3uj6

From Proteopedia

(Difference between revisions)

Current revision

SeMet Phosphoethanolamine methyltransferase from Plasmodium falciparum in complex with SAM and PO4

Structural highlights

3uj6 is a 1 chain structure with sequence from Plasmodium falciparum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.974Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PMT_PLAF7 Catalyzes N-methylation of phosphoethanolamine, phosphomonomethylethanolamine and phosphodimethylethanolamine, the three methylation steps required to convert phosphoethanolamine to phosphocholine (PubMed:15073329, PubMed:15664981, PubMed:18178564, PubMed:18694927, PubMed:22117061). Has no ethanolamine- or phosphatidylethanolamine-N-methyltransferase activity (PubMed:15073329, PubMed:15664981). Required for gametocyte development, maturation and transmission to mosquitoes and for oocyst formation in the mosquito midgut (PubMed:24145416).^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

In the malarial parasite Plasmodium falciparum, a multi-functional phosphoethanolamine methyltransferase (PfPMT) catalyzes the methylation of phosphoethanolamine (pEA) to phosphocholine (pCho) for membrane biogenesis. This pathway is also found in plant and nematodes, but PMT from these organisms use multiple methyltransferse domains for the AdoMet reactions. Because PfPMT is essential for normal growth and survival of Plasmodium and is not found in humans, it is an anti-parasitic target. Here we describe the 1.55 A resolution crystal structure of PfPMT in complex with S-adenosylmethionine (AdoMet) by single-wavelength anomalous dispersion phasing. In addition, 1.19-1.52 A resolution structures of PfPMT with pEA (substrate), pCho (product), sinefungin (inhibitor), and both pEA and S-adenosylhomocysteine (AdoCys) bound were determined. These structures suggest that domain rearrangements occur upon ligand binding and provide insight on active site architecture defining the AdoMet and phosphobase binding sites. Functional characterization of 27 site-directed mutants identifies critical active site residues and suggests that Tyr19 and His132 form a catalytic dyad. Kinetic analysis, isothermal titration calorimetry, and protein crystallography of the Y19F and H132A mutants suggest a reaction mechanism for the PMT. Not only are Tyr19 and His132 required for phosphobase methylation, but they also form a 'catalytic' latch that locks ligands in the active site and orders the site for catalysis. This study provides the first insight on this anti-parasitic target enzyme essential for survival of the malaria parasite; however, further studies of the multi-domain PMT from plants and nematodes are needed to understand the evolutionary division of metabolic function in the phosphobase pathway of these organisms.

Structure and Reaction Mechanism of Phosphoethanolamine Methyltransferase from the Malaria Parasite Plasmodium falciparum: An Anti-Parasitic Drug Target.,Lee SG, Kim Y, Alpert TD, Nagata A, Jez JM J Biol Chem. 2011 Nov 23. PMID:22117061^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Pessi G, Kociubinski G, Mamoun CB. A pathway for phosphatidylcholine biosynthesis in Plasmodium falciparum involving phosphoethanolamine methylation. Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6206-11. PMID:15073329 doi:10.1073/pnas.0307742101
↑ Pessi G, Choi JY, Reynolds JM, Voelker DR, Mamoun CB. In vivo evidence for the specificity of Plasmodium falciparum phosphoethanolamine methyltransferase and its coupling to the Kennedy pathway. J Biol Chem. 2005 Apr 1;280(13):12461-6. PMID:15664981 doi:10.1074/jbc.M414626200
↑ Reynolds JM, Takebe S, Choi JY, El Bissati K, Witola WH, Bobenchik AM, Hoch JC, Voelker DR, Mamoun CB. Biochemical and genetic analysis of the phosphoethanolamine methyltransferase of the human malaria parasite Plasmodium falciparum. J Biol Chem. 2008 Mar 21;283(12):7894-900. PMID:18178564 doi:10.1074/jbc.M709869200
↑ Witola WH, El Bissati K, Pessi G, Xie C, Roepe PD, Mamoun CB. Disruption of the Plasmodium falciparum PfPMT gene results in a complete loss of phosphatidylcholine biosynthesis via the serine-decarboxylase-phosphoethanolamine-methyltransferase pathway and severe growth and survival defects. J Biol Chem. 2008 Oct 10;283(41):27636-27643. PMID:18694927 doi:10.1074/jbc.M804360200
↑ Lee SG, Kim Y, Alpert TD, Nagata A, Jez JM. Structure and Reaction Mechanism of Phosphoethanolamine Methyltransferase from the Malaria Parasite Plasmodium falciparum: An Anti-Parasitic Drug Target. J Biol Chem. 2011 Nov 23. PMID:22117061 doi:10.1074/jbc.M111.315267
↑ Bobenchik AM, Witola WH, Augagneur Y, Nic Lochlainn L, Garg A, Pachikara N, Choi JY, Zhao YO, Usmani-Brown S, Lee A, Adjalley SH, Samanta S, Fidock DA, Voelker DR, Fikrig E, Ben Mamoun C. Plasmodium falciparum phosphoethanolamine methyltransferase is essential for malaria transmission. Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18262-7. PMID:24145416 doi:10.1073/pnas.1313965110
↑ Lee SG, Kim Y, Alpert TD, Nagata A, Jez JM. Structure and Reaction Mechanism of Phosphoethanolamine Methyltransferase from the Malaria Parasite Plasmodium falciparum: An Anti-Parasitic Drug Target. J Biol Chem. 2011 Nov 23. PMID:22117061 doi:10.1074/jbc.M111.315267

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3uj6"

@@ Line 3: / Line 3: @@
 <StructureSection load='3uj6' size='340' side='right'caption='[[3uj6]], [[Resolution|resolution]] 1.97&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3uj6]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plafa Plafa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UJ6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UJ6 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3uj6]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UJ6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UJ6 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.974&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3uj7|3uj7]], [[3uj8|3uj8]], [[3uj9|3uj9]], [[3uja|3uja]], [[3ujb|3ujb]], [[3ujc|3ujc]], [[3ujd|3ujd]]</div></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PMT ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5833 PLAFA])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3uj6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uj6 OCA], [https://pdbe.org/3uj6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3uj6 RCSB], [https://www.ebi.ac.uk/pdbsum/3uj6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3uj6 ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/PMT_PLAF7 PMT_PLAF7] Catalyzes N-methylation of phosphoethanolamine, phosphomonomethylethanolamine and phosphodimethylethanolamine, the three methylation steps required to convert phosphoethanolamine to phosphocholine (PubMed:15073329, PubMed:15664981, PubMed:18178564, PubMed:18694927, PubMed:22117061). Has no ethanolamine- or phosphatidylethanolamine-N-methyltransferase activity (PubMed:15073329, PubMed:15664981). Required for gametocyte development, maturation and transmission to mosquitoes and for oocyst formation in the mosquito midgut (PubMed:24145416).<ref>PMID:15073329</ref> <ref>PMID:15664981</ref> <ref>PMID:18178564</ref> <ref>PMID:18694927</ref> <ref>PMID:22117061</ref> <ref>PMID:24145416</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 24: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Plafa]]
+[[Category: Plasmodium falciparum]]
-[[Category: Alpert, T D]]
+[[Category: Alpert TD]]
-[[Category: Jez, J M]]
+[[Category: Jez JM]]
-[[Category: Kim, Y]]
+[[Category: Kim Y]]
-[[Category: Lee, S G]]
+[[Category: Lee SG]]
-[[Category: Nagata, A]]
+[[Category: Nagata A]]
-[[Category: Methyltransferase]]
-[[Category: Parasite]]
-[[Category: Plasmodium]]
-[[Category: Transferase]]

3uj6

From Proteopedia

Current revision

SeMet Phosphoethanolamine methyltransferase from Plasmodium falciparum in complex with SAM and PO4

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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