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Biosynthesis of isoprenoids: crystal structure of 4-diphosphocytidyl-2C-methyl-D-erythritol kinase.

Miallau L, Alphey MS, Kemp LE, Leonard GA, McSweeney SM, Hecht S, Bacher A, Eisenreich W, Rohdich F, Hunter WN
Proc Natl Acad Sci U S A 100 9173-8 (2003)
Cited: 48 times
EuropePMC logo PMID: 12878729

Abstract

4-Diphosphocytidyl-2C-methyl-d-erythritol kinase, an essential enzyme in the nonmevalonate pathway of isopentenyl diphosphate and dimethylallyl diphosphate biosynthesis, catalyzes the single ATP-dependent phosphorylation stage affording 4-diphosphocytidyl-2C-methyl-d-erythritol-2-phosphate. The 2-A resolution crystal structure of the Escherichia coli enzyme in a ternary complex with substrate and a nonhydrolyzable ATP analogue reveals the molecular determinants of specificity and catalysis. The enzyme subunit displays the alpha/beta fold characteristic of the galactose kinase/homoserine kinase/mevalonate kinase/phosphomevalonate kinase superfamily, arranged into cofactor and substrate-binding domains with the catalytic center positioned in a deep cleft between domains. Comparisons with related members of this superfamily indicate that the core regions of each domain are conserved, whereas there are significant differences in the substrate-binding pockets. The nonmevalonate pathway is essential in many microbial pathogens and distinct from the mevalonate pathway used by mammals. The high degree of sequence conservation of the enzyme across bacterial species suggests similarities in structure, specificity, and mechanism. Our model therefore provides an accurate template to facilitate the structure-based design of broad-spectrum antimicrobial agents.

Reviews - 1oj4 mentioned but not cited (1)

  1. Mechanistic aspects of carotenoid biosynthesis. Moise AR, Al-Babili S, Wurtzel ET. Chem. Rev. 114 164-193 (2014)

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  2. Identification of novel small molecule inhibitors of 4-diphosphocytidyl-2-C-methyl-D-erythritol (CDP-ME) kinase of Gram-negative bacteria. Tang M, Odejinmi SI, Allette YM, Vankayalapati H, Lai K. Bioorg. Med. Chem. 19 5886-5895 (2011)
  3. A triclinic crystal form of Escherichia coli 4-diphosphocytidyl-2C-methyl-D-erythritol kinase and reassessment of the quaternary structure. Kalinowska-Tłuścik J, Miallau L, Gabrielsen M, Leonard GA, McSweeney SM, Hunter WN. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 66 237-241 (2010)
  4. Investigation of structural mimetics of natural phosphate ion binding motifs. Kataev EA, Shumilova TA. Molecules 20 3354-3370 (2015)


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  1. Terpene Specialized Metabolism in Arabidopsis thaliana. Tholl D, Lee S. Arabidopsis Book 9 e0143 (2011)
  2. Cloning and characterization of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway genes of a natural-rubber producing plant, Hevea brasiliensis. Sando T, Takeno S, Watanabe N, Okumoto H, Kuzuyama T, Yamashita A, Hattori M, Ogasawara N, Fukusaki E, Kobayashi A. Biosci. Biotechnol. Biochem. 72 2903-2917 (2008)
  3. Hexameric assembly of the bifunctional methylerythritol 2,4-cyclodiphosphate synthase and protein-protein associations in the deoxy-xylulose-dependent pathway of isoprenoid precursor biosynthesis. Gabrielsen M, Bond CS, Hallyburton I, Hecht S, Bacher A, Eisenreich W, Rohdich F, Hunter WN. J. Biol. Chem. 279 52753-52761 (2004)
  4. Crystal structures of Trypanosoma brucei and Staphylococcus aureus mevalonate diphosphate decarboxylase inform on the determinants of specificity and reactivity. Byres E, Alphey MS, Smith TK, Hunter WN. J. Mol. Biol. 371 540-553 (2007)
  5. Nonphosphate inhibitors of IspE protein, a kinase in the non-mevalonate pathway for isoprenoid biosynthesis and a potential target for antimalarial therapy. Hirsch AK, Lauw S, Gersbach P, Schweizer WB, Rohdich F, Eisenreich W, Bacher A, Diederich F. ChemMedChem 2 806-810 (2007)
  6. Kinetic and functional analysis of L-threonine kinase, the PduX enzyme of Salmonella enterica. Fan C, Fromm HJ, Bobik TA. J. Biol. Chem. 284 20240-20248 (2009)
  7. Structure, substrate recognition and reactivity of Leishmania major mevalonate kinase. Sgraja T, Smith TK, Hunter WN. BMC Struct. Biol. 7 20 (2007)
  8. Characterization of Aquifex aeolicus 4-diphosphocytidyl-2C-methyl-d-erythritol kinase - ligand recognition in a template for antimicrobial drug discovery. Sgraja T, Alphey MS, Ghilagaber S, Marquez R, Robertson MN, Hemmings JL, Lauw S, Rohdich F, Bacher A, Eisenreich W, Illarionova V, Hunter WN. FEBS J. 275 2779-2794 (2008)
  9. Structure of the ternary complex of phosphomevalonate kinase: the enzyme and its family. Andreassi JL, Vetting MW, Bilder PW, Roderick SL, Leyh TS. Biochemistry 48 6461-6468 (2009)
  10. Inhibitors of the kinase IspE: structure-activity relationships and co-crystal structure analysis. Hirsch AK, Alphey MS, Lauw S, Seet M, Barandun L, Eisenreich W, Rohdich F, Hunter WN, Bacher A, Diederich F. Org. Biomol. Chem. 6 2719-2730 (2008)
  11. Structural basis for nucleotide binding and reaction catalysis in mevalonate diphosphate decarboxylase. Barta ML, McWhorter WJ, Miziorko HM, Geisbrecht BV. Biochemistry 51 5611-5621 (2012)
  12. Lethal mutations in the isoprenoid pathway of Salmonella enterica. Cornish RM, Roth JR, Poulter CD. J. Bacteriol. 188 1444-1450 (2006)
  13. Two copies of 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol kinase (CMK) gene in Ginkgo biloba: molecular cloning and functional characterization. Kim SM, Kim YB, Kuzuyama T, Kim SU. Planta 228 941-950 (2008)
  14. Expression and characterization of soluble 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase from bacterial pathogens. Eoh H, Narayanasamy P, Brown AC, Parish T, Brennan PJ, Crick DC. Chem. Biol. 16 1230-1239 (2009)
  15. Absence of substrate channeling between active sites in the Agrobacterium tumefaciens IspDF and IspE enzymes of the methyl erythritol phosphate pathway. Lherbet C, Pojer F, Richard SB, Noel JP, Poulter CD. Biochemistry 45 3548-3553 (2006)
  16. Comparison of the transcriptomes of ginger (Zingiber officinale Rosc.) and mango ginger (Curcuma amada Roxb.) in response to the bacterial wilt infection. Prasath D, Karthika R, Habeeba NT, Suraby EJ, Rosana OB, Shaji A, Eapen SJ, Deshpande U, Anandaraj M. PLoS ONE 9 e99731 (2014)
  17. Synthesis and characterization of cytidine derivatives that inhibit the kinase IspE of the non-mevalonate pathway for isoprenoid biosynthesis. Crane CM, Hirsch AK, Alphey MS, Sgraja T, Lauw S, Illarionova V, Rohdich F, Eisenreich W, Hunter WN, Bacher A, Diederich F. ChemMedChem 3 91-101 (2008)
  18. Crystal structure of 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase (IspE) from Mycobacterium tuberculosis. Shan S, Chen X, Liu T, Zhao H, Rao Z, Lou Z. FASEB J. 25 1577-1584 (2011)
  19. IspE inhibitors identified by a combination of in silico and in vitro high-throughput screening. Tidten-Luksch N, Grimaldi R, Torrie LS, Frearson JA, Hunter WN, Brenk R. PLoS ONE 7 e35792 (2012)
  20. A double mutation of Escherichia coli2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase disrupts six hydrogen bonds with, yet fails to prevent binding of, an isoprenoid diphosphate. Sgraja T, Kemp LE, Ramsden N, Hunter WN. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 61 625-629 (2005)
  21. Mimicking direct protein-protein and solvent-mediated interactions in the CDP-methylerythritol kinase homodimer: a pharmacophore-directed virtual screening approach. Giménez-Oya V, Villacañas O, Fernàndez-Busquets X, Rubio-Martinez J, Imperial S. J Mol Model 15 997-1007 (2009)
  22. Crystallization and preliminary X-ray analysis of 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase (IspE) from Mycobacterium tuberculosis. Shan S, Chen X. Acta Crystallogr Sect F Struct Biol Cryst Commun 67 821-823 (2011)
  23. Design of novel ligands of CDP-methylerythritol kinase by mimicking direct protein-protein and solvent-mediated interactions. Giménez-Oya V, Villacañas O, Obiol-Pardo C, Antolin-Llovera M, Rubio-Martinez J, Imperial S. J. Mol. Recognit. 24 71-80 (2011)
  24. Formal Synthesis of 4-diphosphocytidyl-2-C-methyl D-erythritol From D-(+)-Arabitol. Odejinmi SI, Rascon RG, Chen W, Lai K. Tetrahedron 68 8937-8941 (2012)
  25. Synthesis and biological evaluation of pyrazolopyrimidines as potential antibacterial agents. Goshu GM, Ghose D, Bain JM, Pierce PG, Begley DW, Hewitt SN, Udell HS, Myler PJ, Meganathan R, Hagen TJ. Bioorg. Med. Chem. Lett. 25 5699-5704 (2015)
  26. Synthetic Routes to Methylerythritol Phosphate Pathway Intermediates and Downstream Isoprenoids. Jarchow-Choy SK, Koppisch AT, Fox DT. Curr Org Chem 18 1050-1072 (2014)
  27. A single nucleotide mutation of IspE gene participating in the MEP pathway for isoprenoid biosynthesis causes green-revertible yellow leaf phenotype in rice. Chen N, Wang P, Li C, Wang Q, Pan J, Xiao F, Wang Y, Zhang K, Li C, Yang B, Sun C, Deng X. Plant Cell Physiol. (2018)
  28. Crystal structure of IspF from Bacillus subtilis and absence of protein complex assembly amongst IspD/IspE/IspF enzymes in the MEP pathway. Liu Z, Jin Y, Liu W, Tao Y, Wang G. Biosci. Rep. 38 (2018)
  29. Genome-based identification and comparative analysis of enzymes for carotenoid biosynthesis in microalgae. Narang PK, Dey J, Mahapatra SR, Roy R, Kushwaha GS, Misra N, Suar M, Raina V. World J Microbiol Biotechnol 38 8 (2021)
  30. Inhibitors interacting with the magnesium binding site of reverse transcriptase: synthesis and biological activity studies of 3'-(omega-amino-acyl) amino-3'-deoxy-thymidine. Goud TV, Aubertin AM, Biellmann JF. Nucleosides Nucleotides Nucleic Acids 27 495-505 (2008)
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