ArticleChemMedChem2011
Diverse clinical compounds alter the quaternary structure and inhibit the activity of an essential enzyme.
Article in ChemMedChem, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
13 citing papers in PubMed, 15 citations in OpenAlex.
- Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators.International journal of molecular sciences · 2021Review
- Wrangling Shape-Shifting Morpheeins to Tackle Disease and Approach Drug Discovery.Frontiers in molecular biosciences · 2020Review
- Porphobilinogen synthase: An equilibrium of different assemblies in human health.Progress in molecular biology and translational science · 2020Review
- New protein structures provide an updated understanding of phenylketonuria.Molecular genetics and metabolism · 2017Review
- A framework for application of metabolic modeling in yeast to predict the effects of nsSNV in human orthologs.Biology direct · 2014Article
- wALADin benzimidazoles differentially modulate the function of porphobilinogen synthase orthologs.Journal of medicinal chemistry · 2014Article
- A new model for allosteric regulation of phenylalanine hydroxylase: implications for disease and therapeutics.Archives of biochemistry and biophysics · 2013Article
- Impact of quaternary structure dynamics on allosteric drug discovery.Current topics in medicinal chemistry · 2013Article
- Environmental contaminants perturb fragile protein assemblies and inhibit normal protein function.Current chemical biology · 2013Article
- Structural basis for morpheein-type allosteric regulation of Escherichia coli glucosamine-6-phosphate synthase: equilibrium between inactive hexamer and active dimer.The Journal of biological chemistry · 2012Article
- Allostery and the dynamic oligomerization of porphobilinogen synthase.Archives of biochemistry and biophysics · 2012Review
- Dynamic dissociating homo-oligomers and the control of protein function.Archives of biochemistry and biophysics · 2012Review
- Kinetic Analysis of Guanidine Hydrochloride Inactivation of β-Galactosidase in the Presence of Galactose.Enzyme research · 2012Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
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.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.