ABSTRACT
Kratom is a plant originating in Southeast Asia that has been used for its dose-dependent stimulant and opioid effects. The main active compound in kratom is mitragynine, an alkaloid with affinity for the mu-opioid receptor. Toxicity and fatalities related to kratom use have increased substantially in recent years. In this case report, we describe a 44-year-old man who was found deceased in bed. The only significant finding at autopsy was abdominal distension with >4 L of ascites. Toxicology testing was performed on femoral blood which showed 79 ng/mL of hydromorphone, 560 ng/mL of mitragynine, and 240 ng/mL of olanzapine. In addition, creatinine and urea in vitreous humor were significantly elevated, consistent with renal impairment. Death was attributed to hydromorphone toxicity with mitragynine being a contributing factor.
Subject(s)
Drug Overdose , Mitragyna , Secologanin Tryptamine Alkaloids , Male , Humans , Adult , Hydromorphone , Plant Extracts , Analgesics, OpioidABSTRACT
Sudden death resulting from intracardiac leiomyomatosis is rare. In this case, a 50-year-old woman was found to have intracardiac leiomyomatosis, which originated in veins in the broad ligament. Tumor filled the entire inferior vena cava and extended into the right heart where it had embolized and occluded the right main pulmonary artery. The mechanism of death was sudden right heart failure.
Subject(s)
Death, Sudden/etiology , Heart Neoplasms/pathology , Leiomyomatosis/pathology , Female , Heart Failure/etiology , Humans , Middle AgedABSTRACT
The apicomplexan parasite Toxoplasma gondii, the etiologic agent of toxoplasmosis, is estimated to infect 10-80% of different human populations. T. gondii encodes a large pentafunctional polypeptide known as the AROM complex which catalyzes five reactions in the shikimate pathway, a metabolic pathway required for the biosynthesis of the aromatic amino acids and a promising target for anti-parasitic agents. Here, we present the isolation, cloning and kinetic characterization of the shikimate dehydrogenase domain (TgSDH) from the T. gondii AROM complex. Recombinant TgSDH catalyzed the NADP(+)-dependent oxidation of shikimate in the absence of the remaining AROM domains and was sensitive to inhibition by a previously identified SDH inhibitor. Analysis of the TgSDH amino acid sequence revealed a number of novel insertions not found in SDH homologs from other organisms. Nevertheless, a three-dimensional structural model of TgSDH predicts a high level of conservation in the 'core' structure of the enzyme.
Subject(s)
Alcohol Oxidoreductases/metabolism , Toxoplasma/enzymology , Alcohol Oxidoreductases/chemistry , Alcohol Oxidoreductases/genetics , Alcohol Oxidoreductases/isolation & purification , Amino Acid Sequence , Cloning, Molecular , Genetic Variation , Kinetics , Models, Molecular , NADP/metabolism , Oxidation-Reduction , Protein Conformation , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/isolation & purification , Recombinant Proteins/metabolism , Shikimic Acid/metabolism , Toxoplasma/geneticsABSTRACT
Shikimate dehydrogenase (AroE) is an attractive target for herbicides and antimicrobial agents due to its conserved and essential nature in plants, fungi, and bacteria. Here, we have performed an in vitro screen using a collection of more than 5500 compounds and identified 24 novel inhibitors of AroE from Pseudomonas putida The IC50 values for the two most potent inhibitors we identified, epigallocatechin gallate (EGCG) and epicatechin gallate (ECG), were 3.0 ± 0.2 µM and 3.7 ± 0.5 µM, respectively. Based on the high level of structural conservation between AroE orthologs, we predicted that the identified compounds would also inhibit AroE enzymes from other organisms. Consistent with this hypothesis, we found that EGCG and ECG inhibit the AroE domain of the bifunctional dehydroquinate dehydratase-shikimate dehydrogenase (DHQ-SDH) from Arabidopsis thaliana with IC50 values of 2.1 ± 0.3 µM and 2.0 ± 0.2 µM, respectively.
