Inhibition of monoterpene cyclases by inert analogues of geranyl diphosphate and linalyl diphosphate.
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| Abstract |
The tightly coupled nature of the reaction sequence catalyzed by monoterpene synthases has prevented direct observation of the topologically required isomerization step leading from geranyl diphosphate to the enzyme-bound, tertiary allylic intermediate linalyl diphosphate, which then cyclizes to the various monoterpene skeletons. X-ray crystal structures of these enzymes complexed with suitable analogues of the substrate and intermediate could provide a clearer view of this universal, but cryptic, step of monoterpenoid cyclase catalysis. Toward this end, the functionally inert analogues 2-fluorogeranyl diphosphate, (+/-)-2-fluorolinalyl diphosphate, and (3R)- and (3S)-homolinalyl diphosphates (2,6-dimethyl-2-vinyl-5-heptenyl diphosphates) were prepared, and compared to the previously described substrate analogue 3-azageranyl diphosphate (3-aza-2,3-dihydrogeranyl diphosphate) as inhibitors and potential crystallization aids with two representative monoterpenoid cyclases, (-)-limonene synthase and (+)-bornyl diphosphate synthase. Although these enantioselective synthases readily distinguished between (3R)- and (3S)-homolinalyl diphosphates, both of which were more effective inhibitors than was 3-azageranyl diphosphate, the fluorinated analogues proved to be the most potent competitive inhibitors and have recently yielded informative liganded structures with limonene synthase.
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| Authors | Frank Karp, Yuxin Zhao, Bindu Santhamma, Bryce Assink, Robert M Coates, Rodney B Croteau |
| Journal | Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 468 Issue 1 Pg. 140-6 (Dec 01 2007) ISSN: 1096-0384 [Electronic] United States |
| PMID | 17949678 (Publication Type: Journal Article, Research Support, N.I.H., Extramural) |
| Chemical References |
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