| RRC ID |
15728
|
| Author |
Kim W, Lee D, Hong SS, Na Z, Shin JC, Roh SH, Wu CZ, Choi O, Lee K, Shen YM, Paik SG, Lee JJ, Hong YS.
|
| Title |
Rational biosynthetic engineering for optimization of geldanamycin analogues.
|
| Journal |
Chembiochem
|
| Abstract |
Tailor made: We report the rational biosynthesis of C15 hydroxylated non-quinone geldanamycin analogues by site-directed mutagenesis of the geldanamycin polyketide synthase (PKS), together with a combination of post-PKS tailoring genes. Rational biosynthetic engineering allowed the generation of geldanamycin derivatives, such as DHQ3 illustrated in the figure, which had superior pharmacological properties in comparison to the parent compound. A rational biosynthetic engineering approach was applied to the optimization of the pharmacological properties of the benzoquinone ansamycin, geldanamycin. Geldanamycin and its natural or semisynthetic derivatives have the potential to serve as anticancer chemotherapeutic agents. However, these first-generation Hsp90 inhibitors share an unfavorable structural feature that causes both reduced efficacy and toxicity during clinical evaluation. We report the rationally designed biosynthesis of C15 hydroxylated non-quinone geldanamycin analogues by site-directed mutagenesis of the geldanamycin polyketide synthase (PKS), together with a combination of post-PKS tailoring genes. A 15-hydroxyl-17-demethoxy non-quinone analogue, DHQ3, exhibited stronger inhibition of Hsp90 ATPase activity (4.6-fold) than geldanamycin. Taken together, the results of the present study indicate that rational biosynthetic engineering allows the generation of derivatives of geldanamycin with superior pharmacological properties.
|
| Volume |
10(7)
|
| Pages |
1243-51
|
| Published |
2009-5-4
|
| DOI |
10.1002/cbic.200800763
|
| PMID |
19308924
|
| MeSH |
Amino Acid Sequence
Amino Acid Substitution
Antibiotics, Antineoplastic / chemistry*
Antibiotics, Antineoplastic / metabolism
Antibiotics, Antineoplastic / pharmacology
Benzoquinones / chemistry*
Benzoquinones / metabolism*
Benzoquinones / pharmacology
Genetic Engineering
HSP90 Heat-Shock Proteins / antagonists & inhibitors
HSP90 Heat-Shock Proteins / metabolism
Lactams, Macrocyclic / chemistry*
Lactams, Macrocyclic / metabolism*
Lactams, Macrocyclic / pharmacology
Molecular Sequence Data
Multigene Family
Mutagenesis, Site-Directed
Polyketide Synthases / genetics
Polyketide Synthases / metabolism
Sequence Alignment
|
| IF |
2.576
|
| Times Cited |
35
|
|
WOS Category
|
CHEMISTRY, MEDICINAL
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| Resource |
| General Microbes |
JCM 4427 |
