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  wALADin benzimidazoles differentially modulate the function of porphobilinogen synthase orthologs

Lentz, C. S., Halls, V. S., Hannam, J. S., Strassel, S., Lawrence, S. H., Jaffe, E. K., et al. (2014). wALADin benzimidazoles differentially modulate the function of porphobilinogen synthase orthologs. Journal of medicinal chemistry, 57(6), 2498-510. doi:10.1021/jm401785n.

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Item Permalink: https://hdl.handle.net/11858/00-001M-0000-0028-63E7-1 Version Permalink: https://hdl.handle.net/11858/00-001M-0000-0028-63E8-0
Genre: Journal Article

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 Creators:
Lentz, C. S., Author
Halls, V. S., Author
Hannam, J. S., Author
Strassel, S., Author
Lawrence, S. H., Author
Jaffe, E. K., Author
Famulok, M.1, Author
Hoerauf, A., Author
Pfarr, K. M., Author
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1External Organizations, ou_persistent22              

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Free keywords: Animals Anti-Bacterial Agents/*chemical synthesis/*pharmacology Antiprotozoal Agents/chemical synthesis/pharmacology Benzimidazoles/*chemical synthesis/*pharmacology Chlamydia/drug effects Herbicides/chemical synthesis/pharmacology Humans Hydrogen-Ion Concentration Microbial Sensitivity Tests Molecular Weight Peas Plants Porphobilinogen Synthase/*antagonists & inhibitors Porphyrias/drug therapy Pseudomonas aeruginosa/drug effects/enzymology Rickettsia/drug effects Stereoisomerism Structure-Activity Relationship Wolbachia/drug effects
 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.

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 Dates: 2014
 Publication Status: Issued
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 Identifiers: Other: 24568185
DOI: 10.1021/jm401785n
ISSN: 1520-4804 (Electronic)
ISSN: 0022-2623 (Linking)
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Title: Journal of medicinal chemistry
  Alternative Title : J. Med. Chem.
Source Genre: Journal
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Pages: - Volume / Issue: 57 (6) Sequence Number: - Start / End Page: 2498 - 510 Identifier: -