Abstract
A new metabolite of vitamin K, 2(3)-hydroxy-2,3-dihydro-2-methyl,3-phytyl-1,4-naphthoquinone (hydroxyvitamin K), has been identified as a product of vitamin K epoxide metabolism in hepatic microsomes from warfarin-resistant rats, but not in those derived from normal rats. The structure was determined by comparison of the high performance liquid chromatography retention times, UV, IR, CD, and mass spectra of the unknown with chemically synthesized standards. Alterations in the formation of hydroxyvitamin K occur in parallel with alterations in total vitamin K epoxide conversion with respect to reaction time, extent of reaction, detergent stimulation, and inhibition by warfarin. Thus, hydroxyvitamin K appears to be a product of the warfarin-resistant vitamin K epoxide reductase. It is neither a substrate nor an inhibitor of epoxide reduction. Hydroxyvitamin K is formed from both enantiomers of racemic vitamin K epoxide with little stereoselectivity for the configuration of either the oxirane ring or the phytyl side chain. The reaction is stereospecific; however, the biologically formed (+)-vitamin K epoxide yields exclusively (+)-3-hydroxyvitamin K. Observation of this product is discussed as a key to understanding the normal reaction mechanism of the enzyme.
Highlights
From the New York StateDepartment of Health, Center for Laboratories andResearch, Empire State Plaza, Albany,New York 12201
Dihydro-2-methyl,3-phytyl-1,4-naphthoquinon(ehy- The same microsomal preparation that catalyzes the carboxdroxyvitamin K), has been identified as a product of ylation reaction generates vitamin K 2,3-epoxidefrom vitamin K epoxide metabolism in hepatic microsomes vitamin KHz and current evidence [5,6,7] suggeststhat thetwo frolp warfarin-resistant rats, but not in those derived reactions are catalyzed by the same enzyme
The reaction is droxyvitamin K is shownhere to be a product of the enzyme stereospecific; the biologicallyformed (+)- vitamin K epoxide reductase in warfarin-resistant rat liver vitamin K epoxide yields exclusively (+)-3-hydroxyvi- microsomes
Summary
Vol 258, No 7, Iasue of April 10, pp. 4372-4380, 1983 Printed in U.S.A. Formation of Hydroxyvitamin K by VitaminK Epoxide Reductaseof Warfarin-resistant Rats*. Dihydro-2-methyl,3-phytyl-1,4-naphthoquinon(ehy- The same microsomal preparation that catalyzes the carboxdroxyvitamin K), has been identified as a product of ylation reaction generates vitamin K 2,3-epoxidefrom vitamin K epoxide metabolism in hepatic microsomes vitamin KHz and current evidence [5,6,7] suggeststhat thetwo frolp warfarin-resistant rats, but not in those derived reactions are catalyzed by the same enzyme. Thestructure was determinedby somal enzyme,vitamin K epoxide reductase, converts vitamin ritofcrAcnhaeaooflreapmnttpihecuhvnaprteeny.riaaoraktTwrsnrliniiloeh,saoeontoulrnewdnsfswnwean,ottiriiifehttwnoihhrntynihgr-tdaeteehrrhtlsneitocpemshethxierisyeegscaftmsvtthoatW i,iimrnotimacptnuam,etsavlloIrlaitiioyRfnintKtofo,raisrohenCmytamnoaynapDitc,dtannapK,thrndilaeooeceanvsnxepiridinytztsoiahvemlmximdiitqibtaoedausibis,ntetmeiesiadxoKnsiratnnpeedceKendphabpcturrryotoodocrcxdtmsawcia.uduooasacerffertto-. g-mdKrnoKKefreadocveehrugeppiiytcsneooadstnxxmaaaraisiorndsdiyeqtneeeiuscafrKtoioceaonrtda.roiegvucvnuoiciaetttlnabyaatml(snies1nethi0s,unta,o,neraKd1oirsnet1cagqdw)abu.umrelSibcylnluaeoosnacxvenhsyynietlcosraae(efimtt8rciitto,vyiahn9nicietn)lya.KipntNAtrgopqoArhupioenDyieflnhsraHottiitoihben-eleidlesotiingtooveokifpnicetoavvadblxmiiyttdilaadieecmmnevhoeyiiuKinnls--s
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