A5053688843- Malaria Research and Control
- HIV/AIDS drug development and treatment
- Toxoplasma gondii Research Studies
- Microbial Natural Products and Biosynthesis
- Invertebrate Immune Response Mechanisms
- Genomics and Phylogenetic Studies
- Protist diversity and phylogeny
- Research on Leishmaniasis Studies
- Plant biochemistry and biosynthesis
- Autophagy in Disease and Therapy
- Mosquito-borne diseases and control
- Ubiquitin and proteasome pathways
- Synthesis and Catalytic Reactions
- RNA and protein synthesis mechanisms
- Microbial bioremediation and biosurfactants
- Biochemical and Structural Characterization
- Biochemical and Molecular Research
- Computational Drug Discovery Methods
- Metal-Catalyzed Oxygenation Mechanisms
- Blood groups and transfusion
- Microbial Community Ecology and Physiology
- Pneumocystis jirovecii pneumonia detection and treatment
- Water Treatment and Disinfection
- Vibrio bacteria research studies
- Bacterial Identification and Susceptibility Testing
Stanford University
2005-2024
Chan Zuckerberg Initiative (United States)
2017-2024
Stanford Medicine
2011-2024
Bipar
2017
Harvard University
2004-2007
Massachusetts Institute of Technology
2007
Pennsylvania State University
2006
University of Illinois Urbana-Champaign
2005-2006
University of Michigan
2006
Washington University in St. Louis
2002
Plasmodium spp parasites harbor an unusual plastid organelle called the apicoplast. Due to its prokaryotic origin and essential function, apicoplast is a key target for development of new anti-malarials. Over 500 proteins are predicted localize this several biochemical pathways have been annotated, yet role during human infection remains mystery. Previous work showed that treatment with fosmidomycin, inhibitor non-mevalonate isoprenoid precursor biosynthesis in apicoplast, inhibits growth...
The indolocarbazole antitumor agent rebeccamycin is modified by chlorine atoms on each of two indole moieties the aglycone scaffold. These halogens are incorporated during initial step its biosynthesis from conversion l -Trp to 7-chlorotryptophan. Two genes in biosynthetic cluster, rebF and rebH , predicted encode flavin reductase halogenase components an FADH 2 -dependent halogenase, a class enzymes involved numerous halogenated natural products. Here, we report that, presence O chloride...
The flavin-dependent halogenase RebH catalyzes the formation of 7-chlorotryptophan as initial step in biosynthesis antitumor agent rebeccamycin. reaction FADH2, Cl-, and O2 active site generates powerful oxidant HOCl, which was presumed to carry out chlorination reaction. Herein, we demonstrate a long-lived chlorinating intermediate (t1/2 = 63 h at 4 °C) when RebH, react absence substrate tryptophan. This remained on enzyme after removal FAD transferred chlorine tryptophan with kinetically...
The antifungal natural product pyoluteorin contains a 4,5-dichloropyrrole moiety. timing of dichlorination in the heteroaromatic ring is now shown to occur after proline tethered by thioester linkage carrier protein PltL and enzymatically desaturated pyrrolyl- S -PltL. Surprisingly, FADH 2 -dependent halogenase PltA catalyzes chlorination at both positions ring, generating 5-chloropyrrolyl- -PltL intermediate then 4,5-dichloropyrrolyl- product. activity strictly depends on heterologous...
Malaria parasites (Plasmodium spp.) and related apicomplexan pathogens contain a nonphotosynthetic plastid called the apicoplast. Derived from an unusual secondary eukaryote–eukaryote endosymbiosis, apicoplast is fascinating organelle whose function biogenesis rely on complex amalgamation of bacterial algal pathways. Because these pathways are distinct human host, excellent source novel antimalarial targets. Despite its biomedical importance evolutionary significance, absence reliable...
The flavin-dependent halogenase RebH catalyzes chlorination at the C7 position of tryptophan as initial step in biosynthesis chemotherapeutic agent rebeccamycin. reaction requires reduced FADH2 (provided by a partner flavin reductase), chloride ion, and oxygen cosubstrates. Given similarity its sequence to those flavoprotein monooxygenases their common cosubstrate requirements, O2 active site was presumed form typical FAD(C4a)−OOH intermediate observed monooxygenase reactions. By using...
The apicoplast is an essential plastid organelle found in Plasmodium parasites which contains several clinically validated antimalarial-drug targets. A chemical rescue screen identified MMV-08138 from the "Malaria Box" library of growth-inhibitory antimalarial compounds as having specific activity against apicoplast. inhibition blood-stage falciparum growth stereospecific and potent, with most active diastereomer demonstrating a 50% effective concentration (EC50) 110 nM. Whole-genome...
ABSTRACT Plasmodium parasites and related pathogens contain an essential nonphotosynthetic plastid organelle, the apicoplast, derived from secondary endosymbiosis. Intriguingly, a highly conserved eukaryotic protein, autophagy-related protein 8 (ATG8), has autophagy-independent function in apicoplast. Little is known about novel apicoplast of ATG8 its importance blood-stage falciparum . Using P. strain which expression was conditionally regulated, we showed that ( Pf ATG8) for parasite...
Abstract Epithemia spp. diatoms contain obligate, nitrogen-fixing endosymbionts, or diazoplasts, derived from cyanobacteria. These algae are a rare example of photosynthetic eukaryotes that have successfully coupled oxygenic photosynthesis with oxygen-sensitive nitrogenase activity. Here, we report newly-isolated species, E. clementina, as model to investigate endosymbiotic acquisition nitrogen fixation. We demonstrate the diazoplast, which has lost photosynthesis, provides fixed diatom host...
Fidelity and efficiency. Nonribosomal peptide synthetases, which contain domains for the activation (A), thiolation (T), condensation (C) of amino acids (AA), are high-efficiency, high-fidelity assembly lines synthesizing natural products. Errors in a single step can have serious consequences product formation. Type II thioesterases (TEII) might play critical role ensuring efficiency accuracy these systems, essential features any attempt to engineer NRPSs produce novel
The malaria parasite Plasmodium falciparum and related apicomplexan pathogens contain an essential plastid organelle, the apicoplast, which is a key anti-parasitic target. Derived from secondary endosymbiosis, apicoplast depends on novel, but largely cryptic, mechanisms for protein/lipid import organelle inheritance during replication. These critical biogenesis pathways present untapped opportunities to discover new parasite-specific drug targets. We used innovative screen identify actinonin...
Plasmodium parasites contain several unique membrane compartments in which prenylated proteins may play important roles pathogenesis. Protein prenylation has also been proposed as an antimalarial drug target because farnesyltransferase inhibitors cause potent growth inhibition of blood-stage However, the specific that mediate activity have yet to be identified. Given potential for new parasite biology and elucidating mechanism-of-action, we performed a large-scale identification proteome P....
Endosymbiosis has driven major molecular and cellular innovations. Plasmodium spp. parasites that cause malaria contain an essential, non-photosynthetic plastid-the apicoplast-which originated from a secondary (eukaryote-eukaryote) endosymbiosis. To discover organellar pathways with evolutionary biomedical significance, we performed mutagenesis screen for essential genes required apicoplast biogenesis in falciparum. Apicoplast(-) mutants were isolated using chemical rescue permits...
Nucleic acid amplification tests (NAATs) have revolutionized infectious disease diagnosis, allowing for the rapid and sensitive identification of pathogens in clinical specimens. Real-time PCR testing mecA gene (mecA PCR), which confers methicillin resistance staphylococci, has added potential to reduce antibiotic usage, improve outcomes, lower health care costs, avoid emergence drug resistance. A retrospective study was performed identify patients infected with methicillin-sensitive...
In vitro gamma interferon release assays (IGRAs) are increasingly used as an alternative to the traditional tuberculin skin test for diagnosis of latent Mycobacterium tuberculosis infection. Evaluation QuantiFERON-TB Gold in-tube assay (QFT-IT) prior large-scale implementation at Stanford Hospital and Clinics a health care worker screening program revealed critical preanalytical factor affecting results. We found that incubation delay significantly increased frequency indeterminate this...
Background Blood agar is used for the identification and antibiotic susceptibility testing of many bacterial pathogens. In developing world, microbiologists use human blood because high cost inhospitable conditions raising wool sheep or horses to supply blood. Many pathogens either fail grow entirely exhibit morphologies hemolytic patterns on that confound colony recognition. Furthermore, can be hazardous handle due HIV hepatitis [1], [2]. This study investigated whether from hair sheep, a...
We report a case of 2009 influenza A(H1N1) virus infection in which was detected predominantly specimens from the lower respiratory tract but absent or at very low levels nasopharyngeal swab samples. This presentation suggests that, certain hosts for particular variants virus, may be preferred site infection.
Parasitic infections are a major source of human suffering, mortality, and economic loss, but drug development for these diseases has been stymied by the significant expense involved in bringing though clinical trials to market. Identification single compounds active against multiple parasitic pathogens could improve incentives as well simplifying treatment regimens. We recently performed screen repurposed protozoan parasite Entamoeba histolytica, causative agent amebic dysentery, identified...
The biosynthesis of the coronamic acid fragment pseudomonal phytotoxin coronatine involves construction cyclopropane ring from a γ-chloro-l-allo-Ile intermediate while covalently tethered as phosphopantetheinyl thioester to carrier protein CmaD. cyclopropane-forming catalyst is CmaC, catalyzing an intramolecular displacement γ-Cl group by α carbon. CmaC can be isolated Zn2+ with about 10-fold higher activity over apo form. will not cyclize free γ-chloro amino acids or their...