Fatty acid synthase (FASN, EC 2.3.1.85), is a multi-enzyme dimer complex that plays a critical role in lipogenesis. This lipogenic enzyme has gained importance beyond its physiological role due to its implications in several clinical conditions-cancers, obesity, and diabetes. This has made FASN an attractive pharmacological target. Here, we have attempted to predict the theoretical models for the human enoyl reductase (ER) and beta-ketoacyl reductase (KR) domains based on the porcine FASN crystal structure, which was the structurally closest template available at the time of this study. Comparative modeling methods were used for studying the structure-function relationships. Different validation studies revealed the predicted structures to be highly plausible. The respective substrates of ER and KR domains-namely, trans-butenoyl and beta-ketobutyryl-were computationally docked into active sites using Glide in order to understand the probable binding mode. The molecular dynamics simulations of the apo and holo states of ER and KR showed stable backbone root mean square deviation trajectories with minimal deviation. Ramachandran plot analysis showed 96.0% of residues in the most favorable region for ER and 90.3% for the KR domain, respectively. Thus, the predicted models yielded significant insights into the substrate binding modes of the ER and KR catalytic domains and will aid in identifying novel chemical inhibitors of human FASN that target these domains.
Catalytic Domain* ; Humans ; Lipogenesis ; Models, Theoretical ; Molecular Dynamics Simulation* ; Obesity ; Oxidoreductases*

BACKGROUND: This study was undertaken to identify the prevalence of pulmonary embolism (PE) in the emergency department (ED) of an urban teaching hospital and also to test a Bayesian model in estimating the number of CT pulmonary angiography (CTA) expected to be performed in an emergency department. METHODS: The data for this study was obtained through a retrospective review of electronic medical records for all ED patients suspected of PE who underwent chest CTA or ventilation perfusion scanning (V/Q) between 2009 and 2010. The data is presented as means and standard deviation for continuous variables and percentages with 95％ confidence intervals (95％CI) for proportions. The prevalence of PE was used as pre-test probability in the Bayesian model. Post-test probability was obtained using a Fagan nomogram and likelihood ratios for CTA. RESULTS: A total of 778 patients (560 females) with mean age of 50 years (range 18–98 years) were enrolled (98.3％ underwent chest CTA and 1.7％ underwent V/Q scan). A total of 69 patients had PE, rendering an overall prevalence of 8.9％ (95％CI, 7.1％ to 11.1％) for PE. We calculated that 132 CTA's per year could be avoided in our institution, without compromising safe exclusions of PE (keeping post-test probability of PE below 2％). CONCLUSIONS: Despite differences in our patient populations and /or study designs, the prevalence of PE in our institution is about average compared to other institutions. Our proposed model for calculating redundant chest CTA is simple and can be used by institutions to identify overuse of CTA.