Journal: Nature medicine

Article Title: Kynurenine–3–monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis

doi: 10.1038/nm.4020

Figure Lengend Snippet: Discovery of the KMO inhibitor GSK180 ( a ) Kynurenine cyclization strategy that led to the discovery of GSK180. ( b ) Indicative dose-response inhibition plots of GSK180 vs. human KMO expressed in insect cell lysates, human and rat KMO expressed in intact HEK293 cells and human primary hepatocytes. ( c ) Pharmacokinetic/pharmacodynamic profile of GSK180 in rat administered as an i.v. bolus. Plasma levels of drug and concentrations of kynurenine and kynurenic acid are shown. Data are mean ± s.d. of n = 3 rats. ( d ) Crystal structure of KMO in complex with the inhibitor. Enzyme residues (grey) surrounding the bound inhibitor (cyan) are shown in stick representation, with hydrogen bonds shown as dashed lines (magenta). Heteroatoms are colored according to atom type: nitrogen (blue), oxygen (red), sulphur (yellow) and chlorine (green).

Article Snippet: Briefly, full length human KMO was expressed as a GST fusion in Sf9 cells (obtained from EACC, catalogue number 89070101; tested for mycoplasma according to the ATCC Universal Mycoplasma detection protocol, catalogue number 30-1012K when each vial was drawn for propagation) and used as a membrane suspension.

Techniques: Inhibition, Clinical Proteomics