Sandbox Reserved 962: Difference between revisions
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We remark that there is no contact between the enzyme and <scene name='60/604481/S_n7/1'>the guanine N-7 nucleophile, the AdoHcy sulfur leaving group</scene> or the AdoMet methyl carbon.{{clear}} | We remark that there is no contact between the enzyme and <scene name='60/604481/S_n7/1'>the guanine N-7 nucleophile, the AdoHcy sulfur leaving group</scene> or the AdoMet methyl carbon.{{clear}} | ||
Indeed the enzyme does not stabilize the transition state of the chemical reaction, does not promote the activation of the nucleophile or the expulsion of the leaving group. mRNA Cap Methyltransferase brings the two substrates closer and orientates the substrates to facilitate the methyl transfer. | Indeed the enzyme does not stabilize the transition state of the chemical reaction, does not promote the activation of the nucleophile or the expulsion of the leaving group. mRNA Cap Methyltransferase brings the two substrates closer and orientates the substrates to facilitate the methyl transfer. | ||
<ref name="Fabrega C, Hausmann S, Shen V, Shuman S, Lima CD. Structure and mechanism of mRNA cap (guanine-N7) methyltransferase. Mol Cell. 2004 Jan 16;13(1):77-89. ">PMID:14731396</ref> | |||
==Inhibition== | ==Inhibition== | ||
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[[Image:Inhibitor_structure.png ]] [[Image:Inhibitor.png]]{{clear}} | [[Image:Inhibitor_structure.png ]] [[Image:Inhibitor.png]]{{clear}} | ||
It was show that the methylation of GTP increase with the concentration of AdoMet (Km of 25μM) and it was determined that the product AdoHcy has a similar affinity than AdoMet. But the activity of Ecm1 is inhibited by AdoHcy in a concentration-dependant way and the apparent IC50 was 4μm. {{clear}} | *'''AdoHcy'''{{clear}} | ||
Sinefugin, an analog of AdoMet differs from AdoMet only in the S-CH3 which is replaced by a C-NH2. It was show that sinefugin inhibit Ecm1 in a concentration-dependant manner too, the apparent IC50 is 1.5μm. The Ecm1 has an affinity for sinefugin 2/3 fold higher than for AdoMet and AdoHcy. Sinefugin has been shown to have antifungal, antiprotozoal and antiviral activities, these activities is probably related to his capacity to inhibit a variety of AdoMet-dependent methyltransferase.{{clear}} | It was show that the methylation of GTP increase with the concentration of AdoMet (Km of 25μM) and it was determined that the product AdoHcy has a similar affinity than AdoMet. But the activity of Ecm1 is inhibited by AdoHcy in a concentration-dependant way and the apparent IC50 was 4μm. | ||
Aza-AdoMet and | <ref name="Hausmann S, Zheng S, Fabrega C, Schneller SW, Lima CD, Shuman S. Encephalitozoon cuniculi mRNA cap (guanine N-7) methyltransferase: methyl acceptor specificity, inhibition BY S-adenosylmethionine analogs, and structure-guided mutational analysis. J Biol Chem. 2005 May 27;280(21):20404-12. Epub 2005 Mar 9.">PMID:15760890 </ref> {{clear}} | ||
* '''Sinefugin'''{{clear}} | |||
Sinefugin, an analog of AdoMet differs from AdoMet only in the S-CH3 which is replaced by a C-NH2. It was show that sinefugin inhibit Ecm1 in a concentration-dependant manner too, the apparent IC50 is 1.5μm. The Ecm1 has an affinity for sinefugin 2/3 fold higher than for AdoMet and AdoHcy. Sinefugin has been shown to have antifungal, antiprotozoal and antiviral activities, these activities is probably related to his capacity to inhibit a variety of AdoMet-dependent methyltransferase. | |||
<ref name="Hausmann S, Zheng S, Fabrega C, Schneller SW, Lima CD, Shuman S. Encephalitozoon cuniculi mRNA cap (guanine N-7) methyltransferase: methyl acceptor specificity, inhibition BY S-adenosylmethionine analogs, and structure-guided mutational analysis. J Biol Chem. 2005 May 27;280(21):20404-12. Epub 2005 Mar 9.">PMID:15760890 </ref>{{clear}} | |||
*'''Aza-AdoMet & carbocyclic aza-AdoMet'''{{clear}} | |||
Aza-AdoMet and carbocyclic aza-AdoMet are analogs of AdoMet too. In these two molecules the sulfur atom is replaced by nitrogen. And in the carbocyclic derivate the O4-atom of the ribose is replaced by a methylene group. These two molecules are weak inhibitorsof Ecm1. The IC50 values of Aza-AdoMet is 100μm and of carbocyclic aza-AdoMet is 35μm | |||
<ref name="Hausmann S, Zheng S, Fabrega C, Schneller SW, Lima CD, Shuman S. Encephalitozoon cuniculi mRNA cap (guanine N-7) methyltransferase: methyl acceptor specificity, inhibition BY S-adenosylmethionine analogs, and structure-guided mutational analysis. J Biol Chem. 2005 May 27;280(21):20404-12. Epub 2005 Mar 9.">PMID:15760890 </ref> | |||
== References == | == References == | ||
<references/> | <references/> | ||
