| Structural highlights
Function
[ISPD_ARATH] Enzyme of the plastid non-mevalonate pathway for isoprenoid biosynthesis that catalyzes the formation of 4-diphosphocytidyl-2-C-methyl-D-erythritol from CTP and 2-C-methyl-D-erythritol 4-phosphate (MEP). Is essential for chloroplast development and required for pigments and gibberellins biosynthesis.[1] [2] [3]
Publication Abstract from PubMed
Enzymes of the nonmevalonate pathway of isoprenoid biosynthesis are attractive targets for the development of herbicides and drugs against infectious diseases. While this pathway is essential for many pathogens and plants, mammals do not depend on it for the synthesis of isoprenoids. IspD, the third enzyme of the nonmevalonate pathway, is unique in that it has an allosteric regulatory site. We elucidated the binding mode of phenylisoxazoles, a new class of allosteric inhibitors. Allosteric inhibition is effected by large conformational changes of a loop region proximal to the active site. We investigated the different roles of residues in this loop by mutation studies and identified repulsive interactions with Asp291 and Asp292 to be responsible for inhibition. Crystallographic data and the response of mutant enzymes to three different classes of allosteric inhibitors provide an in-depth understanding of the allosteric mechanism. The obtained mutant enzymes show selective resistance to allosteric inhibitors and provide conceptually valuable information for future engineering of herbicide-resistant crops. We found that the isoprenoid precursors IPP and DMAPP are natural inhibitors of Arabidopsis thaliana IspD; however, they do not seem to bind to the allosteric site.
Mechanism of Allosteric Inhibition of the Enzyme IspD by Three Different Classes of Ligands.,Schwab A, Illarionov B, Frank A, Kunfermann A, Seet M, Bacher A, Witschel MC, Fischer M, Groll M, Diederich F ACS Chem Biol. 2017 Aug 18;12(8):2132-2138. doi: 10.1021/acschembio.7b00004. Epub, 2017 Jul 7. PMID:28686408[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Rohdich F, Wungsintaweekul J, Eisenreich W, Richter G, Schuhr CA, Hecht S, Zenk MH, Bacher A. Biosynthesis of terpenoids: 4-diphosphocytidyl-2C-methyl-D-erythritol synthase of Arabidopsis thaliana. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6451-6. PMID:10841550
- ↑ Okada K, Kawaide H, Kuzuyama T, Seto H, Curtis IS, Kamiya Y. Antisense and chemical suppression of the nonmevalonate pathway affects ent-kaurene biosynthesis in Arabidopsis. Planta. 2002 Jun;215(2):339-44. Epub 2002 Apr 12. PMID:12029484 doi:http://dx.doi.org/10.1007/s00425-002-0762-0
- ↑ Hsieh MH, Chang CY, Hsu SJ, Chen JJ. Chloroplast localization of methylerythritol 4-phosphate pathway enzymes and regulation of mitochondrial genes in ispD and ispE albino mutants in Arabidopsis. Plant Mol Biol. 2008 Apr;66(6):663-73. doi: 10.1007/s11103-008-9297-5. Epub 2008 , Jan 31. PMID:18236010 doi:http://dx.doi.org/10.1007/s11103-008-9297-5
- ↑ Schwab A, Illarionov B, Frank A, Kunfermann A, Seet M, Bacher A, Witschel MC, Fischer M, Groll M, Diederich F. Mechanism of Allosteric Inhibition of the Enzyme IspD by Three Different Classes of Ligands. ACS Chem Biol. 2017 Aug 18;12(8):2132-2138. doi: 10.1021/acschembio.7b00004. Epub, 2017 Jul 7. PMID:28686408 doi:http://dx.doi.org/10.1021/acschembio.7b00004
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