Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase

Jonathan P Hutchinson; Paul Rowland; Mark R D Taylor; Erica M Christodoulou; Carl Haslam; Clare M  Hobbs; Duncan Holmes; Paul  Homes; John  Liddle; Damian J Mole; Iain J  Uings; Ann L Walker; Scott P Webster; Christopher Mowat; Chun-wa Chung

doi:10.1038/ncomms15827

Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase

Jonathan P Hutchinson, Paul Rowland, Mark R D Taylor, Erica M Christodoulou, Carl Haslam, Clare M Hobbs, Duncan Holmes, Paul Homes, John Liddle, Damian J Mole, Iain J Uings, Ann L Walker, Scott P Webster, Christopher Mowat, Chun-wa Chung

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Abstract / Description of output

Kynurenine-3-monooxygenase (KMO) is a key FAD-dependent enzyme of tryptophan metabolism. In animal models, KMO inhibition has shown benefit in neurodegenerative diseases such as Huntington’s and Alzheimer’s. Most recently it has been identified as a target for Acute Pancreatitis multiple organ dysfunction syndrome (AP-MODS); a devastating inflammatory condition with a mortality rate in excess of 20%. Here we report and dissect the molecular mechanism of action of three classes of KMO inhibitors with differentiated binding modes and kinetics. Two novel inhibitor classes trap the catalytic flavin in a previously unobserved tilting conformation. This correlates with picomolar affinities, increased residence times and an absence of the peroxide production seen with previous substrate site inhibitors. These structural and mechanistic insights culminated in GSK065(C1) and GSK366(C2), molecules suitable for preclinical evaluation. Moreover, revising the repertoire of flavin dynamics in this enzyme class offers exciting new opportunities for inhibitor design.

Original language	English
Article number	15827
Number of pages	12
Journal	Nature Communications
Volume	8
Early online date	12 Jun 2017
DOIs	https://doi.org/10.1038/ncomms15827
Publication status	Published - 12 Jun 2017

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Damian Mole
- Deanery of Clinical Sciences - 1777 Chair of Surgery
- Edinburgh Imaging
- Centre for Inflammation Research
Person: Academic: Research Active
Chris Mowat
- School of Chemistry - Senior Lecturer
- EaStCHEM
Person: Academic: Research Active
Scott Webster
- Scott.Webstered.acuk
- Deanery of Clinical Sciences - Personal Chair of Medicines Discovery
- Centre for Cardiovascular Science
- Edinburgh Imaging
Person: Academic: Research Active

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Hutchinson, J. P., Rowland, P., Taylor, M. R. D., Christodoulou, E. M., Haslam, C., Hobbs, C. M., Holmes, D., Homes, P., Liddle, J., Mole, D. J., Uings, I. J., Walker, A. L., Webster, S. P., Mowat, C., & Chung, C. (2017). Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase. Nature Communications, 8, Article 15827. https://doi.org/10.1038/ncomms15827

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title = "Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase",

abstract = "Kynurenine-3-monooxygenase (KMO) is a key FAD-dependent enzyme of tryptophan metabolism. In animal models, KMO inhibition has shown benefit in neurodegenerative diseases such as Huntington{\textquoteright}s and Alzheimer{\textquoteright}s. Most recently it has been identified as a target for Acute Pancreatitis multiple organ dysfunction syndrome (AP-MODS); a devastating inflammatory condition with a mortality rate in excess of 20%. Here we report and dissect the molecular mechanism of action of three classes of KMO inhibitors with differentiated binding modes and kinetics. Two novel inhibitor classes trap the catalytic flavin in a previously unobserved tilting conformation. This correlates with picomolar affinities, increased residence times and an absence of the peroxide production seen with previous substrate site inhibitors. These structural and mechanistic insights culminated in GSK065(C1) and GSK366(C2), molecules suitable for preclinical evaluation. Moreover, revising the repertoire of flavin dynamics in this enzyme class offers exciting new opportunities for inhibitor design.",

author = "Hutchinson, {Jonathan P} and Paul Rowland and Taylor, {Mark R D} and Christodoulou, {Erica M} and Carl Haslam and Hobbs, {Clare M} and Duncan Holmes and Paul Homes and John Liddle and Mole, {Damian J} and Uings, {Iain J} and Walker, {Ann L} and Webster, {Scott P} and Christopher Mowat and Chun-wa Chung",

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Hutchinson, JP, Rowland, P, Taylor, MRD, Christodoulou, EM, Haslam, C, Hobbs, CM, Holmes, D, Homes, P, Liddle, J, Mole, DJ, Uings, IJ, Walker, AL, Webster, SP , Mowat, C & Chung, C 2017, 'Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase', Nature Communications, vol. 8, 15827. https://doi.org/10.1038/ncomms15827

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T1 - Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase

AU - Hutchinson, Jonathan P

AU - Rowland, Paul

AU - Taylor, Mark R D

AU - Christodoulou, Erica M

AU - Haslam, Carl

AU - Hobbs, Clare M

AU - Holmes, Duncan

AU - Homes, Paul

AU - Liddle, John

AU - Mole, Damian J

AU - Uings, Iain J

AU - Walker, Ann L

AU - Webster, Scott P

AU - Mowat, Christopher

AU - Chung, Chun-wa

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AB - Kynurenine-3-monooxygenase (KMO) is a key FAD-dependent enzyme of tryptophan metabolism. In animal models, KMO inhibition has shown benefit in neurodegenerative diseases such as Huntington’s and Alzheimer’s. Most recently it has been identified as a target for Acute Pancreatitis multiple organ dysfunction syndrome (AP-MODS); a devastating inflammatory condition with a mortality rate in excess of 20%. Here we report and dissect the molecular mechanism of action of three classes of KMO inhibitors with differentiated binding modes and kinetics. Two novel inhibitor classes trap the catalytic flavin in a previously unobserved tilting conformation. This correlates with picomolar affinities, increased residence times and an absence of the peroxide production seen with previous substrate site inhibitors. These structural and mechanistic insights culminated in GSK065(C1) and GSK366(C2), molecules suitable for preclinical evaluation. Moreover, revising the repertoire of flavin dynamics in this enzyme class offers exciting new opportunities for inhibitor design.

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JO - Nature Communications

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Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase

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Damian Mole

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Scott Webster

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