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Human Phosphate Cytidylyltransferase 2

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PDB Code 3ELB Target Class AA metabolic enzymes Target PCYT2 Alias ET, PCYT2 Disease Area/Function cancer Date Deposited Sep 22 2008 Authors T.KARLBERG, M.WELIN, J.ANDERSSON, C.H.ARROWSMITH, H.BERGLUND, C.BOUNTRA, R.COLLINS, L.G.DAHLGREN, A.M.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, A.JOHANSSON, I.JOHANSSON, T.KOTENYOVA, L.LEHTIO, M.MOCHE, M.E.NILSSON, P.NORDLUND, T.NYMAN, C.PERSSON, J.SAGEMARK, A.G.THORSELL, L.TRESAUGUES, S.VAN DEN BERG, J.WEIGELT, M.WIKSTROM, M.WISNIEWSKA, H.SCHULER

About this structure

Ethanolamine phospholipids (PE) are a major component of cell membranes in eukaryotes and the most abundant in prokaryotic membranes. Three biosynthetic pathways of PE formation are known in eukaryotes: the major route CDP-ethanolamine pathway (Kennedy pathway), decarboxylation of phosphatidylserine and base exchange with phosphatidylserine. CTP:Phosphoethanolamine cytidylyltransferase (PCYT2; ECT) catalyzes the transformation of CTP and phosphoethanolamine into CDP-Ethanolamine and pyrophosphate using the hydrolysis of CTP to CMP, the penultimate step in the Kennedy pathway of de novo synthesis of phospholipids. After which CDP-Ethanolamine:1,2-diacylglycerol ethanolaminephosphotransferase catalyses the final step producing PE. Recent studies suggest that increase in phosphoethanolamine in some breast cancer cells is caused by the down-regulation of PCYT2.

Here we present the crystal structure of PCYT2 in complex with CMP at a resolution of 2.0Å. The structure was solved by SAD using selenomethionine-labelled protein. PCYT2 is a monomer which consists of two cytidylyltransferase domains and each domain contains a nucleotide-binding motif HxGH. The N-terminal domain (residues Gly19-Leu155) consists of a five-stranded parallel β-sheet with topology 3-2-1-4-5 flanked by five α-helices and a sixth helix making considerable domain-domain interactions. The C-terminal domain (Trp187-Thr351) has a similar fold. Interestingly, only the C-terminal domain has CMP bound in its nucleotide binding pocket. CTP and MgCl2 were added to the protein in the crystallization trials.

References

  1. Bakovic M., Fullerton MD., Michel V. Metabolic and molecular aspects of ethanolamine phospholipid biosynthesis: the role of CTP:phosphoethanolamine cytidylyltransferase (Pcyt2). Biochem. Cell. Biol. 2007, 85(3):283-300.
  2. Bleijerveld OB., Brouwers JFHM., Vaandrager AB., Helms JB, Houweling M. The CDP-ethanolamine pathway and Phosphatidylserine decarboxylation generate different Phosphatidylethanolamine molecular species. J. Biol. Chem. 2007, 282: 28362-28372.
  3. Signorell A., Rauch M., Jelk J., Ferguson MAJ., Bütikofer P. Phosphatidylethanolamine in Trypanosoma brucei is organized in two separate pools and is synthesized exclusively by the Kennedy Pathway J. Biol. Chem. 2008, 283: 23636–23644.
  4. Zhu L., Johnson C., Bakovic M. Stimulation of the human CTP: phosphoethanolamine cytidylyltransferase gene by early growth response protein 1 J. Lipid Res. 2008 [Epub ahead of print]