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Roberta Ranieri, Elena Ciaglia, Giuseppina Amodio, Paola Picardi, Maria Chiara Proto, Patrizia Gazzerro, Chiara Laezza, Paolo Remondelli, Maurizio Bifulco, Simona Pisanti
Targeting the autophagic process is considered a promising therapeutic strategy in cancer since a great number of tumors, including melanoma, show high basal levels of protective autophagy that contributes to tumor progression and chemoresistance. Here, exploiting both in vitro and in vivo approaches, we identified N6-isopentenyladenosine (iPA), an end product of the mevalonate pathway, as a novel autophagy inhibitor with an interesting anti-melanoma activity. iPA, after being phosphorylated by adenosine kinase into 5'-iPA-monophosphate, induces autophagosome accumulation through AMPK activation, measured by increased fluorescent GFP-LC3 puncta and enhanced conversion into the lipidated autophagosome-associated LC3-II...
October 13, 2017: Cell Death and Differentiation
Chun-Liang Chen, James C Mermoud, Lake N Paul, Calvin Nicklaus Steussy, Cynthia V Stauffacher
The mevalonate pathway produces isopentenyl diphosphate (IPP), a building block for polyisoprenoid synthesis, and is a crucial pathway for growth of the human bacterial pathogen Enterococcus faecalis. The final enzyme in this pathway, mevalonate diphosphate decarboxylase (MDD), acts on mevalonate diphosphate (MVAPP) to produce IPP while consuming ATP. This essential enzyme has been suggested as a therapeutic target for the treatment of drug-resistant bacterial infections. Here we report functional and structural studies on the mevalonate diphosphate decarboxylase from E...
October 12, 2017: Journal of Biological Chemistry
Xiangxiang Meng, Qiling Song, Jiabao Ye, Lanlan Wang, Feng Xu
3-Hydroxy-3-methylglutaryl-CoA synthase (HMGS) is one of the rate-limiting enzymes in the mevalonate pathway as it catalyzes the condensation of acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA. In this study, A HMGS gene (designated as GbHMGS1) was cloned from Ginkgo biloba for the first time. GbHMGS1 contained a 1422-bp open-reading frame encoding 474 amino acids. Comparative and bioinformatics analysis revealed that GbHMGS1 was extensively homologous to HMGSs from other plant species. Phylogenetic analysis indicated that the GbHMGS1 belonged to the plant HMGS superfamily, sharing a common evolutionary ancestor with other HMGSs, and had a further relationship with other gymnosperm species...
October 12, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Ammara Khalid, Hiroshi Takagi, Suresh Panthee, Makoto Muroi, Joe Chappell, Hiroyuki Osada, Shunji Takahashi
Terpenoids represent the largest class of natural products, some of which are resources for pharmaceuticals, fragrances, and fuels. Generally, mass production of valuable terpenoid compounds is hampered by their low production levels in organisms and difficulty of chemical synthesis. Therefore, the development of microbial biosynthetic platforms represents an alternative approach. Although microbial terpenoid-production platforms have been established in Escherichia coli and yeast, an optimal platform has not been developed for Streptomyces species, despite the large capacity to produce secondary metabolites, such as polyketide compounds...
October 11, 2017: ACS Synthetic Biology
Hui Huang, En-Hua Xia, Hai-Bin Zhang, Qiu-Yang Yao, Li-Zhi Gao
Camellia sasanqua is one of the most famous horticultural plants in Camellia (Theaceae) due to its aesthetic appeal as landscape plant. Knowledge regarding the genetic basis of flowering time, floral aroma and color in C. sasanqua is limited, but is essential to breed new varieties with desired floral traits. Here, we described the de novo transcriptome of young leaves, flower buds and flowers of C. sasanqua. A total of 60,127 unigenes were functionally annotated based on the sequence similarity. After analysis, we found that two floral integrator genes, SOC1 and AP1, in flowering time pathway showed evidence of gene family expansion...
September 1, 2017: Plant Physiology and Biochemistry: PPB
Paola Andrade, Daniel Caudepon, Teresa Altabella, Montserrat Arró, Albert Ferrer, David Manzano
Isoprenoids comprise the largest class of natural compounds and are found in all kinds of organisms. In plants, they participate in both primary and specialized metabolism, playing essential roles in nearly all aspects of growth and development. The enormous diversity of this family of compounds is extensively exploited for biotechnological and biomedical applications as biomaterials, biofuels or drugs. Despite their variety of structures, all isoprenoids derive from the common C5 precursor Isopentenil diphosphate (IPP)...
October 9, 2017: Plant Signaling & Behavior
Daichiro Fujiwara, Masanobu Tsubaki, Tomoya Takeda, Yoshika Tomonari, Yu-Ichi Koumoto, Katsuhiko Sakaguchi, Shozo Nishida
Recently, statins have been demonstrated to improve cancer-related mortality or prognosis in patients of various cancers. However, the details of the apoptosis-inducing mechanisms remain unknown. This study showed that the induction of apoptosis by statins in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of mevalonate or geranylgeranyl pyrophosphate biosynthesis. In addition, statins decreased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin through suppressing Ras prenylation...
October 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
S Eric Nybo, Jacqueline Saunders, Sean P McCormick
Valeriana officinalis is a medicinal herb which produces a suite of compounds in its root tissue useful for treatment of anxiety and insomnia. The sesquiterpene components of the root extract, valerenic acid and valerena-1,10-diene, are thought to contribute to most of the observed anxiolytic of Valerian root preparations. However, valerenic acid and its biosynthetic intermediates are only produced in low quantities in the roots of V. officinalis. Thus, in this report, Escherichia coli was metabolically engineered to produce substantial quantities of valerena-1,10-diene in shake flask fermentations with decane overlay...
October 5, 2017: Journal of Biotechnology
Khadija G Syeda, Anjan Kowluru
BACKGROUND/AIMS: Lamins are intermediate filament proteins that constitute the main components of the lamina underlying the inner-nuclear membrane and serve to organize chromatin. Lamins (e.g., lamin B) undergo posttranslational modifications (e.g., isoprenylation) at their C-terminal cysteine residues. Such modifications are thought to render optimal association of lamins with the nuclear envelop. Using human islets, rodent islets, and INS-1 832/13 cells, we recently reported significant metabolic defects under glucotoxic and endoplasmic reticulum (ER) stress conditions, including caspase 3 activation and lamin B degradation...
October 2, 2017: Cellular Physiology and Biochemistry
Sérgio R Domingos, Cristóbal Pérez, Melanie Schnell
We use high-resolution rotational spectroscopy to investigate the structural intricacies of the lactone form of mevalonic acid, precursor of the mevalonate pathway. By combining microwave spectroscopy with supersonic expansions and quantum-chemical calculations, we determine the two most stable conformations of the precursor. Complementary micro-solvation studies reveal that aggregation of the first water molecule induces a substantial structural rearrangement comprising a hydroxy rotation and an endocyclic core torsion to create a favourable geometry to accommodate the water molecule...
September 28, 2017: Journal of Chemical Physics
Miki Tashiro, Akira Fujii, Shigeko Kawai-Noma, Kyoichi Saito, Daisuke Umeno
To achieve an efficient production of geraniol and its derivatives in Escherichia coli, we aimed to improve the activity of geraniol synthase (GES) through a single round of mutagenesis and screening for higher substrate consumption. We isolated GES variants that outperform their parent in geraniol production. The analysis of GES variants indicated that the expression level of GES was the bottleneck for geraniol synthesis. Over-expression of the mutant GESM53 with a 5'-untranslated sequence designed for high translational efficiency, along with the additional expression of mevalonate pathway enzymes, isopentenyl pyrophosphate isomerase, and geranyl pyrophosphate synthase, yielded 300 mg/L/12 h geraniol and its derivatives (>1000 mg/L/42 h in total) in a shaking flask...
September 26, 2017: Journal of General and Applied Microbiology
Wanwisa Waiyaput, Somphoch Pumipichet, Sawaek Weerakiet, Sasivimol Rattanasiri, Areepan Sophonsritsuk
BACKGROUND: Simvastatin is a promising new drug for the treatment of endometriosis. It is a cholesterol-lowering drug that acts by inhibiting HMG-CoA reductase, resulting in a decrease in mevalonate, a precursor of cholesterol and monocyte chemoattractant protein-1 (MCP-1). This study investigated the effect of pre-operative oral simvastatin administration on MCP-1 gene expression and serum MCP-1 protein levels in patients with endometriosis. METHODS: A prospective, randomized, controlled study was conducted at the Reproductive Endocrinology Unit of the Department of Obstetrics and Gynecology at the Faculty of Medicine Ramathibodi Hospital...
September 26, 2017: BMC Women's Health
Marios Margaritis, Fabio Sanna, Charalambos Antoniades
Statins are widely established as an important class of medications for primary and secondary prevention of cardiovascular disease. In addition to their lipid-lowering effects, mounting evidence suggests that statins exhibit non-lipid-lowering mediated effects in the cardiovascular system. These so called "pleiotropic" effects are partly due to antioxidant properties of statins. These are mediated by inhibition of the mevalonate pathway, which interferes with small GTP-ase protein prenylation. This, in turn, leads to anti-oxidant effects of statins via a plethora of mechanisms...
September 26, 2017: Current Pharmaceutical Design
Jiangrong Huang, Xiaoyu Yang, Xiaochun Peng, Wei Huang
Prenylation is a posttranslational lipid modification required for the proper functions of a number of proteins involved in cell regulation. Here, we show that prenylation inhibition is important for renal cell carcinoma (RCC) growth, survival and response to chemotherapy, and its underlying mechanism may be contributed to mitochondrial dysfunction. We first demonstrated that a HMG-CoA reductase inhibitor pitavastatin inhibited mevalonate pathway and thereby prenylation in RCC cells. In addition, pitavastatin is effective in inhibiting growth and inducing apoptosis in a panel of RCC cell lines...
November 18, 2017: Biochemical and Biophysical Research Communications
Noriaki Yamauchi, Ryo Tanoue
The stereochemical reaction course for the two C-3 hydrogens of leucine to produce a characteristic isoprenoidal lipid in halophilic archaea was observed using incubation experiments with whole cell Halobacterium salinarum. Deuterium-labeled (3R)- and (3S)-[3-(2)H]leucine were freshly prepared as substrates from 2,3-epoxy-4-methyl-1-pentanol. Incorporation of deuterium from (3S)-[3-(2)H]leucine and loss of deuterium from (3R)-[3-(2)H]leucine in the lipid-core of H. salinarum was observed. Taken together with the results of our previous report, involving the incubation of chiral-labeled [5-(2)H]leucine, these results strongly suggested an involvement of isovaleryl-CoA dehydrogenase in leucine conversion to isoprenoid lipid in halophilic archaea...
September 25, 2017: Bioscience, Biotechnology, and Biochemistry
Sheng Wang, Ruishan Wang, Tan Liu, Zhilai Zhan, Liping Kang, Yanan Wang, Chaogeng Lv, Daniele Werck-Reichhart, Lanping Guo, Luqi Huang
Shikonin and its derivatives are the main active components in the medicinal plant Arnebia euchroma and possess extensive pharmaceutical properties. In this study, we developed an optimized yeast system to obtain high-level production of 3-geranyl-4-hydroxybenzoate acid (GBA), an important intermediate involved in shikonin biosynthesis pathway. For host selection, recombinant expression of p-hydroxybenzoate:geranyltransferase (PGT) derived from A. euchroma was performed in Saccharomyces cerevisiae WAT11U strain and high yield monoterpene strain...
November 1, 2017: FEMS Yeast Research
Francesca Urbano, Marco Bugliani, Agnese Filippello, Alessandra Scamporrino, Stefania Di Mauro, Antonino Di Pino, Roberto Scicali, Davide Noto, Agata Maria Rabuazzo, Maurizio Averna, Piero Marchetti, Francesco Purrello, Salvatore Piro
Statins are a class of drugs widely prescribed as frontline therapy for lowering plasma LDL-cholesterol in cardiovascular risk prevention. Several clinical reports have recently suggested an increased risk of type 2 diabetes associated with chronic use of these drugs. The pathophysiology of this effect remains to be fully elucidated but impaired β-cell function constitutes a potential mechanism. The aim of this study was to explore the effect of a chronic treatment with lipophilic and hydrophilic statins on β-cell function, using human pancreatic islets and rat insulin-secreting INS-1 cells; we particularly focused on the role of mitochondria and oxidative stress...
September 19, 2017: Scientific Reports
Jiali Xu, Siyi Zuo, Chengjia Xie, Ling Jiang, Shuang Li, He Huang, Xian Xu
Lycopene plays a crucial role in the biosynthesis pathway of 2-methyl-derythritol-4-phosphate (MEP) and mevalonic acid (MVA). It is a representative product of isoprenoid family, and a typical product of multi-enzyme catalytic reaction in organism. In this paper, we first introduced the general regulation methods in multi-enzyme synthesis reaction, including the construction of multi gene co-expression plasmid, gene order regulation, promoter and ribosome binding site regulation, gene knockout and replacement, aiming at the optimization strategies of multi-enzyme catalytic reaction in lycopene synthesis pathway...
April 25, 2017: Sheng Wu Gong Cheng Xue Bao, Chinese Journal of Biotechnology
Paola Maura Tricarico, Rossella Gratton, Luca Braga, Fulvio Celsi, Sergio Crovella
Mevalonate pathway deregulation has been observed in several diseases, including Mevalonate kinase deficiency (MKD). MKD is a hereditary auto-inflammatory disorder, due to mutations at mevalonate kinase gene (MVK), encoding mevalonate kinase (MK) enzyme. MVK mutations have been reported as associated with impairment of mevalonate pathway with consequent decrease of protein prenylation levels, defective autophagy and increase of IL-1β secretion, followed by cell death. Since 25-hydroxycholesterol (25-HC), a metabolite of cholesterol, can suppress IL-1β production, thus reducing inflammation, we evaluated the effect of 25-HC in an in vitro model of mevalonate pathway alteration, obtained using Lovastatin...
September 14, 2017: International Journal of Biochemistry & Cell Biology
Helen Benson, Steven Watterson, Joanna Sharman, Chido Mpamhanga, Andrew Parton, Christopher Southan, Anthony Harmar, Peter Ghazal
BACKGROUND AND PURPOSE: An ever-growing wealth of information on current drugs and their pharmacological effects is available from online databases. As our understanding of systems biology increases, we have the opportunity to predict, model and quantify how drug combinations can be introduced that outperform conventional single-drug therapies. Here, we explore the feasibility of such systems pharmacology approaches with an analysis of the mevalonate branch of the cholesterol biosynthesis pathway...
September 14, 2017: British Journal of Pharmacology
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