Details
| Original language | English |
|---|---|
| Pages (from-to) | 1221-1225 |
| Number of pages | 5 |
| Journal | ChemBioChem |
| Volume | 7 |
| Issue number | 8 |
| Publication status | Published - 27 Jul 2006 |
Abstract
The biosynthesis of the antitumor antibiotic, ansamitocin, involves the assembly of a linear octaketide on the ansamitocin (asm) polyketide synthase (PKS), which is then cyclized to proansamitocin and further modified to the final product. In the first chain-extension step on the asm PKS, a stereocenter is generated which is then obliterated in a subsequent double-bond migration. The cryptic configuration at this stereocenter was determined by first synthesizing the two enantiomers of the intermediate diketide as their N-acetylcysteamine (SNAC) thioesters. These were then used to demonstrate that only the R enantiomer complements a 3-amino-5-hydroxybenzaic acid (AHBA) deficient mutant of Actinosynnema pretiosum to restore ansamitocin formation. The low efficiency of complementation by the diketide, compared to AHBA, is due to inefficient loading onto the PKS and not the inhibition of the enzyme. A presumed next chain-extension intermediate-the triketide with an unrearranged double bond-was also synthesized as its SNAC ester, but did not complement the AHBA- mutant.
Keywords
- Ansamitocin, Antitumor agents, Biosynthesis, Geldanamycin, Polyketides
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Medicine
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Biology
- Chemistry(all)
- Organic Chemistry
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In: ChemBioChem, Vol. 7, No. 8, 27.07.2006, p. 1221-1225.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Determination of the cryptic stereochemistry of the first PKS chain-extension step in ansamitocin biosynthesis by Actinosynnema pretiosum
AU - Kubota, Takaaki
AU - Brünjes, Marco
AU - Frenzel, Thomas
AU - Xu, Jun
AU - Kirschning, Andreas
AU - Floss, Heinz G.
PY - 2006/7/27
Y1 - 2006/7/27
N2 - The biosynthesis of the antitumor antibiotic, ansamitocin, involves the assembly of a linear octaketide on the ansamitocin (asm) polyketide synthase (PKS), which is then cyclized to proansamitocin and further modified to the final product. In the first chain-extension step on the asm PKS, a stereocenter is generated which is then obliterated in a subsequent double-bond migration. The cryptic configuration at this stereocenter was determined by first synthesizing the two enantiomers of the intermediate diketide as their N-acetylcysteamine (SNAC) thioesters. These were then used to demonstrate that only the R enantiomer complements a 3-amino-5-hydroxybenzaic acid (AHBA) deficient mutant of Actinosynnema pretiosum to restore ansamitocin formation. The low efficiency of complementation by the diketide, compared to AHBA, is due to inefficient loading onto the PKS and not the inhibition of the enzyme. A presumed next chain-extension intermediate-the triketide with an unrearranged double bond-was also synthesized as its SNAC ester, but did not complement the AHBA- mutant.
AB - The biosynthesis of the antitumor antibiotic, ansamitocin, involves the assembly of a linear octaketide on the ansamitocin (asm) polyketide synthase (PKS), which is then cyclized to proansamitocin and further modified to the final product. In the first chain-extension step on the asm PKS, a stereocenter is generated which is then obliterated in a subsequent double-bond migration. The cryptic configuration at this stereocenter was determined by first synthesizing the two enantiomers of the intermediate diketide as their N-acetylcysteamine (SNAC) thioesters. These were then used to demonstrate that only the R enantiomer complements a 3-amino-5-hydroxybenzaic acid (AHBA) deficient mutant of Actinosynnema pretiosum to restore ansamitocin formation. The low efficiency of complementation by the diketide, compared to AHBA, is due to inefficient loading onto the PKS and not the inhibition of the enzyme. A presumed next chain-extension intermediate-the triketide with an unrearranged double bond-was also synthesized as its SNAC ester, but did not complement the AHBA- mutant.
KW - Ansamitocin
KW - Antitumor agents
KW - Biosynthesis
KW - Geldanamycin
KW - Polyketides
UR - http://www.scopus.com/inward/record.url?scp=33747203202&partnerID=8YFLogxK
U2 - 10.1002/cbic.200500506
DO - 10.1002/cbic.200500506
M3 - Article
C2 - 16927319
AN - SCOPUS:33747203202
VL - 7
SP - 1221
EP - 1225
JO - ChemBioChem
JF - ChemBioChem
SN - 1439-4227
IS - 8
ER -