Abstract

The stereochemical course of polyketide antibiotic biosynthesis is to be examined by determination of the biochemical origin, regiochemistry, and stereospecificity of hydrogen introduction/elimination during the biosynthesis of erythromycin, 6-methyl-salicyclic acid, and brefeldin A, all microbial macrolide or aromatic antibiotics. The stereochemistry of acetate-polymalonate and propionate-polymethylmalonate condensations and the overall sterospecificity of polyketide biosynthesis is to be established through analysis of the incorporation of chirally labeled acetate and propionate into these antibiotics. The experimental approach will use chiral precursors containing isotopic hydrogen labels whose incorporation into the antibiotics will be achieved in vitro and in vivo. Chemical and biochemical methods will be used for determination of labeling sites and the associated stereospecificity within the antibiotics. The results will define the biochemical relationship between fatty acid and polyketide biosynthesis, provide new information about the enzymology of polyketide biosynthesis, and examine the relationship between prostaglandin biosynthesis and the ring cyclization mechanism of other monocylopentanoid polyketide metabolites, specifically brefeldin A.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM025799-06
Application #
3273300
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1979-01-01
Project End
1985-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
6
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
University of Wisconsin Madison
Department
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715

  Publications

Gallo, M A; Ward, J; Hutchinson, C R (1996) The dnrM gene in Streptomyces peucetius contains a naturally occurring frameshift mutation that is suppressed by another locus outside of the daunorubicin-production gene cluster. Microbiology 142 ( Pt 2):269-75
Tang, L; Zhang, Y X; Hutchinson, C R (1994) The genetic basis of precursor supply for the biosynthesis of macrolide and polyether antibiotics. Ann N Y Acad Sci 721:105-16
Hutchinson, C R (1994) Drug synthesis by genetically engineered microorganisms. Biotechnology (N Y) 12:375-80
Tang, L; Hutchinson, C R (1993) Sequence, transcriptional, and functional analyses of the valine (branched-chain amino acid) dehydrogenase gene of Streptomyces coelicolor. J Bacteriol 175:4176-85
Hutchinson, C R; Decker, H; Madduri, K et al. (1993) Genetic control of polyketide biosynthesis in the genus Streptomyces. Antonie Van Leeuwenhoek 64:165-76
Navarrete, R M; Vara, J A; Hutchinson, C R (1990) Purification of an inducible L-valine dehydrogenase of Streptomyces coelicolor A3(2). J Gen Microbiol 136:273-81
Hutchinson, C R; Borell, C W; Otten, S L et al. (1989) Drug discovery and development through the genetic engineering of antibiotic-producing microorganisms. J Med Chem 32:929-37
Kinashi, H; Otten, S L; Duncan, J S et al. (1988) Frequent loss and restoration of antibiotic production by Streptomyces lasaliensis. J Antibiot (Tokyo) 41:624-37
Gonzalez de la Parra, M; Hutchinson, C R (1987) Macrolide biosynthesis: stereochemistry of the hydroxylation of brefeldin C. J Antibiot (Tokyo) 40:1170-4
Sherman, M M; Hutchinson, C R (1987) Biosynthesis of lasalocid A: biochemical mechanism for assembly of the carbon framework. Biochemistry 26:438-45

Showing the most recent 10 out of 13 publications