Structure-based Drug Design Targeting Biosynthesis of Isoprenoids: A Crystallographic State of the Art of the Involved Enzymes

de Ruyck, J.; Wouters, J.
April 2008
Current Protein & Peptide Science;Apr2008, Vol. 9 Issue 2, p117
Academic Journal
Biosynthesis of the universal terpenoid precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), from three acetyl CoA moieties through mevalonate was studied extensively in the 1950s. For several decades, the mevalonate paradigm reigned supreme and a mevalonate origin was attributed to a growing number of natural products, in many cases erroneously. Besides this biosynthetic pathway, the existence of a second one leading to IPP and DMAPP through 1-deoxy-D-xylulose 5-phosphate and 2C-methyl-D-erythritol 4-phosphate was discovered more recently in plants and some eubacteria. This pathway is widely distributed in the bacterial kingdom including major human pathogens, such as Mycobacterium tuberculosis or Helicobacter pylori and is also essential in the malaria vector Plasmodium falciparum. During the last few years, the genes, enzymes, intermediates and mechanisms of the biosynthetic route have been elucidated by a combination of methods including comparative genomics, enzymology, advanced NMR technology and crystallography. The present crystallographic review of enzymes involved in isoprenoid biosynthesis will be useful for understanding the various catalytic mechanisms and could potentially help for structure-based drug design.


Related Articles

  • Studies of Mevalonate Pathway Influence on Biosynthesis of Terpenoids in Basidiomycota. LI Liang; SHANG Xiao-dong; TAN Qi // Journal of Agricultural Science & Technology (1008-0864);2014, Vol. 16 Issue 3, p53 

    There are numerous active terpenoids in Basidiomycota cellular. These active substances have important influence on human nutrition and health. Mevalonate pathway, which can govern biosynthesis of some kinds of terpenoids, is an essential path in regulating secondary metabolism in Basidiomycota...

  • Biosynthesis of isoprenoids via the non-mevalonate pathway. Eisenreich, W.; Bacher, A.; Arigoni, D.; Rohdich, F. // Cellular & Molecular Life Sciences;Jun2004, Vol. 61 Issue 12, p1401 

    The mevalonate pathway for the biosynthesis of the universal terpenoid precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), is known in considerable detail. Only recently, the existence of a second mevalonate-independent pathway for the biosynthesis of IPP and DMAPP...

  • Isoprenoid biosynthesis in chloroplasts via the methylerythritol phosphate pathway: the (E)-4-hydroxy-3-methylbut-2-enyl diphosphate synthase (GcpE) fromArabidopsis thalianais a [4Fe-4S] protein. Seemann, Myriam; Wegner, Patrick; Sch�nemann, Volker; Bui, Bernadette; Wolff, Murielle; Marquet, Andr�e; Trautwein, Alfred; Rohmer, Michel // Journal of Biological Inorganic Chemistry;Mar2005, Vol. 10 Issue 2, p131 

    The mevalonate-independent methylerythritol phosphate pathway is widespread in bacteria. It is also present in the chloroplasts of all phototrophic organisms. Whereas the first steps, are rather well known, GcpE and LytB, the enzymes catalyzing the last two steps have been much less...

  • Mutations in Escherichia coli aceE and ribB Genes Allow Survival of Strains Defective in the First Step of the Isoprenoid Biosynthesis Pathway. Perez-Gil, Jordi; Uros, Eva Maria; Sauret-Güeto, Susanna; Lois, L. Maria; Kirby, James; Nishimoto, Minobu; Baidoo, Edward E. K.; Keasling, Jay D.; Boronat, Albert; Rodriguez-Concepcion, Manuel; McCutcheon, John // PLoS ONE;Aug2012, Vol. 7 Issue 8, Special section p1 

    A functional 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway is required for isoprenoid biosynthesis and hence survival in Escherichia coli and most other bacteria. In the first two steps of the pathway, MEP is produced from the central metabolic intermediates pyruvate and glyceraldehyde...

  • Biosynthesis and engineering of isoprenoid small molecules. Withers, Sydnor T.; Keasling, Jay D. // Applied Microbiology & Biotechnology;Dec2006, Vol. 73 Issue 5, p980 

    Isoprenoid secondary metabolites are a rich source of commercial products that have not been fully explored. At present, there are isoprenoid products used in cancer therapy, the treatment of infectious diseases, and crop protection. All isoprenoids share universal prenyl diphosphate precursors...

  • HMG-CoA-reductase-inhibitors. Schmidt, Erik Berg; Larsen, Mogens Lytken // Encyclopedic Reference of Molecular Pharmacology;2004, p460 

    A definition of the term "HMG-CoA-reductase-inhibitors" is presented. It refers to a class of important pharmacological compounds that are the most effective drugs for lowering plasma levels of total cholesterol and in particular low-density-lipoprotein-cholesterol. HMG-CoA-reductase-inhibitors...

  • New Approaches to Target Gram-Negative Bacteria. Yanming Du // Current Topics in Medicinal Chemistry;Dec2010, Vol. 10 Issue 18, p1846 

    The article discusses papers published within the issue, including one by Jean-Marie Pag�s et al on the recent progress in the characterization of efflux pump structures and another by Andrew J. wiemer et al on the necessity of isoprenoid biosynthesis for bacterial growth and the...

  • 1-Hydroxy-2-methyl-2-( E)-butenyl 4-diphosphate reductase (IDS) is encoded by multicopy genes in gymnosperms Ginkgo biloba and Pinus taeda. Sang-Min Kim; Kuzuyama, Tomohisa; Kobayashi, Akio; Sando, Tomoki; Yung-Jin Chang; Soo-Un Kim // Planta;Jan2008, Vol. 227 Issue 2, p287 

    Isoprenoids are synthesized through the condensation of five-carbon intermediates, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), derived from two distinct biosynthetic routes: cytosolic mevalonate (MVA) and plastidial 2- C-methyl- d-erythritol 4-phosphate (MEP) pathways....

  • Isoprenoid Pigments in Representatives of the Family Microbacteriaceae. Trutko, S. M.; Dorofeeva, L. V.; Evtushenko, L. I.; Ostrovskii, D. N.; Hintz, M.; Wiesner, J.; Jomaa, H.; Baskunov, B. P.; Akimenko, V. K. // Microbiology (00262617);May2005, Vol. 74 Issue 3, p284 

    By using fosmidomycin and mevinolin (inhibitors of the synthesis of isoprenoid pigments), spectrophotometry, and mass spectrometry, the presence of isoprenoid pigments is shown in 71 of the 78 strains under study. All of these strains belong to 11 genera of the family Microbacteriaceae. Yellow,...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics