Production of hybrid 16-membered macrolides by expressing combinations of polyketide synthase genes in engineered Streptomyces fradiae hosts

被引：31

作者：

Reeves, CD ^{[1
]}

Ward, SL ^{[1
]}

Revill, WP ^{[1
]}

Suzuki, H ^{[1
]}

Marcus, M ^{[1
]}

Petrakovsky, OV ^{[1
]}

Marquez, S ^{[1
]}

Fu, H ^{[1
]}

Dong, SD ^{[1
]}

Katz, L ^{[1
]}

机构：

[1] Kosan Biosci Inc, Hayward, CA 94545 USA

来源：

CHEMISTRY & BIOLOGY | 2004年 / 11卷 / 10期

关键词：

D O I：

10.1016/j.chembiol.2004.08.019

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Combinations of the five polyketide synthase (PKS) genes for biosynthesis of tylosin in Streptomyces fradiae (tylG), spiramycin in Streptomyces ambofaciens (srmG), or chalcomycin in Streptomyces bikiniensis (chmG) were expressed in engineered hosts derived from a tylosin-producing strain of S. fradiae. Surprisingly efficient synthesis of compounds predicted from the expressed hybrid PKS was obtained. The post-PKS tailoring enzymes of tylosin biosynthesis acted efficiently on the hybrid intermediates with the exception of TylH-catalyzed hydroxylation of the methyl group at C14, which was efficient if C4 bore a methyl group, but inefficient if a methoxyl was present. Moreover, for some compounds, oxidation of the C6 ethyl side chain to an unprecedented carboxylic acid was observed. By also expressing chmH, a homolog of tylH from the chalcomycin gene cluster, efficient hydroxylation of the 14-methyl group was restored.

引用

页码：1465 / 1472

页数：8

共 39 条

[21] STRUCTURE-ACTIVITY RELATIONSHIP STUDIES ON 4''-ORTHO-ACYLTYLOSIN DERIVATIVES - SIGNIFICANCE OF THEIR 23-ORTHO-MYCINOSYL AND 4''-ORTHO-ACYL MOIETIES IN ANTIMICROBIAL ACTIVITY AGAINST MACROLIDE-RESISTANT MICROBES [J].