000151189 001__ 151189
000151189 005__ 20181203021956.0
000151189 022__ $$a0021-9258
000151189 02470 $$2PMID$$a18818197
000151189 02470 $$a000261183700045$$2ISI
000151189 0247_ $$2doi$$a10.1074/jbc.M802115200
000151189 037__ $$aARTICLE
000151189 245__ $$aCharacterization of active site structure in CYP121: A cytochrome P450 essential for viability of Mycobacterium tuberculosis H37Rv
000151189 269__ $$a2008
000151189 260__ $$c2008
000151189 336__ $$aJournal Articles
000151189 520__ $$aMycobacterium tuberculosis (Mtb) cytochrome P450 gene CYP121 is shown to be essential for viability of the bacterium in vitro by gene knock-out with complementation. Production of CYP121 protein in Mtb cells is demonstrated. Minimum inhibitory concentration values for azole drugs against Mtb H37Rv were determined, the rank order of which correlated well with Kd values for their binding to CYP121. Solution-state spectroscopic, kinetic, and thermodynamic studies and crystal structure determination for a series of CYP121 active site mutants provide further insights into structure and biophysical features of the enzyme. Pro346 was shown to control heme cofactor conformation, whereas Arg386 is a critical determinant of heme potential, with an unprecedented 280-mV increase in heme iron redox potential in a R386L mutant. A homologous Mtb redox partner system was reconstituted and transported electrons faster to CYP121 R386L than to wild type CYP121. Heme potential was not perturbed in a F338H mutant, suggesting that a proposed P450 superfamily-wide role for the phylogenetically conserved phenylalanine in heme thermodynamic regulation is unlikely. Collectively, data point to an important cellular role for CYP121 and highlight its potential as a novel Mtb drug target.
000151189 700__ $$aMcLean, Kirsty J
000151189 700__ $$aCarroll, Paul
000151189 700__ $$aLewis, D Geraint
000151189 700__ $$aDunford, Adrian J
000151189 700__ $$aSeward, Harriet E
000151189 700__ $$aNeeli, Rajasekhar
000151189 700__ $$aCheesman, Myles R
000151189 700__ $$aMarsollier, Laurent
000151189 700__ $$aDouglas, Philip
000151189 700__ $$aSmith, W Ewen
000151189 700__ $$aRosenkrands, Ida
000151189 700__ $$0243892$$g177247$$aCole, Stewart T
000151189 700__ $$aLeys, David
000151189 700__ $$aParish, Tanya
000151189 700__ $$aMunro, Andrew W
000151189 773__ $$j283$$tThe Journal of biological chemistry$$k48$$q33406-16
000151189 909C0 $$xU11742$$0252302$$pUPCOL
000151189 909CO $$pSV$$particle$$ooai:infoscience.tind.io:151189
000151189 937__ $$aEPFL-ARTICLE-151189
000151189 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000151189 980__ $$aARTICLE