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Lentz CS , Halls VS , Hannam JS , Strassel S , Lawrence SH , Jaffe EK , Famulok M , Hoerauf A , Pfarr KM
wALADin benzimidazoles differentially modulate the function of porphobilinogen synthase orthologs
J Med Chem. 2014 Mar 27;57(6) :2498-510
PMID: 24568185    PMCID: PMC3983392    URL: https://www.ncbi.nlm.nih.gov/pubmed/24568185
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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.
Lentz, Christian S Halls, Victoria S Hannam, Jeffrey S Strassel, Silke Lawrence, Sarah H Jaffe, Eileen K Famulok, Michael Hoerauf, Achim Pfarr, Kenneth M eng R01 ES003654/ES/NIEHS NIH HHS/ R56 AI077577/AI/NIAID NIH HHS/ AI077577/AI/NIAID NIH HHS/ ES003654/ES/NIEHS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Med Chem. 2014 Mar 27;57(6):2498-510. doi: 10.1021/jm401785n. Epub 2014 Feb 25.