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Lawrence SH , Selwood T , Jaffe EK
Diverse clinical compounds alter the quaternary structure and inhibit the activity of an essential enzyme
ChemMedChem. 2011 Jun 6;6(6) :1067-73
PMID: 21506274    PMCID: PMC3236527    URL: https://www.ncbi.nlm.nih.gov/pubmed/21506274
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Abstract
An in vitro evaluation of the Johns Hopkins Clinical Compound Library demonstrates that certain drugs can alter the quaternary structure of an essential human protein. Human porphobilinogen synthase (HsPBGS) is an essential enzyme involved in heme biosynthesis; it exists as an equilibrium of high-activity octamers, low-activity hexamers, and alternate dimer configurations that dictate the stoichiometry and architecture of further assembly. Decreased HsPBGS activity is implicated in toxicities associated with lead poisoning and 5-aminolevulinate dehydratase (ALAD) porphyria, the latter of which involves hexamer-favoring HsPBGS variants. A medium-throughput native PAGE mobility-shift screen coupled with evaluation of hits as HsPBGS inhibitors revealed 12 drugs that stabilize the HsPBGS hexamer and inhibit HsPBGS activity in vitro. A detailed characterization of these effects is presented. Drug inhibition of HsPBGS in vivo by inducing hexamer formation would constitute an unprecedented mechanism for side effects. We suggest that small-molecule perturbation of quaternary structure equilibria be considered as a general mechanism for drug action and side effects.
Notes
Lawrence, Sarah H Selwood, Trevor Jaffe, Eileen K eng P30A006927/PHS HHS/ P30 CA006927-45/CA/NCI NIH HHS/ R56 AI077577-01A2/AI/NIAID NIH HHS/ R56 AI077577/AI/NIAID NIH HHS/ P30 CA006927/CA/NCI NIH HHS/ R01ES003654/ES/NIEHS NIH HHS/ R56AI077577/AI/NIAID NIH HHS/ R01 ES003654-24/ES/NIEHS NIH HHS/ R01 ES003654/ES/NIEHS NIH HHS/ Research Support, N.I.H., Extramural Germany ChemMedChem. 2011 Jun 6;6(6):1067-73. doi: 10.1002/cmdc.201100009. Epub 2011 Apr 19.