NDLI: Revisiting the biosynthesis of dehydrophos reveals a tRNA-dependent pathway

Content Provider	PubMed Central
Author	Bougioukou, Despina J. Mukherjee, Subha Donk, Wilfred A. Van Der
Abstract	Bioactive natural products containing a C-P bond act as mimics of phosphate esters and carboxylic acids, thereby competing with these compounds for active sites of enzymes. Dehydrophos (DHP), a broad-spectrum antibiotic, is a phosphonotripeptide produced by Streptomyces luridus, in which glycine and leucine are linked to an aminophosphonate analog of dehydroalanine, ΔAla(P). This unique feature, in combination with the monomethylation of the phosphonic acid, renders DHP a Trojan horse type antibiotic because peptidase-mediated hydrolysis will release methyl acetylphosphonate, a potent inhibitor of pyruvate dehydrogenase. Bioinformatic analysis of the biosynthetic gene cluster suggested that ΔAla(P) would be generated from Ser(P), the phosphonate analog of Ser, by phosphorylation and subsequent elimination, and that ΔAla(P) would be condensed with Leu-tRNALeu. DhpH was anticipated to carry out this elimination/ligation cascade. DhpH is a multidomain protein, in which a pyridoxal phosphate binding domain is fused to an N-acetyltransferase domain related to the general control nonderepressible-5 (GCN5) family. In this work, the activity of DhpH was reconstituted in vitro. The enzyme was able to catalyze the β-elimination reaction of pSer(P) to generate ΔAla(P), but it was unable to condense ΔAla(P) with Leu. Instead, ΔAla(P) is hydrolyzed to acetyl phosphonate, which is converted to Ala(P) by a second pyridoxal phosphate-dependent enzyme, DhpD. Ala(P) is the substrate for the condensation with Leu-tRNALeu catalyzed by the C-terminal domain of DhpH. DhpJ, a 2-oxoglutarate/Fe(II)-dependent enzyme, introduces the vinyl functionality into Leu-Ala(P) acting as a desaturase, and addition of Gly by DhpK in a Gly-tRNAGly-dependent manner completes the in vitro biosynthesis of dehydrophos.
Related Links	http://dx.doi.org/10.1073/pnas.1303568110
Ending Page	10957
Page Count	6
Starting Page	10952
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	27
Volume Number	110
Language	English
Publisher	National Academy of Sciences
Publisher Date	2013-07-02
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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