title: wALADin benzimidazoles differentially modulate the function of porphobilinogen synthase orthologs.
abstract: The heme biosynthesis enzyme porphobilinogen synthase (PBGS) is a potential drug target in several human pathogens. wALADin1 benzimidazoles have emerged as species-selective PBGS inhibitors against Wolbachia endobacteria of filarial worms. In the present study, we have systematically tested wALADins against PBGS orthologs from bacteria, protozoa, metazoa, and plants to elucidate the inhibitory spectrum. However, the effect of wALADin1 on different PBGS orthologs was not limited to inhibition: several orthologs were stimulated by wALADin1; others remained unaffected. We demonstrate that wALADins allosterically modulate the PBGS homooligomeric equilibrium with inhibition mediated by favoring low-activity oligomers, while 5-aminolevulinic acid, Mg(2+), or K(+) stabilized high-activity oligomers. Pseudomonas aeruginosa PBGS could be inhibited or stimulated by wALADin1 depending on these factors and pH. We have defined the wALADin chemotypes responsible for either inhibition or stimulation, facilitating the design of tailored PBGS modulators for potential application as antimicrobial agents, herbicides, or drugs for porphyric disorders.
authors.affiliation: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn , Sigmund-Freud Strasse 25, 53127 Bonn, Germany.
authors.forename: Christian S
authors.initials: CS
authors.lastname: Lentz
authors.forename: Victoria S
authors.initials: VS
authors.lastname: Halls
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Hannam
authors.forename: Silke
authors.initials: S
authors.lastname: Strassel
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Lawrence
authors.forename: Eileen K
authors.initials: EK
authors.lastname: Jaffe
authors.forename: Michael
authors.initials: M
authors.lastname: Famulok
authors.forename: Achim
authors.initials: A
authors.lastname: Hoerauf
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Pfarr
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D002689:Chlamydia / Q000187:drug effects; D006540:Herbicides / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008826:Microbial Sensitivity Tests; D008970:Molecular Weight; D018532:Pisum sativum; D010944:Plants; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors*; D011164:Porphyrias / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology; D012281:Rickettsia / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D020577:Wolbachia / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000981:Antiprotozoal Agents; D001562:Benzimidazoles; D006540:Herbicides; D000623:Porphobilinogen Synthase