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.

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.

scholarly journals Mevalonate-independent methylerythritol phosphate pathway for isoprenoid biosynthesis. Elucidation and distribution

2003 ◽  
Vol 75 (2-3) ◽  
pp. 375-388 ◽  
Author(s):  
M. Rohmer
Keyword(s):  
Metabolic Pathway ◽  
Biosynthetic Pathway ◽  
Mevalonate Pathway ◽  
State Of The Art ◽  
Isoprenoid Biosynthesis ◽  
Methylerythritol Phosphate Pathway ◽  
Methylerythritol Phosphate ◽  
Antiparasitic Drugs ◽  
Novel Target ◽  
Key Steps

A long-overlooked metabolic pathway for isoprenoid biosynthesis, the mevalonate-independent methylerythritol phosphate (MEP) pathway, is present in many bacteria and in the chloroplasts of all phototrophic organisms. It represents an alternative to the well known mevalonate pathway, which is present in animals, fungi, plant cytoplasm, archaebacteria, and some eubacteria. This contribution summarizes key steps of its elucidation and the state-of-the-art knowledge of this biosynthetic pathway, which represents a novel target for antibacterial and antiparasitic drugs.

Isoprenoid biosynthesis via the methylerythritol phosphate pathway: accumulation of 2- C -methyl- d -erythritol 2,4-cyclodiphosphate in a gcpE deficient mutant of Escherichia coli

2002 ◽  
Vol 43 (5) ◽  
pp. 775-778 ◽  
Author(s):  
Myriam Seemann ◽  
Narciso Campos ◽  
Manuel Rodrı́guez-Concepción ◽  
Jean-François Hoeffler ◽  
Catherine Grosdemange-Billiard ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Isoprenoid Biosynthesis ◽  
Deficient Mutant ◽  
Methylerythritol Phosphate Pathway ◽  
Methylerythritol Phosphate

scholarly journals Co-expression of human malaria parasite Plasmodium falciparum orotate phosphoribosyltransferase and orotidine 5’-monophosphate decarboxylase as enzyme complex in Escherichia coli: a novel strategy for drug development

2010 ◽  
Vol 4 (2) ◽  
pp. 297-306 ◽  
Author(s):  
Panan Kanchanaphum ◽  
Jerapan Krungkrai
Keyword(s):  
Escherichia Coli ◽  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Enzyme Complex ◽  
Orotate Phosphoribosyltransferase ◽  
Human Malaria Parasite ◽  
E Coli ◽  
Parasite Plasmodium ◽  
Monophosphate Decarboxylase ◽  
Parasite Plasmodium Falciparum

Abstract Background: Human malaria parasite Plasmodium falciparum operates de novo pyrimidine biosynthetic pathway. The fifth and sixth enzymes of the pathway form a heterotetrameric complex, containing two molecules each of orotate phosphoribosyltransferase (OPRT) and orotidine 5’-monophosphate decarboxylase (OMPDC). Objective: Define the function of OPRT-OMPDC enzyme complex of P. falciparum by co-expressing the enzymes in Escherichia coli. Methods: The constructed plasmids containing either P. falciparum OPRT or OMPDC were cloned in E. coli by co-transformation. Both genes were co-expressed as OPRT-OMPDC enzyme complex and the complex was purified by chromatographic techniques, including N2+-NTA affinity, Hi Trap Q HP anion-exchange, uridine 5’- monophosphate affinity, and Superose 12 gel-filtration columns. Physical and kinetic properties of the enzyme complex were analyzed for its molecular mass. Results: Co-transformation of PfOPRT and PfOMPDC plasmids in E. coli were achieved with a clone containing DNA ratio of 1:2, respectively. Both plasmids remained stable and were functionally expressed in the E. coli cell for at least 20 weeks. The P. falciparum OPRT-OMPDC enzyme complex were co-expressed and the complex was co-eluted in all chromatographic columns during purification and physical analysis. The molecular mass of the complex was 130 kDa, whereas the PfOPRT and PfOMPDC component were 35.6 and 41.5 kDa, respectively. The enzymatic activities of the complex were competitively inhibited by their products of each enzyme component. Conclusion: P. falciparum OPRT and OMPDC in E. coli as an enzyme complex were co-transformed and functionally co-expressed. These have similar properties to the native enzyme purified directly from P. falciparum, and this character is different from that of the human host organism. The enzyme complex would be suitable as new target to research selective inhibitors as suitable drugs to better control this disease.

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