Analysis of the molecular recognition features of individual modules derived from the erythromycin polyketide synthase

被引：70

作者：

Wu, N

Kudo, F

Cane, DE

Khosla, C

机构：

[1] Brown Univ, Dept Chem, Providence, RI 02912 USA

[2] Stanford Univ, Dept Chem Engn, Stanford, CA 94305 USA

[3] Stanford Univ, Dept Biochem, Stanford, CA 94305 USA

[4] Stanford Univ, Dept Chem, Stanford, CA 94305 USA

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2000年 / 122卷 / 20期

关键词：

D O I：

10.1021/ja000023d

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

6-Deoxyerythronolide B synthase (DEBS), the multifunctional enzyme responsible for the biosynthesis of the macrolide aglycon of the antibiotic erythromycin, is an excellent model system for studying the properties of modular polyketide synthases. In these studies, we analyzed the substrate specificity of selected individual modules of DEBS. Unexpectedly, we observed (i) a high degree of similarity in the specificity of all modules tested, despite the diverse structural features of their natural substrates, and (ii) a distinct preference by all modules for syn diketides over anti diketides. The implications of these results are analyzed from an evolutionary and a protein engineering perspective.

引用

收藏

页码：4847 / 4852

页数：6

相关论文

共 27 条

[1] Engineering of a minimal modular polyketide synthase, and targeted alteration of the stereospecificity of polyketide chain extension [J].

Bohm, I ;

Holzbaur, IE ;

Hanefeld, U ;

Cortes, J ;

Staunton, J ;

Leadlay, PF .

CHEMISTRY & BIOLOGY, 1998, 5 (08) :407-412

[2] Efficient purification and kinetic characterization of a bimodular derivative of the erythromycin polyketide synthase [J].

Bycroft, M ;

Weissman, KJ ;

Staunton, J ;

Leadlay, PF .

EUROPEAN JOURNAL OF BIOCHEMISTRY, 2000, 267 (02) :520-526

[3] Molecular recognition of diketide substrates by a beta-ketoacyl-acyl carrier protein synthase domain within a bimodular polyketide synthase [J].

Chuck, JA ;

McPherson, M ;

Huang, H ;

Jacobsen, JR ;

Khosla, C ;

Cane, DE .

CHEMISTRY & BIOLOGY, 1997, 4 (10) :757-766

[4] AN ERYTHROMYCIN ANALOG PRODUCED BY REPROGRAMMING OF POLYKETIDE SYNTHESIS [J].

DONADIO, S ;

MCALPINE, JB ;

SHELDON, PJ ;

JACKSON, M ;

KATZ, L .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (15) :7119-7123

[5] Dissecting and exploiting intermodular communication in polyketide synthases [J].

Gokhale, RS ;

Tsuji, SY ;

Cane, DE ;

Khosla, C .

SCIENCE, 1999, 284 (5413) :482-485

[6] Mechanism and specificity of the terminal thioesterase domain from the erythromycin polyketide synthase [J].

Gokhale, RS ;

Hunziker, D ;

Cane, DE ;

Khosla, C .

CHEMISTRY & BIOLOGY, 1999, 6 (02) :117-125

[7] Enantiospecific synthesis of analogues of the diketide intermediate of the erythromycin polyketide synthase (PKS) [J].

Harris, RC ;

Cutter, AL ;

Weissman, KJ ;

Hanefeld, U ;

Timoney, MC ;

Staunton, J .

JOURNAL OF CHEMICAL RESEARCH-S, 1998, (06) :283-+

[8] Molecular basis of Celmer's rules: the role of two ketoreductase domains in the control of chirality by the erythromycin modular polyketide synthase [J].

Holzbaur, IE ;

Harris, RC ;

Bycroft, M ;

Cortes, J ;

Bisang, C ;

Staunton, J ;

Rudd, BAM ;

Leadlay, PF .

CHEMISTRY & BIOLOGY, 1999, 6 (04) :189-195

[9] Precursor directed biosynthesis of novel 6-deoxyerythronolide B analogs containing non-natural oxygen substituents and reactive functionalities [J].

Hunziker, D ;

Wu, N ;

Kenoshita, K ;

Cane, DE ;

Khosla, C .

TETRAHEDRON LETTERS, 1999, 40 (04) :635-638

[10] Precursor-directed biosynthesis of erythromycin analogs by an engineered polyketide synthase [J].

Jacobsen, JR ;

Hutchinson, CR ;

Cane, DE ;

Khosla, C .

SCIENCE, 1997, 277 (5324) :367-369