ArticleProceedings of the National Academy of Sciences of the United States of America2010
Mechanism of action and inhibition of dehydrosqualene synthase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 90 citations in OpenAlex.
- Chemical Profiling and Antimicrobial Activity of the Leaf Essential Oil ofInternational journal of molecular sciences · 2026Article
- Selective bioactive effects ofFrontiers in pharmacology · 2026Article
- Pharmacophore- and QSAR-guided discovery of natural product inhibitors targeting dehydrosqualene synthase in Staphylococcus aureus.PloS one · 2026Article
- PLiCat: decoding protein-lipid interactions by large language model.Briefings in bioinformatics · 2025Article
- Evolution of linear triterpenoid biosynthesis within the Euphorbia genus.Nature communications · 2025Article
- Synergistic Antibacterial Interaction of Geraniol and Biogenic Silver Nanoparticles on Methicillin-ResistantPlants (Basel, Switzerland) · 2025Article
- Antimicrobial and Anesthetic Niosomal Formulations Based on Amino Acid-Derived Surfactants.Molecules (Basel, Switzerland) · 2024Article
- Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease.Nature metabolism · 2024Article
- The Promiscuity of Squalene Synthase-Like Enzyme: Dehydrosqualene Synthase, a Natural Squalene Hyperproducer?Journal of agricultural and food chemistry · 2024Article
- Article
- The development of thymol-isatin hybrids as broad-spectrum antibacterial agents with potent anti-MRSA activity.RSC medicinal chemistry · 2024Article
- Investigating the effect ofIn silico pharmacology · 2024Article
- Review
- Roles of Two Phytoene Synthases and Orange Protein in Carotenoid Metabolism of the β-Carotene-AccumulatingMicrobiology spectrum · 2023Article
- Diclofenac and Meloxicam Exhibited Anti-Virulence Activities Targeting Staphyloxanthin Production in Methicillin-ResistantAntibiotics (Basel, Switzerland) · 2023Article
- A Structural and Bioinformatics Investigation of a Fungal Squalene Synthase and Comparisons with Other Membrane Proteins.ACS omega · 2022Article
- Antibacterial Effect of Some Eukaryotic Sterol Biosynthesis Inhibitors.Advanced biomedical research · 2022Article
- Antivirulence Strategies for the Treatment ofFrontiers in microbiology · 2020Review
- Disruption of the OLE ribonucleoprotein complex causes magnesium toxicity in Bacillus halodurans.Molecular microbiology · 2019Article
- A Neighboring Aromatic-Aromatic Amino Acid Combination Governs Activity Divergence between Tomato Phytoene Synthases.Plant physiology · 2019Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
"Head-to-head" terpene synthases catalyze the first committed steps in sterol and carotenoid biosynthesis: the condensation of two isoprenoid diphosphates to form cyclopropylcarbinyl diphosphates, followed by ring opening. Here, we report the structures of Staphylococcus aureus dehydrosqualene synthase (CrtM) complexed with its reaction intermediate, presqualene diphosphate (PSPP), the dehydrosqualene (DHS) product, as well as a series of inhibitors. The results indicate that, on initial diphosphate loss, the primary carbocation so formed bends down into the interior of the protein to react with C2,3 double bond in the prenyl acceptor to form PSPP, with the lower two-thirds of both PSPP chains occupying essentially the same positions as found in the two farnesyl chains in the substrates. The second-half reaction is then initiated by the PSPP diphosphate returning back to the Mg(2+) cluster for ionization, with the resultant DHS so formed being trapped in a surface pocket. This mechanism is supported by the observation that cationic inhibitors (of interest as antiinfectives) bind with their positive charge located in the same region as the cyclopropyl carbinyl group; that S-thiolo-diphosphates only inhibit when in the allylic site; activity results on 11 mutants show that both DXXXD conserved domains are essential for PSPP ionization; and the observation that head-to-tail isoprenoid synthases as well as terpene cyclases have ionization and alkene-donor sites which spatially overlap those found in CrtM.
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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.