Allantoin catabolism influences the production of antibiotics in Streptomyces coelicolor
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Purines are a primary source of carbon and nitrogen in soil; however, their metabolism is poorly understood in Streptomyces. Using a combination of proteomics, metabolomics, and metabolic engineering, we characterized the allantoin pathway in Streptomyces coelicolor. When cells grew in glucose minimal medium with allantoin as the sole nitrogen source, quantitative proteomics identified 38 enzymes upregulated and 28 downregulated. This allowed identifying six new functional enzymes involved in allantoin metabolism in S. coelicolor. From those, using a combination of biochemical and genetic engineering tools, it was found that allantoinase (EC 184.108.40.206) and allantoicase (EC 220.127.116.11) are essential for allantoin metabolism in S. coelicolor. Metabolomics showed that under these growth conditions, there is a significant intracellular accumulation of urea and amino acids, which eventually results in urea and ammonium release into the culture medium. Antibiotic production of a urease mutant strain showed that the catabolism of allantoin, and the subsequent release of ammonium, inhibits antibiotic production. These observations link the antibiotic production impairment with an imbalance in nitrogen metabolism and provide the first evidence of an interaction between purine metabolism and antibiotic biosynthesis.
KeywordsStreptomyces Allantoin Ammonium Antibiotic regulation
This work was supported by ANPCyT grants PICT 2007–00711 to PC and PICT2008-644 to HG, Fundación Perez-Guerrero grant to ER and PIP 100764 from CONICET to ER. ER, PC, and HG are members of the Research Career and LN is a doctoral fellow of CONICET. CLC is a doctoral fellow of CONACYT. We kindly thank Dr. Alun Jones and Dr. Amanda Nouwens for LC-MS assistance and David Hopwood for helpful comments. All proteomics work was performed at the proteomics facility at IMB and/or SCMB. We thank Paul Dyson (Swansea University) for kindly providing the derivative cosmids carrying transposon insertions and Monica Hourcade (Universidad Nacional de Rosario) for technical assistance in the metabolomic analysis.
Conflict of interest
The authors declare no competing financial interests.
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