Structures of trihydroxynaphthalene reductase-fungicide complexes: implications for structure-based design and catalysis

Structure
D I LiaoD B Jordan

Abstract

Trihydroxynaphthalene reductase catalyzes two intermediate steps in the fungal melanin biosynthetic pathway. The enzyme, a typical short-chain dehydrogenase, is the biochemical target of three commercial fungicides. The fungicides bind preferentially to the NADPH form of the enzyme. Three X-ray structures of the Magnaporthe grisea enzyme complexed with NADPH and two commercial and one experimental fungicide were determined at 1.7 A (pyroquilon), 2.0 A (2,3-dihydro-4-nitro-1H-inden-1-one, 1), and 2.1 A (phthalide) resolutions. The chemically distinct inhibitors occupy similar space within the enzyme's active site. The three inhibitors share hydrogen bonds with the side chain hydroxyls of Ser-164 and Tyr-178 via a carbonyl oxygen (pyroquilon and 1) or via a carbonyl oxygen and a ring oxygen (phthalide). Active site residues occupy similar positions among the three structures. A buried water molecule that is hydrogen bonded to the NZ nitrogen of Lys-182 in each of the three structures likely serves to stabilize the cationic form of the residue for participation in catalysis. The pro S hydrogen of NADPH (which is transferred as a hydride to the enzyme's naphthol substrates) is directed toward the carbonyl carbon of the inhibitors t...Continue Reading

References

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Citations

Nov 5, 2002·Current Opinion in Chemical Biology·Peter KuhnRaymond C Stevens
Mar 3, 2006·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Alberto CassettaDoriano Lamba
Jun 12, 2012·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Jing HouWladek Minor
Feb 11, 2014·AMB Express·Daijiro TakeshitaMasaru Tanokura
Feb 2, 2008·Archives of Biochemistry and Biophysics·Agnieszka Dybala-DefratykaPiotr Paneth
Feb 1, 2017·Proceedings of the National Academy of Sciences of the United States of America·Zhuan ZhangGong-Li Tang
Mar 7, 2003·The Journal of Biological Chemistry·Satoshi SogabeMasaru Wada
Feb 27, 2003·Chemico-biological Interactions·Udo OppermannHans Jörnvall

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