Project Details
Description
The broad objective of this research program is to understand which
chemical reactions are available in Nature and how they are linked
together to produce complex structures with significant bio-medically
relevant activity. This objective will be attained through a multi-faceted
approach that blends synthesis, biosynthesis, enzymology and molecular
genetics. Such an interdisciplinary approach has become more and more
essential for the modern bioorganic chemist who desires to study
metabolism, its regulation and its consequences. It is in such
laboratories that new chemists with an understanding of biology and a
broad range of skills for solving important biochemical problems are being
produced. The specific aims of this program are to continue work on blasticidin S,
streptothricin F and capreomycin 1A. Research carried out during earlier
phases of this NIH supported program has established important biogenetic
and biochemical connections amongst the three, and each represents a
substantial family of antibiotics. The Research Design includes structural
studies to identify biosynthetic intermediates in each pathway. This will
be done through the in vivo use of enzyme inhibitors to block specific
biosynthetic steps and induce accumulation of pathway intermediates, an
approach that has already been very successful with the blasticidin
pathway. The Research Design will also include biochemical studies to
detect and characterize enzymes that catalyze a number of important
reactions in each pathway, and will include genetIcs studies to clone and
sequence self-resistance genes and biosynthetic genes for sets of enzymes
that carry out the same, or similar, reaction on similar, or identical,
substrates. New nucleosides that will be identified from the blasticidin and
streptothricin studies may prove useful directly as - or in the design of
- antiviral agents. The capreomycin studies may provide new leads to
efficacious agents against the new "killer" strains of Mycobacterium
tuberculosis.
chemical reactions are available in Nature and how they are linked
together to produce complex structures with significant bio-medically
relevant activity. This objective will be attained through a multi-faceted
approach that blends synthesis, biosynthesis, enzymology and molecular
genetics. Such an interdisciplinary approach has become more and more
essential for the modern bioorganic chemist who desires to study
metabolism, its regulation and its consequences. It is in such
laboratories that new chemists with an understanding of biology and a
broad range of skills for solving important biochemical problems are being
produced. The specific aims of this program are to continue work on blasticidin S,
streptothricin F and capreomycin 1A. Research carried out during earlier
phases of this NIH supported program has established important biogenetic
and biochemical connections amongst the three, and each represents a
substantial family of antibiotics. The Research Design includes structural
studies to identify biosynthetic intermediates in each pathway. This will
be done through the in vivo use of enzyme inhibitors to block specific
biosynthetic steps and induce accumulation of pathway intermediates, an
approach that has already been very successful with the blasticidin
pathway. The Research Design will also include biochemical studies to
detect and characterize enzymes that catalyze a number of important
reactions in each pathway, and will include genetIcs studies to clone and
sequence self-resistance genes and biosynthetic genes for sets of enzymes
that carry out the same, or similar, reaction on similar, or identical,
substrates. New nucleosides that will be identified from the blasticidin and
streptothricin studies may prove useful directly as - or in the design of
- antiviral agents. The capreomycin studies may provide new leads to
efficacious agents against the new "killer" strains of Mycobacterium
tuberculosis.
| Status | Finished |
|---|---|
| Effective start/end date | 12/1/82 → 7/31/99 |
Funding
- National Institutes of Health
ASJC
- Medicine(all)
- Biochemistry, Genetics and Molecular Biology(all)
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