scholarly journals Isoprenoid biosynthesis via 1-deoxy-D-xylulose 5-phosphate/2-C-methyl-D-erythritol 4-phosphate (DOXP/MEP) pathway.

2001 ◽  
Vol 48 (3) ◽  
pp. 663-672 ◽  
Author(s):  
M Wanke ◽  
K Skorupinska-Tudek ◽  
E Swiezewska
Keyword(s):  
Mevalonate Pathway ◽  
Higher Plants ◽  
Developmental State ◽  
Isoprenoid Biosynthesis ◽  
Mep Pathway ◽  
The Novel ◽  
Dimethylallyl Diphosphate ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum ◽  
Mixed Origin

Higher plants, several algae, bacteria, some strains of Streptomyces and possibly malaria parasite Plasmodium falciparum contain the novel, plastidic DOXP/MEP pathway for isoprenoid biosynthesis. This pathway, alternative with respect to the classical mevalonate pathway, starts with condensation of pyruvate and glyceraldehyde-3-phosphate which yields 1-deoxy-D-xylulose 5-phosphate (DOXP); the latter product can be converted to isopentenyl diphosphate (IPP) and eventually to isoprenoids or thiamine and pyridoxal. Subsequent reactions of this pathway involve transformation of DOXP to 2-C-methyl-D-erythritol 4-phosphate (MEP) which after condensation with CTP forms 4-diphosphocytidyl-2-amethyl-D-erythritol (CDP-ME). Then CDP-ME is phosphorylated to 4-diphosphocytidyl-2-amethyl-D-erythritol 2-phosphate (CDP-ME2P) and to 2-C-methyl-D-erythritol-2,4-cyclodiphosphate (ME-2,4cPP) which is the last known intermediate of the DOXP/MEP pathway. For- mation of IPP and dimethylallyl diphosphate (DMAPP) from ME-2,4cPP still requires clarification. This novel pathway appears to be involved in biosynthesis of carotenoids, phytol (side chain of chlorophylls), isoprene, mono-, di-, tetraterpenes and plastoquinone whereas the mevalonate pathway is responsible for formation of sterols, sesquiterpenes and triterpenes. Several isoprenoids were found to be of mixed origin suggesting that some exchange and/or cooperation exists between these two pathways of different biosynthetic origin. Contradictory results described below could indicate that these two pathways are operating under different physiological conditions of the cell and are dependent on the developmental state of plastids.

The Non-Mevalonate Isoprenoid Biosynthesis of Plants as a Test System for New Herbicides and Drugs against Pathogenic Bacteria and the Malaria Parasite

2000 ◽  
Vol 55 (5-6) ◽  
pp. 305-313 ◽  
Author(s):  
Hartmut K. Lichtenthaler ◽  
Johannes Zeidler ◽  
Jörg Schwender ◽  
Christian Müller
Keyword(s):  
Malaria Parasite ◽  
Pathogenic Bacteria ◽  
Higher Plants ◽  
Test System ◽  
Isoprenoid Biosynthesis ◽  
Mep Pathway ◽  
New Drugs ◽  
Security Measures ◽  
Isoprenoid Pathway ◽  
Parasite Plasmodium Falciparum

Higher plants and several photosynthetic algae contain the plastidic 1-deoxy-ᴅ-xylulose 5- phosphate / 2-C-methyl-ᴅ-erythritol 4-phosphate pathway (DOXP/MEP pathway) for isoprenoid biosynthesis. The first four enzymes and their genes are known of this novel pathway. All of the ca. 10 enzymes of this isoprenoid pathway are potential targets for new classes of herbicides. Since the DOXP/MEP pathway also occurs in several pathogenic bacteria, such as Mycobacterium tuberculosis, and in the malaria parasite Plasmodium falciparum, all inhibitors and potential herbicides of the DOXP/MEP pathway in plants are also potential drugs against pathogenic bacteria and the malaria parasite. Plants with their easily to handle DOXP/MEP-pathway are thus very suitable test-systems also for new drugs against pathogenic bacteria and the malaria parasite as no particular security measures are required. In fact, the antibiotic herbicide fosmidomycin specifically inhibited not only the DOXP reductoisomerase in plants, but also that in bacteria and in the parasite P. falciparum, and cures malaria-infected mice. This is the first successful application of a herbicide of the novel isoprenoid pathway as a possible drug against malaria.

Non-mevalonate isoprenoid biosynthesis: enzymes, genes and inhibitors

2000 ◽  
Vol 28 (6) ◽  
pp. 785-789 ◽  
Author(s):  
H. K. Lichtenthaler
Keyword(s):  
Malaria Parasite ◽  
Pathogenic Bacteria ◽  
Mevalonate Pathway ◽  
Isoprenoid Biosynthesis ◽  
Mep Pathway ◽  
Isopentenyl Diphosphate ◽  
The Novel ◽  
Isoprenoid Pathway

The essential steps of the novel non-mevalonate pathway of isopentenyl diphosphate and isoprenoid biosynthesis in plants are described. The first five enzymes and genes of this 1-deoxy-D-xylulose 5-phosphate/2-C-methyl-D-erythritol 4-phosphate (DOXP/MEP) pathway are known. The herbicide fosmidomycin specifically blocks the second enzyme, the DOXP reductoisomerase. The DOXP/MEP pathway is also present in several pathogenic bacteria and the malaria parasite. Hence, all herbicides and inhibitors blocking this novel isoprenoid pathway in plants are also potential drugs against malaria and diseases caused by pathogenic bacteria.

scholarly journals Isoprenoid biosynthesis in higher plants and in Escherichia coli: on the branching in the methylerythritol phosphate pathway and the independent biosynthesis of isopentenyl diphosphate and dimethylallyl diphosphate

2002 ◽  
Vol 366 (2) ◽  
pp. 573-583 ◽  
Author(s):  
Jean-François HOEFFLER ◽  
Andréa HEMMERLIN ◽  
Catherine GROSDEMANGE-BILLIARD ◽  
Thomas J. BACH ◽  
Michel ROHMER
Keyword(s):  
Escherichia Coli ◽  
Higher Plants ◽  
Mevalonic Acid ◽  
Cell Suspension Cultures ◽  
Mep Pathway ◽  
Isopentenyl Diphosphate ◽  
Higher Plant ◽  
Methylerythritol Phosphate Pathway ◽  
Dimethylallyl Diphosphate ◽  
Deuterium Retention

In the bacterium Escherichia coli, the mevalonic-acid (MVA)-independent 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway is characterized by two branches leading separately to isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). The signature of this branching is the retention of deuterium in DMAPP and the deuterium loss in IPP after incorporation of 1-[4-2H]deoxy-d-xylulose ([4-2H]DX). Feeding tobacco BY-2 cell-suspension cultures with [4-2H]DX resulted in deuterium retention in the isoprene units derived from DMAPP, as well as from IPP in the plastidial isoprenoids, phytoene and plastoquinone, synthesized via the MEP pathway. This labelling pattern represents direct evidence for the presence of the DMAPP branch of the MEP pathway in a higher plant, and shows that IPP can be synthesized from DMAPP in plant plastids, most probably via a plastidial IPP isomerase.

The deoxyxylulose phosphate pathway of isoprenoid biosynthesis. Discovery and function of the ispDEFGH genes and their cognate enzymes

2003 ◽  
Vol 75 (2-3) ◽  
pp. 393-405 ◽  
Author(s):  
F. Rohdich ◽  
Stefan Hecht ◽  
Adelbert Bacher ◽  
Wolfgang Eisenreich
Keyword(s):  
Biosynthetic Pathway ◽  
Mevalonate Pathway ◽  
Isoprenoid Biosynthesis ◽  
Catalytic Action ◽  
Isopentenyl Diphosphate ◽  
Dimethylallyl Diphosphate ◽  
And Function

Isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) serve as the universal precursors for the biosynthesis of terpenes. Besides the well-known mevalonate pathway, a second biosynthetic pathway conducive to IPP and DMAPP via 1-deoxy-d-xylulose-5-phosphate and 2C-methyl-d-erythritol-4-phosphate has been discovered recently in plants and certain eubacteria. 2C-Methyl-d-erythritol-4-phosphate, the first committed intermediate of the deoxyxylulose phosphate pathway, is converted into 2C-methyl-d-erythritol 2,4-cyclodiphosphate by the catalytic action of three enzymes specified by the ispDEF genes. The cyclic diphosphate is reductively opened by the IspG protein affording 1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate. This compound can be converted into IPP as well as DMAPP by the catalytic action of IspH protein. The enzymes of this pathway are potential targets for novel antibacterial, antimalarial, and herbicide agents.

Properties and inhibition of the first two enzymes of the non-mevalonate pathway of isoprenoid biosynthesis

2000 ◽  
Vol 28 (6) ◽  
pp. 792-793 ◽  
Author(s):  
C. Mueller ◽  
J. Schwender ◽  
J. Zeidler ◽  
H. K. Lichtenthaler
Keyword(s):  
Escherichia Coli ◽  
Mevalonate Pathway ◽  
Isoprenoid Biosynthesis ◽  
Mep Pathway ◽  
Ph Optimum ◽  
Antibacterial Drugs ◽  
Chloroplast Stroma

Enzymes of the 1-deoxy-D-xylulose 5-phosphate/2-C-methylerythritol 4-phosphate (DOXP/MEP) pathway are targets for new herbicides and antibacterial drugs. Until now, no inhibitors for the DOXP synthase have been known of. We show that one of the breakdown products of the herbicide clomazone affects the DOXP synthase. One inhibitor of the non-mevalonate pathway, fosmidomycin, blocks the DOXP reductoisomerase (DXR) of plants and bacteria. The I50 values of plants are, however, higher than those found for the DXR of Escherichia coli. The DXR of plants, isolated from barley seedlings, shows a pH optimum of 8.1, which is typical for enzymes active in the chloroplast stroma.

scholarly journals Isoprenoid biosynthesis as a target for antibacterial and antiparasitic drugs: phosphonohydroxamic acids as inhibitors of deoxyxylulose phosphate reducto-isomerase

2005 ◽  
Vol 386 (1) ◽  
pp. 127-135 ◽  
Author(s):  
Lionel KUNTZ ◽  
Denis TRITSCH ◽  
Catherine GROSDEMANGE-BILLIARD ◽  
Andréa HEMMERLIN ◽  
Audrey WILLEM ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Malaria Parasite ◽  
Pathogenic Bacteria ◽  
Isoprenoid Biosynthesis ◽  
Methylerythritol Phosphate Pathway ◽  
Methylerythritol Phosphate ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum ◽  
Petri Dishes ◽  
Antiparasitic Drugs

Isoprenoid biosynthesis via the methylerythritol phosphate pathway is a target against pathogenic bacteria and the malaria parasite Plasmodium falciparum. 4-(Hydroxyamino)-4-oxobutylphosphonic acid and 4-[hydroxy(methyl)amino]-4-oxobutyl phosphonic acid, two novel inhibitors of DXR (1-deoxy-D-xylulose 5-phosphate reducto-isomerase), the second enzyme of the pathway, have been synthesized and compared with fosmidomycin, the best known inhibitor of this enzyme. The latter phosphonohydroxamic acid showed a high inhibitory activity towards DXR, much like fosmidomycin, as well as significant antibacterial activity against Escherichia coli in tests on Petri dishes.

Escherichia coli engineered to synthesize isopentenyl diphosphate and dimethylallyl diphosphate from mevalonate: a novel system for the genetic analysis of the 2-C-methyl-d-erythritol 4-phosphate pathway for isoprenoid biosynthesis

2000 ◽  
Vol 353 (1) ◽  
pp. 59-67 ◽  
Author(s):  
Narciso CAMPOS ◽  
Manuel RODRÍGUEZ-CONCEPCIÓN ◽  
Susanna SAURET-GÜETO ◽  
Francesca GALLEGO ◽  
Luisa-María LOIS ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Genetic Analysis ◽  
Mevalonate Pathway ◽  
Mep Pathway ◽  
Isopentenyl Diphosphate ◽  
Isopentenyl Diphosphate Isomerase ◽  
E Coli ◽  
Dimethylallyl Diphosphate ◽  
And Function ◽  
Synthetic Operon

Isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP) constitute the basic building block of isoprenoids, a family of compounds that is extraordinarily diverse in structure and function. IPP and DMAPP can be synthesized by two independent pathways: the mevalonate pathway and the recently discovered 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway. Although the MEP pathway is essential in most eubacteria, algae and plants and has enormous biotechnological interest, only some of its steps have been determined. We devised a system suitable for the genetic analysis of the MEP pathway in Escherichia coli. A synthetic operon coding for yeast 5-diphosphomevalonate decarboxylase, human 5-phosphomevalonate kinase, yeast mevalonate kinase and E. coli isopentenyl diphosphate isomerase was incorporated in the chromosome of this bacterium. The expression of this operon allowed the synthesis of IPP and DMAPP from mevalonate added exogenously and complementation of lethal mutants of the MEP pathway. We used this system to show that the ygbP, ychB and ygbB genes are essential in E. coli and that the steps catalysed by the products of these genes belong to the trunk line of the MEP pathway.

scholarly journals Isoprenoid Biosynthesis in Synechocystis sp. Strain PCC6803 Is Stimulated by Compounds of the Pentose Phosphate Cycle but Not by Pyruvate or Deoxyxylulose-5-Phosphate

2002 ◽  
Vol 184 (18) ◽  
pp. 5045-5051 ◽  
Author(s):  
Yuri V. Ershov ◽  
R. Raymond Gantt ◽  
Francis X. Cunningham, ◽  
Elisabeth Gantt
Keyword(s):  
Pentose Phosphate ◽  
Isoprenoid Biosynthesis ◽  
Mep Pathway ◽  
Dihydroxyacetone Phosphate ◽  
E Coli ◽  
Dimethylallyl Diphosphate ◽  
Isomerase Activity ◽  
Pentose Phosphate Cycle ◽  
Initial Substrate ◽  
Alternative Routes

ABSTRACT The photosynthetic cyanobacterium Synechocystis sp. strain PCC6803 possesses homologs of known genes of the non-mevalonate 2-C-methyl-d-erythritol 2-phosphate (MEP) pathway for synthesis of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Isoprenoid biosynthesis in extracts of this cyanobacterium, measured by incorporation of radiolabeled IPP, was not stimulated by pyruvate, an initial substrate of the MEP pathway in Escherichia coli, or by deoxyxylulose-5-phosphate, the first pathway intermediate in E. coli. However, high rates of IPP incorporation were obtained with addition of dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (GA3P), as well as a variety of pentose phosphate cycle compounds. Fosmidomycin (at 1 μM and 1 mM), an inhibitor of deoxyxylulose-5-phosphate reductoisomerase, did not significantly inhibit phototrophic growth of the cyanobacterium, nor did it affect [14C]IPP incorporation stimulated by DHAP plus GA3P. To date, it has not been possible to unequivocally demonstrate IPP isomerase activity in this cyanobacterium. The combined results suggest that the MEP pathway, as described for E. coli, is not the primary path by which isoprenoids are synthesized under photosynthetic conditions in Synechocystis sp. strain PCC6803. Our data support alternative routes of entry of pentose phosphate cycle substrates derived from photosynthesis.

Metabolic plasticity for isoprenoid biosynthesis in bacteria

2013 ◽  
Vol 452 (1) ◽  
pp. 19-25 ◽  
Author(s):  
Jordi Pérez-Gil ◽  
Manuel Rodríguez-Concepción
Keyword(s):  
Mevalonate Pathway ◽  
Large Family ◽  
Isoprenoid Biosynthesis ◽  
Mep Pathway ◽  
Host Cells ◽  
Mva Pathway ◽  
Metabolic Intermediates ◽  
Metabolic Plasticity ◽  
New Antibiotics ◽  
Living Organisms

Isoprenoids are a large family of compounds synthesized by all free-living organisms. In most bacteria, the common precursors of all isoprenoids are produced by the MEP (methylerythritol 4-phosphate) pathway. The MEP pathway is absent from archaea, fungi and animals (including humans), which synthesize their isoprenoid precursors using the completely unrelated MVA (mevalonate) pathway. Because the MEP pathway is essential in most bacterial pathogens (as well as in the malaria parasites), it has been proposed as a promising new target for the development of novel anti-infective agents. However, bacteria show a remarkable plasticity for isoprenoid biosynthesis that should be taken into account when targeting this metabolic pathway for the development of new antibiotics. For example, a few bacteria use the MVA pathway instead of the MEP pathway, whereas others possess the two full pathways, and some parasitic strains lack both the MVA and the MEP pathways (probably because they obtain their isoprenoids from host cells). Moreover, alternative enzymes and metabolic intermediates to those of the canonical MVA or MEP pathways exist in some organisms. Recent work has also shown that resistance to a block of the first steps of the MEP pathway can easily be developed because several enzymes unrelated to isoprenoid biosynthesis can produce pathway intermediates upon spontaneous mutations. In the present review, we discuss the major advances in our knowledge of the biochemical toolbox exploited by bacteria to synthesize the universal precursors for their essential isoprenoids.

scholarly journals GcpE Is Involved in the 2-C-Methyl-d-Erythritol 4-Phosphate Pathway of Isoprenoid Biosynthesis in Escherichia coli

2001 ◽  
Vol 183 (8) ◽  
pp. 2411-2416 ◽  
Author(s):  
Boran Altincicek ◽  
Ann-Kristin Kollas ◽  
Silke Sanderbrand ◽  
Jochen Wiesner ◽  
Martin Hintz ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Mevalonate Pathway ◽  
Genetically Engineered ◽  
Isoprenoid Biosynthesis ◽  
Mep Pathway ◽  
E Coli

ABSTRACT In a variety of organisms, including plants and several eubacteria, isoprenoids are synthesized by the mevalonate-independent 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway. Although different enzymes of this pathway have been described, the terminal biosynthetic steps of the MEP pathway have not been fully elucidated. In this work, we demonstrate that thegcpE gene of Escherichia coli is involved in this pathway. E. coli cells were genetically engineered to utilize exogenously provided mevalonate for isoprenoid biosynthesis by the mevalonate pathway. These cells were then deleted for the essential gcpE gene and were viable only if the medium was supplemented with mevalonate or the cells were complemented with an episomal copy of gcpE.

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