scholarly journals The Methylerythritol Phosphate Pathway Is Functionally Active in All Intraerythrocytic Stages ofPlasmodium falciparum

2004 ◽  
Vol 279 (50) ◽  
pp. 51749-51759 ◽  
Author(s):  
María B. Cassera ◽  
Fabio C. Gozzo ◽  
Fabio L. D'Alexandri ◽  
Emilio F. Merino ◽  
Hernando A. del Portillo ◽  
...  
Keyword(s):  
De Novo ◽  
Isoprenoid Biosynthesis ◽  
Mep Pathway ◽  
Vitamin B ◽  
Methylerythritol Phosphate Pathway ◽  
Methylerythritol Phosphate ◽  
Isolation And Characterization ◽  
Ofplasmodium Falciparum ◽  
Genes Encoding ◽  
First Time

Two genes encoding the enzymes 1-deoxy-d-xylulose-5-phosphate synthase and 1-deoxy-d-xylulose-5-phosphate reductoisomerase have been recently identified, suggesting that isoprenoid biosynthesis inPlasmodium falciparumdepends on the methylerythritol phosphate (MEP) pathway, and that fosmidomycin could inhibit the activity of 1-deoxy-d-xylulose-5-phosphate reductoisomerase. The metabolite 1-deoxy-d-xylulose-5-phosphate is not only an intermediate of the MEP pathway for the biosynthesis of isopentenyl diphosphate but is also involved in the biosynthesis of thiamin (vitamin B1) and pyridoxal (vitamin B6) in plants and many microorganisms. Herein we report the first isolation and characterization of most downstream intermediates of the MEP pathway in the three intraerythrocytic stages ofP. falciparum. These include, 1-deoxy-d-xylulose-5-phosphate, 2-C-methyl-d-erythritol-4-phosphate, 4-(cytidine-5-diphospho)-2-C-methyl-d-erythritol, 4-(cytidine-5-diphospho)-2-C-methyl-d-erythritol-2-phosphate, and 2-C-methyl-d-erythritol-2,4-cyclodiphosphate. These intermediates were purified by HPLC and structurally characterized via biochemical and electrospray mass spectrometric analyses. We have also investigated the effect of fosmidomycin on the biosynthesis of each intermediate of this pathway and isoprenoid biosynthesis (dolichols and ubiquinones). For the first time, therefore, it is demonstrated that the MEP pathway is functionally active in all intraerythrocytic forms ofP. falciparum, andde novobiosynthesis of pyridoxal in a protozoan is reported. Its absence in the human host makes both pathways very attractive as potential new targets for antimalarial drug development.

Diversity in isoprene unit biosynthesis: The methylerythritol phosphate pathway in bacteria and plastids

2007 ◽  
Vol 79 (4) ◽  
pp. 739-751 ◽  
Author(s):  
Michel Rohmer
Keyword(s):  
Mep Pathway ◽  
Reduction Step ◽  
Methylerythritol Phosphate Pathway ◽  
Isoprene Unit ◽  
Methylerythritol Phosphate ◽  
Selection Of

The long-overlooked methylerythritol phosphate (MEP) pathway represents an alternative to the mevalonate route for the formation of isoprene units. It is found in most bacteria as well as in the plastids of all phototrophic organisms. A selection of significant steps of its discovery and elucidation are presented in this contribution, as well as a complete hypothetical biogenetic scheme for the last reduction step.

scholarly journals Structure and Phylogeny of the Curly Birch Chloroplast Genome

2021 ◽  
Vol 12 ◽  
Author(s):  
Konstantin A. Shestibratov ◽  
Oleg Yu. Baranov ◽  
Eugenia N. Mescherova ◽  
Pavel S. Kiryanov ◽  
Stanislav V. Panteleev ◽  
...  
Keyword(s):  
Chloroplast Genome ◽  
Genetic Markers ◽  
De Novo ◽  
Functional Organization ◽  
Protein Coding ◽  
Organelle Genomes ◽  
Genes Encoding ◽  
Cpdna Sequence ◽  
Ssr Loci ◽  
First Time

Curly birch [Betula pendula var. carelica (Merckl.) Hämet-Ahti] is a relatively rare variety of silver birch (B. pendula Roth) that occurs mainly in Northern Europe and northwest part of Russia (Karelia). It is famous for the beautiful decorative texture of wood. Abnormal xylogenesis underlying this trait is heritable, but its genetic mechanism has not yet been fully understood. The high number of potentially informative genetic markers can be identified through sequencing nuclear and organelle genomes. Here, the de novo assembly, complete nucleotide sequence, and annotation of the chloroplast genome (plastome) of curly birch are presented for the first time. The complete plastome length is 160,523 bp. It contains 82 genes encoding structural and enzymatic proteins, 37 transfer RNAs (tRNAs), and eight ribosomal RNAs (rRNAs). The chloroplast DNA (cpDNA) is AT-rich containing 31.5% of A and 32.5% of T nucleotides. The GC-rich regions represent inverted repeats IR1 and IR2 containing genes of rRNAs (5S, 4.5S, 23S, and 16S) and tRNAs (trnV, trnI, and trnA). A high content of GC was found in rRNA (55.2%) and tRNA (53.2%) genes, but only 37.0% in protein-coding genes. In total, 384 microsatellite or simple sequence repeat (SSR) loci were found, mostly with mononucleotide motifs (92% of all loci) and predominantly A or T motifs (94% of all mononucleotide motifs). Comparative analysis of cpDNA in different plant species revealed high structural and functional conservatism in organization of the angiosperm plastomes, while the level of differences depends on the phylogenetic relationship. The structural and functional organization of plastome in curly birch was similar to cpDNA in other species of woody plants. Finally, the identified cpDNA sequence variation will allow to develop useful genetic markers.

scholarly journals Isoprenoid Biosynthesis Inhibition Disrupts Rab5 Localization and Food Vacuolar Integrity in Plasmodium falciparum

2012 ◽  
Vol 12 (2) ◽  
pp. 215-223 ◽  
Author(s):  
Ruth Howe ◽  
Megan Kelly ◽  
John Jimah ◽  
Dana Hodge ◽  
Audrey R. Odom
Keyword(s):  
Plasmodium Falciparum ◽  
De Novo ◽  
Small Gtpases ◽  
Isoprenoid Biosynthesis ◽  
Vesicular Trafficking ◽  
Mep Pathway ◽  
Protein Prenylation ◽  
Content Type ◽  
Pathway Inhibition ◽  
Prenylated Proteins

ABSTRACT The antimalarial agent fosmidomycin is a validated inhibitor of the nonmevalonate isoprenoid biosynthesis (methylerythritol 4-phosphate [MEP]) pathway in the malaria parasite, Plasmodium falciparum . Since multiple classes of prenyltransferase inhibitors kill P. falciparum , we hypothesized that protein prenylation was one of the essential functions of this pathway. We found that MEP pathway inhibition with fosmidomycin reduces protein prenylation, confirming that de novo isoprenoid biosynthesis produces the isoprenyl substrates for protein prenylation. One important group of prenylated proteins is small GTPases, such as Rab family members, which mediate cellular vesicular trafficking. We have found that Rab5 proteins dramatically mislocalize upon fosmidomycin treatment, consistent with a loss of protein prenylation. Fosmidomycin treatment caused marked defects in food vacuolar morphology and integrity, consistent with a defect in Rab-mediated vesicular trafficking. These results provide insights to the biological functions of isoprenoids in malaria parasites and may assist the rational selection of secondary agents that will be useful in combination therapy with new isoprenoid biosynthesis inhibitors.

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.

Identification of lethal mutations in Escherichia coli genes encoding enzymes of the methylerythritol phosphate pathway

2003 ◽  
Vol 307 (2) ◽  
pp. 408-415 ◽  
Author(s):  
Susanna Sauret-Güeto ◽  
Ana Ramos-Valdivia ◽  
Ester Ibáñez ◽  
Albert Boronat ◽  
Manuel Rodrı́guez-Concepción
Keyword(s):  
Escherichia Coli ◽  
Methylerythritol Phosphate Pathway ◽  
Methylerythritol Phosphate ◽  
Lethal Mutations ◽  
Genes Encoding
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