Kynurenine-3-monooxygenase (KMO) belongs to a family of NADPH dependent flavin monooxygenases. It has an FAD coenzyme, and one gene encodes it. Meanwhile, KMO utilizes either NADPH or NADH, releases NADP+/NAD+ after flavin reduction, and has one Rossmann fold dinucleotide binding domain. Thus, it is a class A flavoprotein monooxygenase (FPMO). In addition, it catalyses the hydroxylation of L-kynurenine (L-Kyn) to 3-hydroxykynurenine (3-HK), using NADPH as a co-substrate. Its expression is largely in the liver, kidney, some monocytic cells, and to a lesser extent in the microglia within the brain.
In animal models, KMO inhibition has shown benefit in neurodegenerative diseases such as Huntington’s and Alzheimer’s. Thus, it is a potential target for acute pancreatitis multiple organ dysfunction syndrome (AP-MODS).
Human KMO is a 56 kDa protein containing a tightly bound FAD cofactor. The C-terminal region attaches to the mitochondrial outer membrane. However, the crystal structure of human KMO is still unknown. On the other hand, the bacterial P. fluorescens enzyme, Pf-KMO, has been most extensively characterized. Therefore, Pf-KMO is a structural surrogate for inhibitor design.
GSK 366 shows potent inhibition at kynurenine-3-monooxygenase (KMO). The IC50 values of 2.3 nM and 0.7 nM for human KMO and Pf-KMO, respectively. Moreover, detailed kinetic analysis for GSK 366 suggests that it true Ki may be around 12 pM. In adition, GSK 366 exhibits a dissociation half-life of the order of 12 hours.
In summary, it is the first reported inhibitor that exploits this flavin motion in class A FPMOs. GSK 366 is suitable candidates for progression to clinical evaluation in acute pancreatitis multiple organ dysfunction syndrome.
Hutchinson JP, et al. Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase. Nat Commun. 2017 Jun 12;8:15827.