title: Inhibition of aryl acid adenylation domains involved in bacterial siderophore synthesis.
abstract: Aryl acid adenylation domains are the initial enzymes for aryl-capping of catecholic siderophores in a plethora of microorganisms. In order to overcome the problem of iron acquisition in host organisms, siderophore biosynthesis is decisive for virulence development in numerous important human and animal pathogens. Recently, it was shown that growth of Mycobacterium tuberculosis and Yersinia pestis can be inhibited in an iron-dependent manner using the arylic acyl adenylate analogue 5'-O-[N-(salicyl)-sulfamoyl] adenosine that acts on the salicylate activating domains, MbtA and YbtE [Ferreras JA, Ryu JS, Di Lello F, Tan DS, Quadri LEN (2005) Nat Chem Biol1, 29-32]. The present study explores the behaviour of the 2,3-dihydroxybenzoate activating domain DhbE (bacillibactin synthesis) and compares it to that of YbtE (yersiniabactin synthesis) upon enzymatic inhibition using a set of newly synthesized aryl sulfamoyl adenosine derivatives. The obtained results underline the highly specific mode of inhibition for both aryl acid activating domains in accordance with their natively accepted aryl moiety. These findings are discussed regarding the structure-function based aspect of aryl substrate binding to the DhbE and YbtE active sites.
authors.affiliation: Philipps-Universität Marburg, Fachbereich Chemie/Biochemie, Marburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Miethke
authors.forename: Philippe
authors.initials: P
authors.lastname: Bisseret
authors.forename: Carsten L
authors.initials: CL
authors.lastname: Beckering
authors.forename: David
authors.initials: D
authors.lastname: Vignard
authors.forename: Jacques
authors.initials: J
authors.lastname: Eustache
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Marahiel
mesh_terms: D000249:Adenosine Monophosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D017262:Siderophores / Q000096:biosynthesis* / Q000737:chemistry; D015010:Yersinia pestis / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D017262:Siderophores; D000249:Adenosine Monophosphate