journal | Chemical science |
| Volume | 10 |
| Issue number | 36 |
| Early online date | 30 Jul 2019 |
| Publication status | Published - 28 Sept 2019 |
Abstract
Exchange of 32 different sub-fragments of the C-methyltransferase (C-MeT), pseudo-ketoreductase (ΨKR) and ketoreductase (KR) catalytic domains of the tenellin iterative Type I polyketide synthase non ribosomal peptide synthetase (PKS-NRPS) TENS by homologous fragments from the desmethylbassianin (DMBS) and militarinone (MILS) PKS-NRPS led to the creation of chimeric synthetases in which programming fidelity was altered, resulting in the production of mixtures of products with different methylation patterns and chain lengths. Swap of KR domain subfragments with the homologous fragments from the KR of the heptaketide militarinone synthetase resulted in the synthesis of penta, hexa and heptaketides. The results of these and previous experiments are rationalised by considering the existence of competition for acyl-carrier protein (ACP) bound substrates between different catalytic domains of the PKS. In particular, competition between the C-MeT and ketoreductase domains (KR) can account for methylation programming, and competition between the KR and the off-loading NRPS accounts for chain-length selectivity.
ASJC Scopus subject areas
- Chemistry(all)
- General Chemistry
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In: Chemical science, Vol. 10, No. 36, 28.09.2019, p. 8478-8489.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Molecular basis of methylation and chain-length programming in a fungal iterative highly reducing polyketide synthase
AU - Yang, Xiao Long
AU - Friedrich, Steffen
AU - Yin, Sen
AU - Piech, Oliver
AU - Williams, Katherine
AU - Simpson, Thomas J.
AU - Cox, Russell J.
N1 - Funding information: This is supported by the limited number of reported in vitro investigations of hr-PKS catalytic domains. We recently showed that the functional ER domain from squalestatin tetraketide synthase has low selectivity and is able to effectively reduce a wide range of enoyl-pantetheines, even including unnatural isomers and stereoisomers.26 Meanwhile, Vederas and coworkers have shown that the C-MeT domain from the
PY - 2019/9/28
Y1 - 2019/9/28
N2 - Exchange of 32 different sub-fragments of the C-methyltransferase (C-MeT), pseudo-ketoreductase (ΨKR) and ketoreductase (KR) catalytic domains of the tenellin iterative Type I polyketide synthase non ribosomal peptide synthetase (PKS-NRPS) TENS by homologous fragments from the desmethylbassianin (DMBS) and militarinone (MILS) PKS-NRPS led to the creation of chimeric synthetases in which programming fidelity was altered, resulting in the production of mixtures of products with different methylation patterns and chain lengths. Swap of KR domain subfragments with the homologous fragments from the KR of the heptaketide militarinone synthetase resulted in the synthesis of penta, hexa and heptaketides. The results of these and previous experiments are rationalised by considering the existence of competition for acyl-carrier protein (ACP) bound substrates between different catalytic domains of the PKS. In particular, competition between the C-MeT and ketoreductase domains (KR) can account for methylation programming, and competition between the KR and the off-loading NRPS accounts for chain-length selectivity.
AB - Exchange of 32 different sub-fragments of the C-methyltransferase (C-MeT), pseudo-ketoreductase (ΨKR) and ketoreductase (KR) catalytic domains of the tenellin iterative Type I polyketide synthase non ribosomal peptide synthetase (PKS-NRPS) TENS by homologous fragments from the desmethylbassianin (DMBS) and militarinone (MILS) PKS-NRPS led to the creation of chimeric synthetases in which programming fidelity was altered, resulting in the production of mixtures of products with different methylation patterns and chain lengths. Swap of KR domain subfragments with the homologous fragments from the KR of the heptaketide militarinone synthetase resulted in the synthesis of penta, hexa and heptaketides. The results of these and previous experiments are rationalised by considering the existence of competition for acyl-carrier protein (ACP) bound substrates between different catalytic domains of the PKS. In particular, competition between the C-MeT and ketoreductase domains (KR) can account for methylation programming, and competition between the KR and the off-loading NRPS accounts for chain-length selectivity.
UR - http://www.scopus.com/inward/record.url?scp=85072596885&partnerID=8YFLogxK
U2 - 10.1039/c9sc03173a
DO - 10.1039/c9sc03173a
M3 - Article
AN - SCOPUS:85072596885
VL - 10
SP - 8478
EP - 8489
JO - Chemical science
JF - Chemical science
SN - 2041-6520
IS - 36
ER -