The Non-mevalonate Pathway of Isoprenoid Precursor Biosynthesis*

The recently discovered non-mevalonate biosynthetic route to isoprenoid precursors is an essential metabolic pathway in plants, apicomplexan parasites, and many species of bacteria. The pathway relies on eight enzymes exploiting different cofactors and metal ions. Structural and mechanistic data now exist for most components of the pathway though there remain some gaps in our knowledge. The individual enzymes represent new, validated targets for broad spectrum antimicrobial drug and herbicide development. Detailed knowledge of the pathway may also be exploited to genetically modify microorganisms and plants to produce compounds of agricultural and medical interest.

[1]  W. Eisenreich,et al.  The crystal structure of a plant 2C‐methyl‐D‐erythritol 4‐phosphate cytidylyltransferase exhibits a distinct quaternary structure compared to bacterial homologues and a possible role in feedback regulation for cytidine monophosphate , 2006, The FEBS journal.

[2]  G. Schneider,et al.  Snapshot of a key intermediate in enzymatic thiamin catalysis: Crystal structure of the α-carbanion of (α,β-dihydroxyethyl)-thiamin diphosphate in the active site of transketolase from Saccharomyces cerevisiae , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[3]  M. Rohmer.  The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants. , 1999, Natural product reports.

[4]  J. Noel,et al.  Absence of substrate channeling between active sites in the Agrobacterium tumefaciens IspDF and IspE enzymes of the methyl erythritol phosphate pathway. , 2006, Biochemistry.

[5]  B. Clantin,et al.  Crystal structure of isopentenyl diphosphate:dimethylallyl diphosphate isomerase , 2001, The EMBO journal.

[6]  T. Kuzuyama,et al.  Diversity of the biosynthesis of the isoprene units. , 2003, Natural product reports.

[7]  D. Cane,et al.  Structure and Mechanism of 2-C-Methyl-d-erythritol 2,4-Cyclodiphosphate Synthase , 2002, The Journal of Biological Chemistry.

[8]  S. Steinbacher,et al.  Structure of 2C-methyl-d-erythritol-2,4-cyclodiphosphate synthase involved in mevalonate-independent biosynthesis of isoprenoids. , 2002, Journal of molecular biology.

[9]  M. Rodríguez-Concepcíon,et al.  Elucidation of the Methylerythritol Phosphate Pathway for Isoprenoid Biosynthesis in Bacteria and Plastids. A Metabolic Milestone Achieved through Genomics1 , 2002, Plant Physiology.

[10]  M. Cassera,et al.  The Methylerythritol Phosphate Pathway Is Functionally Active in All Intraerythrocytic Stages of Plasmodium falciparum* , 2004, Journal of Biological Chemistry.

[11]  Wolfgang Eisenreich,et al.  Biosynthesis of isoprenoids: a bifunctional IspDF enzyme from Campylobacter jejuni. , 2004, European journal of biochemistry.

[12]  W. Eisenreich,et al.  Perspectives in anti-infective drug design. The late steps in the biosynthesis of the universal terpenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. , 2004, Bioorganic chemistry.

[13]  P. Proteau.  1-Deoxy-D-xylulose 5-phosphate reductoisomerase: an overview. , 2004, Bioorganic chemistry.

[14]  E. Rubin,et al.  Comprehensive identification of conditionally essential genes in mycobacteria , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[15]  K. Puan,et al.  fldA is an essential gene required in the 2‐C‐methyl‐D‐erythritol 4‐phosphate pathway for isoprenoid biosynthesis , 2005, FEBS letters.

[16]  Shunsuke Yajima,et al.  Crystallographic structures of two bisphosphonate:1-deoxyxylulose-5-phosphate reductoisomerase complexes. , 2004, Journal of the American Chemical Society.

[17]  J. Sacchettini,et al.  Creating Isoprenoid Diversity , 1997, Science.

[18]  W. Eisenreich,et al.  Biosynthesis of isoprenoids: Crystal structure of 4-diphosphocytidyl-2C-methyl-d-erythritol kinase , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Z. Rao,et al.  The crystal structure of human isopentenyl diphosphate isomerase at 1.7 A resolution reveals its catalytic mechanism in isoprenoid biosynthesis. , 2007, Journal of molecular biology.

[20]  W. Eisenreich,et al.  Deoxyxylulose phosphate pathway to terpenoids. , 2001, Trends in plant science.

[21]  D. Cane,et al.  Kinetic analysis of Escherichia coli 2-C-methyl-D-erythritol-4-phosphate cytidyltransferase, wild type and mutants, reveals roles of active site amino acids. , 2004, Biochemistry.

[22]  Roland Lange,et al.  The crystal structure of E.coli 1-deoxy-D-xylulose-5-phosphate reductoisomerase in a ternary complex with the antimalarial compound fosmidomycin and NADPH reveals a tight-binding closed enzyme conformation. , 2005, Journal of molecular biology.

[23]  S. Ehrlich,et al.  Essential Bacillus subtilis genes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[24]  H. Lichtenthaler,et al.  Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. , 1999, Science.

[25]  S. Yokoyama,et al.  Crystal Structure of 4-(Cytidine 5′-diphospho)-2-C-methyl-d-erythritol kinase, an Enzyme in the Non-mevalonate Pathway of Isoprenoid Synthesis* , 2003, Journal of Biological Chemistry.

[26]  Yanli Wang,et al.  Crystal structures of human IPP isomerase: new insights into the catalytic mechanism. , 2007, Journal of molecular biology.

[27]  J. Goldstein,et al.  Regulation of the mevalonate pathway , 1990, Nature.

[28]  J. Wouters,et al.  Structure of Thermus thermophilus type 2 isopentenyl diphosphate isomerase inferred from crystallography and molecular dynamics , 2005 .

[29]  C. Poulter,et al.  Chain elongation in the isoprenoid biosynthetic pathway. , 1997, Current opinion in chemical biology.

[30]  Gunter Schneider,et al.  Crystal structure of 1-deoxy-d-xylulose-5-phosphate reductoisomerase from Zymomonas mobilis at 1.9-A resolution. , 2004, Biochimica et biophysica acta.

[31]  D. Bussiere,et al.  Structure of 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase from Shewanella oneidensis at 1.6 A: identification of farnesyl pyrophosphate trapped in a hydrophobic cavity. , 2004, Acta crystallographica. Section D, Biological crystallography.

[32]  J. Wouters,et al.  Catalytic Mechanism of Escherichia coli Isopentenyl Diphosphate Isomerase Involves Cys-67, Glu-116, and Tyr-104 as Suggested by Crystal Structures of Complexes with Transition State Analogues and Irreversible Inhibitors* , 2003, The Journal of Biological Chemistry.

[33]  S. Steinbacher,et al.  Crystal structure of the type II isopentenyl diphosphate:dimethylallyl diphosphate isomerase from Bacillus subtilis. , 2003, Journal of molecular biology.

[34]  U. Laufs,et al.  Pleiotropic effects of statins. - Basic research and clinical perspectives -. , 2010, Circulation journal : official journal of the Japanese Circulation Society.

[35]  Gerhard Klebe,et al.  Crystal Structure of 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase, a Crucial Enzyme in the Non-mevalonate Pathway of Isoprenoid Biosynthesis* , 2002, The Journal of Biological Chemistry.

[36]  Christopher J. Tonkin,et al.  Tropical infectious diseases: Metabolic maps and functions of the Plasmodium falciparum apicoplast , 2004, Nature Reviews Microbiology.

[37]  D. Kingston.  Comprehensive Natural Products Chemistry, Volumes 1−9 Edited by Sir Derek Barton (Texas AM Executive Editor Otto Meth-Cohn. Elsevier Science, Inc., New York, NY. 1999. 19.5 × 28 cm. $3744.00. ISBN 0-08-042709-X. , 2000 .

[38]  W. Eisenreich,et al.  Hexameric Assembly of the Bifunctional Methylerythritol 2,4-Cyclodiphosphate Synthase and Protein-Protein Associations in the Deoxy-xylulose-dependent Pathway of Isoprenoid Precursor Biosynthesis* , 2004, Journal of Biological Chemistry.

[39]  J. Mekalanos,et al.  A genome-scale analysis for identification of genes required for growth or survival of Haemophilus influenzae , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Charles S Bond,et al.  Structure of 2C-methyl-d-erythritol 2,4- cyclodiphosphate synthase: An essential enzyme for isoprenoid biosynthesis and target for antimicrobial drug development , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[41]  L. Tong,et al.  Crystal Structure of 1-Deoxy-d-xylulose 5-Phosphate Synthase, a Crucial Enzyme for Isoprenoids Biosynthesis* , 2007, Journal of Biological Chemistry.

[42]  D. Cane,et al.  Structure of 4-diphosphocytidyl-2-C- methylerythritol synthetase involved in mevalonate- independent isoprenoid biosynthesis , 2001, Nature Structural Biology.

[43]  W. Hunter,et al.  Structure of a tetragonal crystal form of Escherichia coli 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase. , 2003, Acta crystallographica. Section D, Biological crystallography.

[44]  Torsten Unge,et al.  The 1.9 A resolution structure of Mycobacterium tuberculosis 1-deoxy-D-xylulose 5-phosphate reductoisomerase, a potential drug target. , 2006, Acta crystallographica. Section D, Biological crystallography.

[45]  W. Eisenreich,et al.  The identification of isoprenoids that bind in the intersubunit cavity of Escherichia coli 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase by complementary biophysical methods. , 2005, Acta crystallographica. Section D, Biological crystallography.

[46]  J. Keasling,et al.  Engineering a mevalonate pathway in Escherichia coli for production of terpenoids , 2003, Nature Biotechnology.

[47]  Shunsuke Yajima,et al.  Crystal structure of 1-deoxy-D-xylulose 5-phosphate reductoisomerase complexed with cofactors: implications of a flexible loop movement upon substrate binding. , 2002, Journal of biochemistry.

[48]  S. Yokoyama,et al.  Structure and catalytic mechanism of 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (MECDP) synthase, an enzyme in the non-mevalonate pathway of isoprenoid synthesis. , 2003, Acta crystallographica. Section D, Biological crystallography.

[49]  A. Bacher,et al.  Biosynthesis of isoprenoids via the non-mevalonate pathway , 2004, Cellular and Molecular Life Sciences CMLS.

[50]  C. Sander,et al.  Convergent evolution of similar enzymatic function on different protein folds: The hexokinase, ribokinase, and galactokinase families of sugar kinases , 1993, Protein science : a publication of the Protein Society.