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J. Biol. Chem., Vol. 280, Issue 6, 4339-4349, February 11, 2005

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Functional Cross-talk between Fatty Acid Synthesis and Nonribosomal Peptide Synthesis in Quinoxaline Antibiotic-producing Streptomycetes^*

Gernot Schmoock, Frank Pfennig, Julien Jewiarz, Wilhelm Schlumbohm, Werner Laubinger, Florian Schauwecker, and Ullrich Keller

From the Institut für Chemie, Arbeitsgruppe Biochemie und Molekularbiologie, Technische Universität Berlin, Franklinstrasse 29, D-10587 Berlin-Charlottenburg, Germany

Quinoxaline antibiotics are chromopeptide lactones embracing the two families of triostins and quinomycins, each having characteristic sulfur-containing cross-bridges. Interest in these compounds stems from their antineoplastic activities and their specific binding to DNA via bifunctional intercalation of the twin chromophores represented by quinoxaline-2-carboxylic acid (QA). Enzymatic analysis of triostin A-producing Streptomyces triostinicus and quinomycin A-producing Streptomyces echinatus revealed four nonribosomal peptide synthetase modules for the assembly of the quinoxalinoyl tetrapeptide backbone of the quinoxaline antibiotics. The modules were contained in three protein fractions, referred to as triostin synthetases (TrsII, III, and IV). TrsII is a 245-kDa bimodular nonribosomal peptide synthetase activating as thioesters for both serine and alanine, the first two amino acids of the quinoxalinoyl tetrapeptide chain. TrsIII, represented by a protein of 250 kDa, activates cysteine as a thioester. TrsIV, an unstable protein of apparent M_r about 280,000, was identified by its ability to activate and N-methylate valine, the last amino acid. QA, the chromophore, was shown to be recruited by a free-standing adenylation domain, TrsI, in conjunction with a QA-binding protein, AcpPSE. Cloning of the gene for the QA-binding protein revealed that it is the fatty acyl carrier protein, AcpPSE, of the fatty acid synthase of S. echinatus and S. triostinicus. Analysis of the acylation reaction of AcpPSE by TrsI along with other A-domains and the aroyl carrier protein AcmACP from actinomycin biosynthesis revealed a specific requirement for AcpPSE in the activation and also in the condensation of QA with serine in the initiation step of QA tetrapeptide assembly on TrsII. These data show for the first time a functional interaction between nonribosomal peptide synthesis and fatty acid synthesis.

Received for publication, September 24, 2004 , and in revised form, November 24, 2004.

^* This work was supported by Technical University Berlin Grant 42511/08 and Forschungsschwerpunkt SPP1152 of the Deutsche Forschungsgemeinschaft project Ke 452/11-3. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY825941.

Present address: Technische Universität Dresden, Institut für Zoologie, Mommsenstr. 13, D-01062 Dresden, Germany.

To whom correspondence should be addressed. Tel.: 49-303-142-5653; Fax: 49-303-142-4783; E-mail: ullrich.keller{at}tu-berlin.de.

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