# BIOSYNTHESIS OF ANTHRACYCLINE ANTIBIOTICS

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 1992 · $210,628

## Abstract

I propose to continue a study of the biochemistry and genetics of the
production of tetracenomycin C (Tcm C), a metabolite of Streptomyces
glaucescens that is classified chemically as an anthracycline and has
moderate antitumor properties, as a model of secondary metabolism.
Information about the biosynthesis of polyketides, like Tcm C, can be used
to increase the production of known drugs.  In attempts to make new drugs
by genetic engineering, which is an attractive prospect for anthracyclines
because some of them have clinically valuable antitumor and notable anti-
HIV activity, the knowledge that the polyketides represent hundreds of
different structural types suggests that numerous perturbations of this
biochemistry are possible.  This could make the search for new drugs by
genetic engineering especially fruitful.

Antibiotic production is a characteristic of Streptomyces that has
attracted considerable attention.  Probing its genetics is likely to
uncover significantly new information because secondary metabolism, a
unique characteristic of the slow growth (stationary) phase of laboratory
cultures, is quite unlike the primary metabolism of rapidly growing cells
that has been the focal point of most studies of prokaryotic genetics.
Moreover, the value of using the PKS genes and genes that regulate
antibiotic production to construct strains that overproduce secondary
metabolites has been demonstrated; thus, information about the regulatory
mechanisms should have wide-spread utility in biotechnology.

Our goals for the next five years, listed in the priority in which they
will be pursued, are as follows.  1. Enzymology of the tcm polyketide
synthase (PKS).  We will study the enzymology of polyketide metabolism by
(i) determining the properties of the enzymes produced by the tcm PKS
genes, (ii) using these enzymes to develop a system for the production of
Tcm F2 nd Tcm F1 (or D3) in vitro, and then (iii) investigating the effect
of substituting the components of other PKS's for the different enzymes of
the tcm PKS.  New metabolites may be produced in this work.  2. Regulation
of the expression of the tcm genes.  We will investigate the genetics of
Tcm C production by (i) elucidating the transcriptional organization of the
tcmIII/VI/Ia/II, tcmVII, and tcmAR genes, (ii) determining whether
expression of the tcm PKS, tcmVII and tcmA genes is controlled by the tcmR
gene or vice-versa, and (iii) searching for genes or physiological factors
that control expression of the tcmIII/VI/Ia/II and tcmAR genes.  This will
provide insight into the regulation of secondary metabolism.  3. Properties
of the fatty acid synthase (FAS) genes.  We will determine the effect of
deleting the Orf1 gene of the S. glaucescens ACP-II region on cell growth
and development, and the production of the Tcm C metabolites.  This work
will reveal possible interactions between polyketide and fatty acid
metabolism and whether the Orf1 gene is part of the FAS.

## Key facts

- **NIH application ID:** 3172996
- **Project number:** 2R01CA035381-09A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **SAM.gov UEI:** LCLSJAGTNZQ7
- **Principal Investigator:** CHARLES R HUTCHINSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $210,628
- **Award type:** 2
- **Project period:** 1986-09-01 → 1997-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3172996

## Citation

> US National Institutes of Health, RePORTER application 3172996, BIOSYNTHESIS OF ANTHRACYCLINE ANTIBIOTICS (2R01CA035381-09A1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3172996. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*