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squalene synthase like

Nobutaka Suzuki, Tatsuo Ito, Hisanori Matsui, Masayuki Takizawa
TAK-475 (lapaquistat acetate) and its active metabolite-I (TAK-475 M-I) inhibit squalene synthase, which catalyzes the conversion of farnesyl diphosphate (FPP) to squalene. FPP is a substrate for synthesis of other mevalonate-derived isoprenoids (MDIs) such as farnesol (FOH), geranlygeranyl diphosphate (GGPP), and geranylgeraniol. In patients with MKD, a rare autosomal recessive disorder, defective activity of mevalonate kinase leads to a shortage of MDIs. MDIs especially GGPP are required for prenylation of proteins, which is a posttranslation modification necessary for proper functioning of proteins like small guanosine triphosphatases...
2016: SpringerPlus
Elise K Pasoreck, Jin Su, Ian M Silverman, Sager J Gosai, Brian D Gregory, Joshua S Yuan, Henry Daniell
The impact of metabolic engineering on nontarget pathways and outcomes of metabolic engineering from different genomes are poorly understood questions. Therefore, squalene biosynthesis genes FARNESYL DIPHOSPHATE SYNTHASE (FPS) and SQUALENE SYNTHASE (SQS) were engineered via the Nicotiana tabacum chloroplast (C), nuclear (N) or both (CN) genomes to promote squalene biosynthesis. SQS levels were ~4300-fold higher in C and CN lines than in N, but all accumulated ~150-fold higher squalene due to substrate or storage limitations...
September 2016: Plant Biotechnology Journal
Hem R Thapa, Mandar T Naik, Shigeru Okada, Kentaro Takada, István Molnár, Yuquan Xu, Timothy P Devarenne
The green microalga Botryococcus braunii is considered a promising biofuel feedstock producer due to its prodigious accumulation of hydrocarbon oils that can be converted into fuels. B. braunii Race L produces the C40 tetraterpenoid hydrocarbon lycopadiene via an uncharacterized biosynthetic pathway. Structural similarities suggest this pathway follows a biosynthetic mechanism analogous to that of C30 squalene. Confirming this hypothesis, the current study identifies C20 geranylgeranyl diphosphate (GGPP) as a precursor for lycopaoctaene biosynthesis, the first committed intermediate in the production of lycopadiene...
2016: Nature Communications
Marcelo Dutra Arbo, Simone Melega, Regina Stöber, Markus Schug, Eugen Rempel, Jörg Rahnenführer, Patricio Godoy, Raymond Reif, Cristina Cadenas, Maria de Lourdes Bastos, Helena Carmo, Jan G Hengstler
The piperazine derivatives most frequently consumed for recreational purposes are 1-benzylpiperazine, 1-(3,4-methylenedioxybenzyl) piperazine, 1-(3-trifluoromethylphenyl) piperazine and 1-(4-methoxyphenyl) piperazine. Generally, they are consumed as capsules, tablets or pills but also in powder or liquid forms. Currently, the precise mechanism by which piperazine designer drugs induce hepatotoxicity and whether they act by a common pathway is unclear. To answer this question, we performed a gene array study with rat hepatocytes incubated with the four designer drugs...
January 28, 2016: Archives of Toxicology
Elizabeth A Rondini, Zofia Duniec-Dmuchowski, Thomas A Kocarek
Our laboratory previously reported that accumulation of nonsterol isoprenoids following treatment with the squalene synthase inhibitor, squalestatin 1 (SQ1) markedly induced cytochrome P450 (CYP)2B1 mRNA and reporter activity in primary cultured rat hepatocytes, which was dependent on activation of the constitutive androstane receptor (CAR). The objective of the current study was to evaluate whether isoprenoids likewise activate murine CAR (mCAR) or one or more isoforms of human CAR (hCAR) produced by alternative splicing (SPTV, hCAR2; APYLT, hCAR3)...
April 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Asmita Pant, Thomas A Kocarek
Farnesyl pyrophosphate (FPP) is a branch-point intermediate in the mevalonate pathway that is normally converted mainly to squalene by squalene synthase in the first committed step of sterol biosynthesis. Treatment with the squalene synthase inhibitor squalestatin 1 (SQ1) causes accumulation of FPP, its dephosphorylated metabolite farnesol, and several oxidized farnesol-derived metabolites. In addition, SQ1 treatment of primary cultured rat hepatocytes increases CYP2B expression through a mechanism that requires FPP synthesis and activation of the constitutive androstane receptor (CAR)...
March 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Yul-Lye Hwang, Myung Im, Min-Ho Lee, Seok-Seon Roh, Byoung Wook Choi, Sue Jeong Kim, Kyung-Cheol Sohn, Young Lee, Young-Joon Seo, Jeung-Hoon Lee, Chang Deok Kim
AIMS: Acne is a common skin disease that originates in the sebaceous gland. The pathogenesis of acne is very complex, involving the increase of sebum production and perifollicular inflammation. In this study, we screened the anti-lipogenic material and demonstrated its effect using cultured human sebocytes. MAIN METHODS: Normal human sebocytes were cultured by explanting the sebaceous glands. To evaluate the anti-lipogenic effect, sebocytes were treated with test materials and (14)C-acetate incorporation assay was performed...
January 1, 2016: Life Sciences
Fantao Kong, Tomohito Yamasaki, Sari Dewi Kurniasih, Liyuan Hou, Xiaobo Li, Nina Ivanova, Shigeru Okada, Takeshi Ohama
Chlamydomonas is a very attractive candidate plant cell factory. However, its main drawback is the difficulty to find the transformants that robustly express heterologous genes randomly inserted in the nuclear genome. We previously showed that domestic squalene synthase (SQS) gene of Chlamydomonas was much more efficiently overexpressed in a mutant strain [UV-mediated mutant (UVM) 4] than in wild type. In this study, we evaluated the possibility of a new mutant strain, met1, which contains a tag in the maintenance type methyltransferase gene that is expected to play a key role in the maintenance of transcriptional gene silencing...
September 2015: Journal of Bioscience and Bioengineering
Phercyles Veiga-Santos, Kai Li, Lilianne Lameira, Tecia Maria Ulisses de Carvalho, Guozhong Huang, Melina Galizzi, Na Shang, Qian Li, Dolores Gonzalez-Pacanowska, Vanessa Hernandez-Rodriguez, Gustavo Benaim, Rey-Ting Guo, Julio A Urbina, Roberto Docampo, Wanderley de Souza, Eric Oldfield
We tested the antituberculosis drug SQ109, which is currently in advanced clinical trials for the treatment of drug-susceptible and drug-resistant tuberculosis, for its in vitro activity against the trypanosomatid parasite Trypanosoma cruzi, the causative agent of Chagas disease. SQ109 was found to be a potent inhibitor of the trypomastigote form of the parasite, with a 50% inhibitory concentration (IC50) for cell killing of 50 ± 8 nM, but it had little effect (50% effective concentration [EC50], ∼80 μM) in a red blood cell hemolysis assay...
April 2015: Antimicrobial Agents and Chemotherapy
Stephen A Bell, Thomas D Niehaus, S Eric Nybo, Joseph Chappell
Squalene and botryococcene are branched-chain, triterpene compounds that arise from the head-to-head condensation of two molecules of farnesyl diphosphate to yield 1'-1 and 1'-3 linkages, respectively. The enzymes that catalyze their formation have attracted considerable interest from the medical field as potential drug targets and the renewable energy sector for metabolic engineering efforts. Recently, the enzymes responsible for botryococcene and squalene biosynthesis in the green alga Botryococcus braunii race B were characterized...
December 9, 2014: Biochemistry
Susana Sánchez-Fidalgo, Isabel Villegas, Maria Ángeles Rosillo, Marina Aparicio-Soto, Catalina Alarcón de la Lastra
SCOPE: Squalene is a polyunsaturated triterpene, which has exhibited anticancer and antioxidant activities among others. We investigated dietary squalene supplementation effect on an acute colitis model induced by dextran sulfate sodium (DSS) in C57BL/6 mice. METHODS AND RESULTS: Mice were fed from weaning with squalene at 0.02% and 0.1%. After 4 weeks, mice were exposed to 3% DSS for 5 days developing acute colitis. After DSS removal (5 days), colons were histological and biochemically processed...
February 2015: Molecular Nutrition & Food Research
Xinxin Feng, Yumei Hu, Yingying Zheng, Wei Zhu, Kai Li, Chun-Hsiang Huang, Tzu-Ping Ko, Feifei Ren, Hsiu-Chien Chan, Mulugeta Nega, Shannon Bogue, Daniel López, Roberto Kolter, Friedrich Götz, Rey-Ting Guo, Eric Oldfield
YisP is involved in biofilm formation in Bacillus subtilis and has been predicted to produce C30 isoprenoids. We determined the structure of YisP and observed that it adopts the same fold as squalene and dehydrosqualene synthases. However, the first aspartate-rich motif found in essentially all isoprenoid synthases is aspartate poor in YisP and cannot catalyze head-to-head condensation reactions. We find that YisP acts as a phosphatase, catalyzing formation of farnesol from farnesyl diphosphate, and that it is the first phosphatase to adopt the fold seen in the head-to-head prenyl synthases...
November 20, 2014: Chemistry & Biology
Prasad G Jamkhande, Prakash G Chandak, Shashikant C Dhawale, Sonal R Barde, Priti S Tidke, Ram S Sakhare
Non-communicable diseases such as cancer, atherosclerosis and diabetes are responsible for major social and health burden as millions of people are dying every year. Out of which, atherosclerosis is the leading cause of deaths worldwide. The lipid abnormality is one of the major modifiable risk factors for atherosclerosis. Both genetic and environmental components are associated with the development of atherosclerotic plaques. Immune and inflammatory mediators have a complex role in the initiation and progression of atherosclerosis...
July 2014: Saudi Pharmaceutical Journal: SPJ: the Official Publication of the Saudi Pharmaceutical Society
Mariela L Tomazic, Tomas J Poklepovich, Clara B Nudel, Alejandro D Nusblat
Polycyclic triterpenoids, such as sterols and hopanoids, are essential components of plasmatic membrane in eukaryotic organisms. Although it is generally assumed that ciliates do not synthesize sterols, and many of them are indeed auxotrophic, a large set of annotated genomic sequences and experimental data from recently studied organisms indicate that they can carry putative genes and respond to the presence/absence of precursors in various ways. The pre-squalene pathway, for instance, is largely present in all sequenced ciliates except in Ichthyophthirius multifiliis; although Paramecium tetraurelia lacks the squalene synthase and Oxytricha trifallax the squalene hopene synthase, in addition to the former...
May 2014: Molecular Phylogenetics and Evolution
Catherine Gebhard, Gabriel Huard, Ekaterini A Kritikou, Jean-Claude Tardif
Dyslipidemia is one of the main risk factors leading to cardiovascular disease (CVD). The standard of therapy, administration of statins, in conjunction with lifestyle and habit changes, can improve high cholesterol levels in the majority of patients. However, some patients with familial hypercholesterolemia (FH) need low-density-lipoprotein cholesterol (LDL-C) apheresis, as the available medications fail to reduce LDL-C levels sufficiently even at maximum doses. Intense research on cholesterol reducing agents and rapid progress in drug design have yielded many approaches that reduce cholesterol absorption or inhibit its synthesis...
2013: Current Pharmaceutical Design
Zhubo Dai, Yi Liu, Luqi Huang, Xueli Zhang
Metabolic engineering of microorganisms is an alternative and attractive route for production of valuable terpenoids that are usually extracted from plant sources. Tanshinones are the bioactive components of Salvia miltiorrhizha Bunge, which is a well-known traditional Chinese medicine widely used for treatment of many cardiovascular diseases. As a step toward microbial production of tanshinones, copalyl diphosphate (CPP) synthase, and normal CPP kaurene synthase-like genes, which convert the universal diterpenoid precursor geranylgeranyl diphosphate (GGPP) to miltiradiene (an important intermediate of the tanshinones synthetic pathway), was introduced into Saccharomyces cerevisiae, resulting in production of 4...
November 2012: Biotechnology and Bioengineering
Lin-Zhang Huang, Hai-Bo Zhu
Elevated levels of low-density cholesterol (LDL-C) are highly correlated with increased risk of cardiovascular diseases (CVD). Thus, current guidelines have recommended progressively lower LDL-C for cholesterol treatment and CVD prevention as the primary goal of therapy. Even so, some patients in the high risk category fail to achieve recommended LDL-C targets with currently available medications. Thereby, additional pharmaceutical strategies are urgently required. In the review, we aim to provide an overview of both current and emerging LDL-C lowering drugs...
April 2012: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Tom D Niehaus, Scott Kinison, Shigeru Okada, Yun-soo Yeo, Stephen A Bell, Ping Cui, Timothy P Devarenne, Joe Chappell
Botryococcus braunii race B is a colony-forming, green algae that accumulates triterpene oils in excess of 30% of its dry weight. The composition of the triterpene oils is dominated by dimethylated to tetramethylated forms of botryococcene and squalene. Although unusual mechanisms for the biosynthesis of botryococcene and squalene were recently described, the enzyme(s) responsible for decorating these triterpene scaffolds with methyl substituents were unknown. A transcriptome of B. braunii was screened computationally assuming that the triterpene methyltransferases (TMTs) might resemble the S-adenosyl methionine-dependent enzymes described for methylating the side chain of sterols...
March 9, 2012: Journal of Biological Chemistry
Violeta Díaz-Sánchez, Alejandro F Estrada, Danika Trautmann, M Carmen Limón, Salim Al-Babili, Javier Avalos
The orange pigmentation of the fungus Neurospora crassa is due to the accumulation of the xanthophyll neurosporaxanthin and precursor carotenoids. Two key reactions in the synthesis of these pigments, the formation of phytoene from geranylgeranyl pyrophosphate and the introduction of β cycles in desaturated carotenoid products, are catalyzed by two domains of a bifunctional protein, encoded by the gene al-2. We have determined the sequence of nine al-2 mutant alleles and analyzed the carotenoid content in the corresponding strains...
2011: PloS One
Tom D Niehaus, Shigeru Okada, Timothy P Devarenne, David S Watt, Vitaliy Sviripa, Joe Chappell
Botryococcene biosynthesis is thought to resemble that of squalene, a metabolite essential for sterol metabolism in all eukaryotes. Squalene arises from an initial condensation of two molecules of farnesyl diphosphate (FPP) to form presqualene diphosphate (PSPP), which then undergoes a reductive rearrangement to form squalene. In principle, botryococcene could arise from an alternative rearrangement of the presqualene intermediate. Because of these proposed similarities, we predicted that a botryococcene synthase would resemble squalene synthase and hence isolated squalene synthase-like genes from Botryococcus braunii race B...
July 26, 2011: Proceedings of the National Academy of Sciences of the United States of America
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