Journal
ACS SYNTHETIC BIOLOGY
Volume 6, Issue 9, Pages 1757-1765Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acssynbio.7b00099
Keywords
antibiotics; antitumor agents; metabolic engineering; mutasynthesis; natural product production; autophagy activator; prodiginines
Categories
Funding
- CUB Graduate Cluster Industrial Biotechnology
- Ministry of Innovation, Science and Research [313/323-400-002 13]
Ask authors/readers for more resources
The deeply red-colored natural compound prodigiosin is a representative of the prodiginine alkaloid family, which possesses bioactivities as antimicrobial, antitumor, and antimalarial agents. Various bacteria including the opportunistic human pathogen Serratia marcescens and different members of the Streptomycetaceae and Pseudoalteromonadaceae produce prodiginines. In addition, these microbes generally accumulate many structurally related alkaloids making efficient prodiginine synthesis and purification difficult and expensive. Furthermore, it is known that structurally different natural prodiginine variants display differential bioactivities. In the herein described mutasynthesis approach, 13 different derivatives of prodigiosin were obtained utilizing the GRAS (generally recognized as safe) classified strain Pseudomonas putida KT2440. Genetic engineering of the prodigiosin pathway together with incorporation of synthetic intermediates thus resulted in the formation of a so far unprecedented structural diversity of new prodiginine derivatives in P. putida. Furthermore, the formed products allow reliable conclusions regarding the substrate specificity of PigC, the final condensing enzyme in the prodigiosin biosynthesis pathway of S. marcescens. The biological activity of prodigiosin toward modulation of autophagy was preserved in prodiginine derivatives. One prodiginine derivative displayed more potent autophagy inhibitory activity than the parent compound or the synthetic clinical candidate obatoclax.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available