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Keywords = HMBPP

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28 pages, 5206 KiB  
Review
The Multifaceted MEP Pathway: Towards New Therapeutic Perspectives
by Alizée Allamand, Teresa Piechowiak, Didier Lièvremont, Michel Rohmer and Catherine Grosdemange-Billiard
Molecules 2023, 28(3), 1403; https://doi.org/10.3390/molecules28031403 - 1 Feb 2023
Cited by 17 | Viewed by 4974
Abstract
Isoprenoids, a diverse class of natural products, are present in all living organisms. Their two universal building blocks are synthesized via two independent pathways: the mevalonate pathway and the 2-C-methyl-ᴅ-erythritol 4-phosphate (MEP) pathway. The presence of the latter in pathogenic bacteria [...] Read more.
Isoprenoids, a diverse class of natural products, are present in all living organisms. Their two universal building blocks are synthesized via two independent pathways: the mevalonate pathway and the 2-C-methyl-ᴅ-erythritol 4-phosphate (MEP) pathway. The presence of the latter in pathogenic bacteria and its absence in humans make all its enzymes suitable targets for the development of novel antibacterial drugs. (E)-4-Hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), the last intermediate of this pathway, is a natural ligand for the human Vγ9Vδ2 T cells and the most potent natural phosphoantigen known to date. Moreover, 5-hydroxypentane-2,3-dione, a metabolite produced by Escherichia coli 1-deoxy-ᴅ-xylulose 5-phosphate synthase (DXS), the first enzyme of the MEP pathway, structurally resembles (S)-4,5-dihydroxy-2,3-pentanedione, a signal molecule implied in bacterial cell communication. In this review, we shed light on the diversity of potential uses of the MEP pathway in antibacterial therapies, starting with an overview of the antibacterials developed for each of its enzymes. Then, we provide insight into HMBPP, its synthetic analogs, and their prodrugs. Finally, we discuss the potential contribution of the MEP pathway to quorum sensing mechanisms. The MEP pathway, providing simultaneously antibacterial drug targets and potent immunostimulants, coupled with its potential role in bacterial cell–cell communication, opens new therapeutic perspectives. Full article
(This article belongs to the Special Issue Novel Antimicrobial Agents: Design, Synthesis and Activity)
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21 pages, 3451 KiB  
Article
Two Distinct Mechanisms Underlying γδ T Cell-Mediated Regulation of Collagen Type I in Lung Fibroblasts
by Daisuke Okuno, Noriho Sakamoto, Yoshiko Akiyama, Takatomo Tokito, Atsuko Hara, Takashi Kido, Hiroshi Ishimoto, Yuji Ishimatsu, Mohammed S. O. Tagod, Haruki Okamura, Yoshimasa Tanaka and Hiroshi Mukae
Cells 2022, 11(18), 2816; https://doi.org/10.3390/cells11182816 - 9 Sep 2022
Cited by 3 | Viewed by 3179
Abstract
Idiopathic pulmonary fibrosis is a chronic intractable lung disease, leading to respiratory failure and death. Although anti-fibrotic agents delay disease progression, they are not considered curative treatments, and alternative modalities have attracted attention. We examined the effect of human γδ T cells on [...] Read more.
Idiopathic pulmonary fibrosis is a chronic intractable lung disease, leading to respiratory failure and death. Although anti-fibrotic agents delay disease progression, they are not considered curative treatments, and alternative modalities have attracted attention. We examined the effect of human γδ T cells on collagen type I in lung fibroblasts. Collagen type I was markedly reduced in a γδ T cell number-dependent manner following treatment with γδ T cells expanded with tetrakis-pivaloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA) and interleukin-2. Collagen type I levels remained unchanged on addition of γδ T cells to the culture system through a trans-well culture membrane, suggesting that cell–cell contact is essential for reducing its levels in lung fibroblasts. Re-stimulating γδ T cells with (E)-4-hydroxy-3-methylbut-2-enyl diphosphate (HMBPP) reduced collagen type I levels without cell–cell contact, indicating the existence of HMBPP-induced soluble anti-fibrotic factors in γδ T cells. Adding anti-interferon-γ (IFN-γ)-neutralizing mAb restored collagen type I levels, demonstrating that human γδ T cell-derived IFN-γ reduces collagen type I levels. Conversely, interleukin-18 augmented γδ T cell-induced suppression of collagen type I. Therefore, human γδ T cells reduce collagen levels in lung fibroblasts via two distinct mechanisms; adoptive γδ T cell transfer is potentially a new therapeutic candidate. Full article
(This article belongs to the Special Issue Cell Biology: State of the Art and Perspectives in Japan)
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12 pages, 14543 KiB  
Article
Development of Artificial Synthetic Pathway of Endophenazines in Pseudomonas chlororaphis P3
by Ying Liu, Shengjie Yue, Muhammad Bilal, Malik Jan, Wei Wang, Hongbo Hu and Xuehong Zhang
Biology 2022, 11(3), 363; https://doi.org/10.3390/biology11030363 - 24 Feb 2022
Cited by 15 | Viewed by 2553
Abstract
Endophenazine A is a terpenoid phenazine with phenazine-1-carboxylic acid (PCA), and dimethylallyl diphosphate (DMAPP) derived from the 2-methyl-D-erythritol-4-phosphate (MEP) pathway as the precursor, which shows good antimicrobial activity against several Gram-positive bacteria and fungi. However, the highest yield of endophenazine A was about [...] Read more.
Endophenazine A is a terpenoid phenazine with phenazine-1-carboxylic acid (PCA), and dimethylallyl diphosphate (DMAPP) derived from the 2-methyl-D-erythritol-4-phosphate (MEP) pathway as the precursor, which shows good antimicrobial activity against several Gram-positive bacteria and fungi. However, the highest yield of endophenazine A was about 20 mg/L in Streptomyces, limiting its large-scale industrial development. Pseudomonas chlororaphis P3, possessing an efficient PCA synthesis and MEP pathways, is a suitable chassis to synthesize endophenazine A. Herein, we designed an artificial biosynthetic pathway for the synthesis of endophenazine A in P. chlororaphis P3. Primarily, the prenyltransferase PpzP from Streptomyces anulatus 9663 was introduced into P. chlororaphis P3 and successfully synthesized endophenazine A. Another phenazine compound, endophenazine A1, was discovered and identified as a leakage of the intermediate 4-hydroxy-3-methyl-2-butene pyrophosphate (HMBPP). Finally, the yield of endophenazine A reached 279.43 mg/L, and the yield of endophenazine A1 reached 189.2 mg/L by metabolic engineering and medium optimization. In conclusion, we successfully synthesized endophenazine A and endophenazine A1 in P. chlororaphis P3 for the first time and achieved the highest titer, which provides a reference for the heterologous synthesis of terpenoid phenazines. Full article
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26 pages, 3696 KiB  
Review
An Update on the Molecular Basis of Phosphoantigen Recognition by Vγ9Vδ2 T Cells
by Thomas Herrmann, Alina Suzann Fichtner and Mohindar Murugesh Karunakaran
Cells 2020, 9(6), 1433; https://doi.org/10.3390/cells9061433 - 9 Jun 2020
Cited by 50 | Viewed by 7915
Abstract
About 1–5% of human blood T cells are Vγ9Vδ2 T cells. Their hallmark is the expression of T cell antigen receptors (TCR) whose γ-chains contain a rearrangement of Vγ9 with JP (TRGV9JP or Vγ2Jγ1.2) and are paired with Vδ2 (TRDV2)-containing [...] Read more.
About 1–5% of human blood T cells are Vγ9Vδ2 T cells. Their hallmark is the expression of T cell antigen receptors (TCR) whose γ-chains contain a rearrangement of Vγ9 with JP (TRGV9JP or Vγ2Jγ1.2) and are paired with Vδ2 (TRDV2)-containing δ-chains. These TCRs respond to phosphoantigens (PAg) such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), which is found in many pathogens, and isopentenyl pyrophosphate (IPP), which accumulates in certain tumors or cells treated with aminobisphosphonates such as zoledronate. Until recently, these cells were believed to be restricted to primates, while no such cells are found in rodents. The identification of three genes pivotal for PAg recognition encoding for Vγ9, Vδ2, and butyrophilin (BTN) 3 in various non-primate species identified candidate species possessing PAg-reactive Vγ9Vδ2 T cells. Here, we review the current knowledge of the molecular basis of PAg recognition. This not only includes human Vγ9Vδ2 T cells and the recent discovery of BTN2A1 as Vγ9-binding protein mandatory for the PAg response but also insights gained from the identification of functional PAg-reactive Vγ9Vδ2 T cells and BTN3 in the alpaca and phylogenetic comparisons. Finally, we discuss models of the molecular basis of PAg recognition and implications for the development of transgenic mouse models for PAg-reactive Vγ9Vδ2 T cells. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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26 pages, 2730 KiB  
Article
Role of Mitochondria in Regulating Lutein and Chlorophyll Biosynthesis in Chlorella pyrenoidosa under Heterotrophic Conditions
by Zhi-hui Liu, Tao Li, Qing-yu He, Zheng Sun and Yue Jiang
Mar. Drugs 2018, 16(10), 354; https://doi.org/10.3390/md16100354 - 28 Sep 2018
Cited by 14 | Viewed by 5608
Abstract
The green alga Chlorella pyrenoidosa can accumulate lutein and chlorophyll under heterotrophic conditions. We propose that the mitochondrial respiratory electron transport chain (mRET) may be involved in this process. To verify this hypothesis, algal cells were treated with different mRET inhibitors. The biosynthesis [...] Read more.
The green alga Chlorella pyrenoidosa can accumulate lutein and chlorophyll under heterotrophic conditions. We propose that the mitochondrial respiratory electron transport chain (mRET) may be involved in this process. To verify this hypothesis, algal cells were treated with different mRET inhibitors. The biosynthesis of lutein and chlorophyll was found to be significantly stimulated by salicylhydroxamic acid (SHAM), whereas their contents substantially decreased after treatment with antimycin A and sodium azide (NaN3). Proteomic studies revealed profound protein alterations related to the redox and energy states, and a network was proposed: The up-regulation of peroxiredoxin reduces oxidized glutathione (GSSG) to reduced glutathione (GSH); phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the conversion of oxaloacetic acid to phosphoenolpyruvate, and after entering the methylerythritol phosphate (MEP) pathway, 4-hydroxy-3-methylbut-2-en-1yl diphosphate synthase reduces 2-C-methyl-d-erythritol-2,4-cyclodiphosphate (ME-Cpp) to 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate (HMBPP), which is closely related to the synthesis of lutein; and coproporphyrinogen III oxidase and ChlI play important roles in the chlorophyll biosynthetic pathway. These results supported that for the heterotrophic C. pyrenoidosa, the signaling, oriented from mRET, may regulate the nuclear genes encoding the enzymes involved in photosynthetic pigment biosynthesis. Full article
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