A Biosynthetic Pathway to Isovaleryl-CoA in Myxobacteria: The Involvement of the Mevalonate Pathway

ChemBioChem ◽  
2004 ◽  
Vol 6 (2) ◽  
pp. 322-330 ◽  
Author(s):  
Taifo Mahmud ◽  
Silke C. Wenzel ◽  
Eva Wan ◽  
Kwun Wah Wen ◽  
Helge B. Bode ◽  
...  
Keyword(s):  
Biosynthetic Pathway ◽  
Mevalonate Pathway

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.

scholarly journals Carotenoids of Gemmatimonas aurantiaca (Gemmatimonadetes): identification of a novel carotenoid, deoxyoscillol 2-rhamnoside, and proposed biosynthetic pathway of oscillol 2,2′-dirhamnoside

Microbiology ◽  
2010 ◽  
Vol 156 (3) ◽  
pp. 757-763 ◽  
Author(s):  
Shinichi Takaichi ◽  
Takashi Maoka ◽  
Kazuto Takasaki ◽  
Satoshi Hanada
Keyword(s):  
Nucleotide Sequence ◽  
Spectral Data ◽  
Biosynthetic Pathway ◽  
Mevalonate Pathway ◽  
Phytoene Desaturase ◽  
Isopentenyl Pyrophosphate ◽  
Gram Negative ◽  
Geranylgeranyl Pyrophosphate Synthase ◽  
First Finding ◽  
Entire Nucleotide Sequence

Gemmatimonas aurantiaca strain T-27T is an orange-coloured, Gram-negative, facultatively aerobic, polyphosphate-accumulating bacterium belonging to a recently proposed phylum, Gemmatimonadetes. We purified its pigments and identified them as carotenoids and their glycoside derivatives using spectral data. The major carotenoid was (2S,2′S)-oscillol 2,2′-di-(α-l-rhamnoside), and the minor carotenoids were (2S)-deoxyoscillol 2-(α-l-rhamnoside) and didemethylspirilloxanthin. Deoxyoscillol2-rhamnoside is a novel carotenoid. Oscillol 2,2′-diglycosides have hitherto only been reported in a limited number of cyanobacteria, and this is believed to be the first finding of such carotenoids in another bacterial phylum. Based on the identification of the carotenoids and the completion of the entire nucleotide sequence, we propose a biosynthetic pathway for the carotenoids and the corresponding genes and enzymes. We propose the involvement of geranylgeranyl pyrophosphate synthase (CrtE), phytoene synthase (CrtB) and phytoene desaturase (CrtI) for lycopene synthesis; and of carotenoid1,2-hydratase (CruF) and carotenoid 2-O-rhamnosyltransferase (CruG) for oscillol 2,2′-dirhamnoside synthesis. Further, isopentenyl pyrophosphate could be synthesized by a non-mevalonate pathway (DXP pathway).

scholarly journals Screening for Mevalonate Biosynthetic Pathway Inhibitors Using Sensitized Bacterial Strains

2011 ◽  
Vol 16 (6) ◽  
pp. 637-646 ◽  
Author(s):  
Sandrine Ferrand ◽  
Jianshi Tao ◽  
Xiaoyu Shen ◽  
Dorothy McGuire ◽  
Andres Schmid ◽  
...  
Keyword(s):  
Biosynthetic Pathway ◽  
Mevalonate Pathway ◽  
Inducible Promoter ◽  
High Density ◽  
Bacterial Strains ◽  
Differential Growth ◽  
Low Concentrations ◽  
Mevalonate Diphosphate Decarboxylase ◽  
A Cell ◽  
Dependent Pathway

A simple, optical density-based assay for inhibitors of the mevalonate-dependent pathway for isoprenoid biosynthesis was developed. The assay uses pathway-sensitized Staphylococcus aureus strains and is fully compatible with high-density screening in a 1536-well format. S. aureus strains were constructed in which genes required for mevalonate-dependent isopentenyl pyrophosphate (IPP) synthesis were regulated by an isopropyl-β-D-thiogalactopyranoside (IPTG)–inducible promoter. Inhibitors of the target enzymes displayed greater antibacterial potency in media containing low concentrations of IPTG, and therefore less induction of mevalonate pathway genes, than in media with high IPTG conditions. This differential growth phenotype was exploited to bias the cell-based screening hits toward specific inhibitors of mevalonate-dependent IPP biosynthesis. Screens were run against strains engineered for regulation of the enzymes HMG-CoA synthase (MvaS) and mevalonate kinase (mvaK1), mevalonate diphosphate decarboxylase (mvaD), and phosphomevalonate kinase (mvaK2). The latter three enzymes are regulated as an operon. These assays resulted in the discovery of potent antibacterial hits that were progressed to an active hit-to-lead program. The example presented here demonstrates that a cell sensitization strategy can be successfully applied to a 1.3-million compound high-throughput screen in a high-density 1536-well format.

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 biosynthetic pathways as anti-infective drug targets

2005 ◽  
Vol 33 (4) ◽  
pp. 785-791 ◽  
Author(s):  
F. Rohdich ◽  
A. Bacher ◽  
W. Eisenreich
Keyword(s):  
Helicobacter Pylori ◽  
Plasmodium Falciparum ◽  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Biosynthetic Pathway ◽  
Mevalonate Pathway ◽  
Biosynthetic Pathways ◽  
Isopentenyl Diphosphate ◽  
Human Pathogens ◽  
Dimethylallyl Diphosphate

IPP (isopentenyl diphosphate) and DMAPP (dimethylallyl diphosphate) serve as the universal precursors for the biosynthesis of isoprenoids. Besides the well-known mevalonate pathway, the existence of a second biosynthetic pathway conducive to IPP and DMAPP formation through 1-deoxy-D-xylulose 5-phosphate and 2C-methyl-D-erythritol 4-phosphate was discovered approx. 10 years ago in plants and certain eubacteria. It is now known that this pathway is widely distributed in the bacterial kingdom including major human pathogens, such as Mycobacterium tuberculosis and Helicobacter pylori. The pathway 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 comparative genomics, enzymology, advanced NMR technology and crystallography. The results provide the basis for the development of novel anti-infective drugs.

Cytochrome P450 subfamily CYP710A genes encode sterol C-22 desaturase in plants

2006 ◽  
Vol 34 (6) ◽  
pp. 1202-1205 ◽  
Author(s):  
T. Morikawa ◽  
M. Mizutani ◽  
D. Ohta
Keyword(s):  
Cytochrome P450 ◽  
Double Bond ◽  
Steroid Hormones ◽  
Plant Sterol ◽  
Biosynthetic Pathway ◽  
Mevalonate Pathway ◽  
Membrane Integrity ◽  
The Other ◽  
Side Chain ◽  
Cellular Functions

Sterols are isoprenoid-derived lipids that are produced via the mevalonate pathway and are involved in various cellular functions in eukaryotes such as maintenance of membrane integrity and biosynthetic precursors of steroid hormones. Among cellular sterols, Δ22-sterols containing a double bond at C-22 in the sterol side chain specifically occur in fungi (ergosterol) and plants (stigmasterol and brassicasterol), and several lines of experimental evidence have suggested specific physiological roles of Δ22-sterols in plants. Fungal cytochrome P450 (P450), CYP61, has been established as the sterol C-22 desaturase functioning at the penultimate step in the ergosterol biosynthetic pathway. On the other hand, no particular sequence has been assigned as to the enzyme responsible for the introduction of the double bond into the sterol side chain in plants. In this review, we summarize our recent findings demonstrating that CYP710A P450 family genes encode the plant sterol C-22 desaturases to produce stigmasterol and brassicasterol/crinosterol from β-sitosterol and 24-epi-campesterol respectively.

scholarly journals Cholesterol biosynthetic pathway induces cellular senescence through ERRa

2021 ◽  
Author(s):  
Dorian V Ziegler ◽  
Mathieu Vernier ◽  
Joanna Czarnecka-Herok ◽  
Charlotte Scholtes ◽  
Christelle Machon ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Biosynthetic Pathway ◽  
Mevalonate Pathway ◽  
Cholesterol Biosynthesis ◽  
Age Related ◽  
Diet Regimen ◽  
Cholesterol Biosynthetic Pathway ◽  
A Cell ◽  
Normal Human

Cellular senescence is a cell program induced by various stresses that leads to a stable proliferation arrest and to a senescence-associated secretory phenotype. Accumulation of senescent cells during age-related diseases participates in these pathologies and regulates healthy lifespan. Recent evidences point out a global dysregulated intracellular metabolism associated to senescence phenotype. Nonetheless, the functional contribution of metabolic homeostasis in regulating senescence is barely understood. In this work, we describe how the mevalonate pathway, an anabolic pathway leading to the endogenous biosynthesis of poly-isoprenoids, such as cholesterol, acts as a positive regulator of cellular senescence in normal human cells. Mechanistically, this mevalonate-induced senescence is partly mediated by the downstream cholesterol biosynthetic pathway. This pathway promotes transcriptional activity of ERRα leading to dysfunctional mitochondria, ROS production, DNA damage and a p53-dependent senescence. Supporting the relevance of these observations, increase of senescence in liver due to a high-fat diet regimen is abrogated in ERRα knockout mouse. Overall, this work unravels the role of cholesterol biosynthesis in the induction of an ERRα-dependent mitochondrial program leading to cellular senescence and related pathological alterations.

scholarly journals Convergent evolution of mevalonate pathway in Inonotus obliquus and Betula pendula.

2021 ◽  
Author(s):  
Omid Safronov ◽  
Guleycan Lutfullahoglubal ◽  
Nina Sipari ◽  
Maya Wilkens ◽  
Pezhman Safdari ◽  
...  
Keyword(s):  
Biosynthetic Pathway ◽  
Genome Duplication ◽  
Mevalonate Pathway ◽  
Duplication Event ◽  
Fungal Species ◽  
Small Scale ◽  
Terpene Biosynthesis ◽  
Genome Duplication Event ◽  
Inonotus Obliquus ◽  
Pathway Evolution

Inonotus obliquus, Chaga mushroom, is a fungal species from Hymenochaetaceae family (Basidiomycota) which has been widely used for traditional medicine in Europe and Asia. Here, chaga genome was sequenced using Pacbio sequencing into a 50.7Mbp assembly consisting of 301 primary contigs with an N50 value of 375 kbp. Genome evolution analyses revealed a lineage-specific whole genome duplication event and an expansion of Cytochrome P450 superfamily. Fungal biosynthetic clusters were enriched for tandemly duplicated genes, suggesting that biosynthetic pathway evolution has proceeded through small-scale duplications. Metabolomic fingerprinting confirmed a highly complex terpene biosynthesis chemistry when compared against related fungal species lacking the genome duplication event.

scholarly journals Alteration of Mevalonate Pathway in Rat Splenic Lymphocytes: Possible Role in Cytokines Secretion Regulated by L-Theanine

2018 ◽  
Vol 2018 ◽  
pp. 1-8
Author(s):  
Chengjian Li ◽  
Qiongxian Yan ◽  
Shaoxun Tang ◽  
Wenjun Xiao ◽  
Zhiliang Tan
Keyword(s):  
Biosynthetic Pathway ◽  
Mevalonate Pathway ◽  
Drug Candidate ◽  
Splenic Lymphocytes ◽  
Immunomodulatory Effects ◽  
Nonprotein Amino Acid ◽  
Mrna And Protein Expression ◽  
Coa Reductase ◽  
Lymphocytes Subsets ◽  
Cytokines Secretion

L-Theanine is a nonprotein amino acid in tea, and its immunomodulatory function has been confirmed. This study aimed to investigate the effect of L-theanine addition on cytokines secretion in rat splenic lymphocytes and explore its potential immunomodulatory effects on the mevalonate biosynthetic pathway. Our results showed that L-theanine treatment did not influence the proliferation and division indexes of the splenic lymphocytes subsets. Interestingly, L-theanine treatment had regulated the contents of IFN-γ, IL-2, IL-4, IL-10, IL-12, and TNF-α  (P<0.001) except IL-6 and upregulated the mRNA and protein expression of Ras-related protein Rap-1A (Rap1A), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and farnesyl diphosphate synthase (FDPs) (P<0.001). Additionally, there was a positive correlation between Rap1A and HMGCR proteins expression and IFN-γ, IL-4, and IL-6 levels. In conclusion, L-theanine regulated the secretion of cytokines probably by activating expression of Rap1A and HMGCR proteins involved in the mevalonate biosynthetic pathway in rat splenic lymphocytes. Therefore, L-theanine might be a promising potential drug candidate as immunopotentiator.

Balanced Amplification of Mevalonate Pathway Genes Increased Isoprene Production by Pantoea ananatis Recombinant Strain

2019 ◽  
pp. 3-15
Author(s):  
Y. Tajima ◽  
S.V. Mashko
Keyword(s):  
Biosynthetic Pathway ◽  
Mevalonate Pathway ◽  
Joint Work ◽  
Pantoea Ananatis ◽  
Metabolic Intermediates ◽  
Copy Numbers ◽  
Coordinated Expression ◽  
Fruitful Cooperation ◽  
Heterologous Pathway ◽  
Analytical Equipment

Uncoordinated expression of a target biosynthetic pathway often results in low growth and productivity of a producing strain due to the accumulation of toxic metabolic intermediates. In this study, we report an increase in the isoprene accumulation by an engineered strain of Pantoea ananatis possessing foreign artificial mevalonate pathway genes. It was achieved owing to a simultaneous cp80-Int-dependant integration of a mixture of conditionally replicated plasmids carrying the genes for the upper and lower mevalonate pathways and for mevalonate kinase followed by the selection according to isoprene accumulation of clones with optimal copy numbers of the integrative cassettes. The previously developed Dual In/Out method was modified to accelerate constructing of the recipient strains containing several attB sites of ф80 phage in their genomes. coordinated expression, Dual In/Out method, mevalonate pathway, Pantoea ananatis, isoprene, integration of heterologous pathway. The authors are extremely grateful to Dr. A.D. Kivero (CJSC AGRI) for the valuable comments while working with analytical equipment. The authors express their appreciation of Dr. Uehara (Nagai) Yuri for the fruitful cooperation and coordination of the joint work.

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