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Jinchao Zhang, Yunjie Huang, Jing Chen, Haining Zhu, Sidney W Whiteheart
Platelets regulate vascular integrity by secreting a host of molecules that promote hemostasis and its sequelae. Given the importance of platelet exocytosis, it is critical to understand how it is controlled. The t-SNAREs, SNAP-23 and syntaxin-11, lack classical transmembrane domains (TMDs), yet both are associated with platelet membranes and redistributed into cholesterol-dependent, lipid rafts when platelets were activated. Using metabolic labeling and hydroxylamine/HCl (HA) treatment, we showed that both contain thioester-linked acyl groups...
January 19, 2018: Journal of Biological Chemistry
Wei Zhang, Shichun Lun, Shu-Huan Wang, Xingwu Jiang, Fan Yang, Jie Tang, Abigail L Manson, Ashlee M Earl, Hendra Gunosewoyo, William R Bishai, Li-Fang Yu
Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound, whose X-ray co-crystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally-related benzofurans with the aim to improve their potency and bioavailability...
January 12, 2018: Journal of Medicinal Chemistry
Funmilayo Adebesin, Joshua R Widhalm, Joseph H Lynch, Rachel M McCoy, Natalia Dudareva
Peroxisomal β-oxidative degradation of compounds is a common metabolic theme in eukaryotes. Reported benzoyl-CoA (BA-CoA) thioesterase activity in peroxisomes from petunia flowers suggests that, like mammals and fungi, plants contain auxiliary enzymes mediating β-oxidation. Here, we report identification of Petunia hybrida Thioesterase 1 (PhTE1), which catalyzes hydrolysis of aromatic acyl-CoAs to their corresponding acids in peroxisomes. PhTE1 expression is spatially, developmentally and temporally regulated and exhibits a similar pattern to known benzenoid metabolic genes...
January 6, 2018: Plant Journal: for Cell and Molecular Biology
Seohyoung Kim, Ramon Gonzalez
Decanoic acid is a valuable compound used as precursor for industrial chemicals, pharmaceuticals and biofuels. Despite efforts to produce it from renewables, only limited achievements have been reported. Here, we report an engineered cell factory able to produce decanoic acid as a major product from glycerol, and abundant and renewable feedstock. We exploit the overlapping chain-length specificity of β-oxidation reversal (r-BOX) and thioesterase enzymes to selectively generate decanoic acid. This was achieved by selecting r-BOX enzymes that support the synthesis of acyl-CoA of up to 10 carbons (thiolase BktB and enoyl-CoA reductase EgTER) and a thioesterase that exhibited high activity towards decanoyl-CoA and longer-chain acyl-CoAs (FadM)...
January 8, 2018: Biotechnology and Bioengineering
Elisabeth Hühner, Katja Backhaus, Rixa Kraut, Shu-Ming Li
Non-ribosomal peptide synthetases (NRPSs) are key enzymes in microorganisms for the assembly of peptide backbones of biologically and pharmacologically active natural products. The monomodular NRPS-like enzymes comprise often an adenylation (A), a thiolation (T), and a thioesterase (TE) domain. In contrast to the NRPSs, they do not contain any condensation domain and usually catalyze a dimerization of α-keto carboxylic acids and thereby provide diverse scaffolds for further modifications. In this study, we established an expression system for NRPS-like genes in Saccharomyces cerevisiae...
January 5, 2018: Applied Microbiology and Biotechnology
Marco Bürger, Björn C Willige, Joanne Chory
Several Pseudomonas and Xanthomonas species are plant pathogens that infect the model organism Arabidopsis thaliana and important crops such as Brassica. Resistant plants contain the infection by rapid cell death of the infected area through the hypersensitive response (HR). A family of highly related α/β hydrolases is involved in diverse processes in all domains of life. Functional details of their catalytic machinery, however, remained unclear. We report the crystal structures of α/β hydrolases representing two different clades of the family, including the protein SOBER1, which suppresses AvrBsT-incited HR in Arabidopsis...
December 19, 2017: Nature Communications
Christopher M Goins, Celine M Schreidah, Steven Dajnowicz, Donald R Ronning
The Mycobacterium tuberculosis (Mtb) rv3802c gene encodes an essential enzyme with thioesterase and phospholipase A activity. Overexpression of Rv3802 orthologs in Mycobacterium smegmatis and Corynebacterium glutamicum increases mycolate content and decreases glycerophospholipids. While a role in modulating the lipid composition of the unique mycomembrane has been proposed, the true biological function of Rv3802 remains uncertain. In this study, we present the first Mtb Rv3802 X-ray crystal structure, solved to 1...
December 15, 2017: Journal of Biological Chemistry
Sang Joon Won, Melanie Cheung See Kit, Brent R Martin
Protein depalmitoylation describes the removal of thioester-linked long chain fatty acids from cysteine residues in proteins. For many S-palmitoylated proteins, this process is promoted by acyl protein thioesterase enzymes, which catalyze thioester hydrolysis to solubilize and displace substrate proteins from membranes. The closely related enzymes acyl protein thioesterase 1 (APT1; LYPLA1) and acyl protein thioesterase 2 (APT2; LYPLA2) were initially identified from biochemical assays as G protein depalmitoylases, yet later were shown to accept a number of S-palmitoylated protein and phospholipid substrates...
December 14, 2017: Critical Reviews in Biochemistry and Molecular Biology
Huixin Lin, Yuan Kun Lee
Genetic engineering of microalgae to accumulate high levels of medium-chain-length fatty acids (MCFAs) represents an attractive strategy to improve the quality of microalgae-based biodiesel, but it has thus far been least successful. We demonstrate that one limitation is the availability of fatty acyl-acyl carrier protein (ACP) substrate pool for acyl-ACP thioesterase (TE). A combinational expression platform that involved plant lauric acid-biased TE (C12TE) and MCFA-specific ketoacyl-ACP synthase (KASIV) increased lauric acid (C12:0) and myristic acid (C14:0) accumulation by almost sevenfold and fourfold, respectively, compared with native strain...
2017: Journal of Applied Phycology
Rui P P Neves, Maria João Ramos, Pedro A Fernandes, Matilde Viegas
Human Fatty Acid Synthase (hFAS) is a megasynthase whose main function is de novo biosynthesis of saturated fatty acids. Interest has been drawn to this enzyme beyond its physiological role due to the association between high levels of hFAS and clinical conditions such as obesity, diabetes and cancer. Thus, it has become an undeniably attractive pharmacological target. Until now, no crystal structure of the complete hFAS is available, hindering attempts to fully understand this protein. Using homology modelling, we built a model of the entire megasynthase, encompassing all of its domains, including the Acyl Carrier Protein (ACP) and Thioesterase (TE) mobile domains absent in the crystal structure of mammalian Fatty Acid Synthase (FAS)...
December 6, 2017: Journal of Physical Chemistry. B
Anal Desai, Michele Alves-Bezerra, Yingxia Li, Cafer Ozdemir, Curtis J Bare, Yue Li, Susan J Hagen, David E Cohen
Thioesterase superfamily member 1 (Them1) is an acyl CoA-thioesterase that is highly expressed in brown adipose tissue where it functions to suppress energy expenditure. Lower Them1 expression levels in the liver are upregulated in response to high fat feeding. Lower Them1 expression levels in the liver are upregulated in response to high fat feeding. Them1-/- mice are resistant to diet-induced obesity, hepatic steatosis and glucose intolerance, but the contribution of Them1 in liver is unclear. To examine its liver-specific functions, we created conditional transgenic mice, which when bred to Them1-/- mice and activated, expressed Them1 exclusively in the liver...
December 5, 2017: Journal of Lipid Research
Baran A Ersoy, Kristal M Maner-Smith, Yingxia Li, Ipek Alpertunga, David E Cohen
The incorporation of excess saturated free fatty acids (SFAs) into membrane phospholipids within the ER promotes ER stress, insulin resistance, and hepatic gluconeogenesis. Thioesterase superfamily member 2 (Them2) is a mitochondria-associated long-chain fatty acyl-CoA thioesterase that is activated upon binding phosphatidylcholine transfer protein (PC-TP). Under fasting conditions, the Them2/PC-TP complex directs saturated fatty acyl-CoA toward β-oxidation. Here, we showed that during either chronic overnutrition or acute induction of ER stress, Them2 and PC-TP play critical roles in trafficking SFAs into the glycerolipid biosynthetic pathway to form saturated phospholipids, which ultimately reduce ER membrane fluidity...
November 20, 2017: Journal of Clinical Investigation
Madeleine Peschke, Clara Brieke, Michael Heimes, Max J Cryle
The biosynthesis of the glycopeptide antibiotics (GPAs) - which include teicoplanin and vancomycin - is a complex enzymatic process relying on the interplay of non-ribosomal peptide synthesis and a Cytochrome P450-mediated cyclization cascade. This unique cyclization cascade generates the highly crosslinked state of these non-ribosomal peptides, which is crucial for their antimicrobial activity. Given that these essential oxidative transformations occur whilst the peptide remains bound to the terminal module of the non-ribosomal peptide synthetase (NRPS) machinery, it is important to assess the selectivity of the terminal thioesterase (TE) domain and how this domain contributes to the maintenance of an efficient biosynthetic pathway whilst at the same time ensuring GPA maturation is completed...
December 1, 2017: ACS Chemical Biology
Seung Kyou You, Young-Chul Joo, Dae Hee Kang, Sang Kyu Shin, Jeong Eun Hyeon, Han Min Woo, Youngsoon Um, Chulhwan Park, Sung Ok Han
Saccharomyces cerevisiae is used for edible purposes, such as human food or as an animal feed supplement. Fatty acids are also beneficial as feed supplements, but S. cerevisiae produces less fatty acids. In this study, we enhanced fatty acid production of S. cerevisiae by overexpressing acetyl-CoA carboxylase, thioesterase, and malic enzyme associated with fatty acid metabolism. The enhanced strain pAMT showed 2.4-fold higher fatty acids than the wild-type strain. To further increase the fatty acids, various nitrogen sources were analyzed and calcium nitrate was selected as an optimal nitrogen source for fatty acid production...
November 29, 2017: Journal of Agricultural and Food Chemistry
Li Han, Yanfeng Peng, Yuangyuan Zhang, Wujiu Chen, Yuping Lin, Qinhong Wang
Medium-chain (C8-C14) α, ω-dicarboxylic acids (α, ω-DCAs), which have numerous applications as raw materials for producing various commodities and polymers in chemical industry, are mainly produced from chemical or microbial conversion of petroleum-derived alkanes or plant-derived fatty acids at present. Recently, significant attention has been gained to microbial production of medium-chain α, ω-DCAs from simple renewable sugars. Here, we designed and created a synthetic omega oxidation pathway in Saccharomyces cerevisiae to produce C10 and C12 α, ω-DCAs from renewable sugars and fatty acids by introducing a heterogeneous cytochrome P450 CYP94C1 and cytochrome reductase ATR1...
2017: Frontiers in Microbiology
Cristian Botta, Alberto Acquadro, Anna Greppi, Lorenzo Barchi, Marta Bertolino, Luca Cocolin, Kalliopi Rantsiou
The butyrogenic capability of Lactobacillus (L.) plantarum is highly dependent on the substrate type and so far not assigned to any specific metabolic pathway. Accordingly, we compared three genomes of L. plantarum that showed a strain-specific capability to produce butyric acid in human cells growth media. Based on the genomic analysis, butyric acid production was attributed to the complementary activities of a medium-chain thioesterase and the fatty acid synthase of type two (FASII). However, the genomic islands of discrepancy observed between butyrogenic L...
November 21, 2017: Scientific Reports
Wanwisa Panman, Bodee Nutho, Supakarn Chamni, Supaporn Dokmaisrijan, Nawee Kungwan, Thanyada Rungrotmongkol
Thioesterase (TE) domain of fatty acid synthase (FAS) is an attractive therapeutic target for design and development of anticancer drugs. In this present work, we search for the potential FAS inhibitors of TE domain from the ZINC database based on similarity search using three natural compounds as templates, including flavonoids, terpenoids and phenylpropanoids. Molecular docking was used to predict the interaction energy of each screened ligand compared to the reference compound, which is methyl γ-linolenylfluorophosphonate (MGLFP)...
November 21, 2017: Journal of Biomolecular Structure & Dynamics
Ryan A Oliver, Rongfeng Li, Craig A Townsend
The N-sulfonated monocyclic β-lactam ring characteristic of the monobactams confers resistance to zinc metallo-β-lactamases and affords the most effective class to combat carbapenem-resistant enterobacteria (CRE). Here we report unprecedented nonribosomal peptide synthetase activities, wherein an assembled tripeptide is N-sulfonated in trans before direct synthesis of the β-lactam ring in a noncanonical, cysteine-containing thioesterase domain. This means of azetidinone synthesis is distinct from the three others known in nature...
November 20, 2017: Nature Chemical Biology
Tian Qiu, Rahul S Kathayat, Yang Cao, Michael William Beck, Bryan C Dickinson
S-palmitoylation is an abundant lipid post-translational modification (PTM) that is dynamically installed on and removed from target proteins to regulate their activity and cellular localization. A dearth of tools to study the activities and regulation of protein S-depalmitoylases - thioesterase "erasers" of protein cysteine S-palmitoylation - has contributed to an incomplete understanding of the role of dynamic S-palmitoylation in regulating proteome lipidation. Recently, we developed "depalmitoylation probes" (DPPs), small molecule probes that become fluorescent upon S-depalmitoylase enzymatic activity...
October 12, 2017: Biochemistry
Yanbin Feng, Yayue Wang, Jiao Liu, Yinghui Liu, Xupeng Cao, Song Xue
Acyl-ACP thioesterase (TE) catalyzes the hydrolysis of thioester bonds during type II fatty acid synthesis and directly determines fatty acid chain length. Most TEs are responsible for recognition of 16:0 and 18:1 substrates, while specific TEs interrupt acyl-ACP elongation at C8-C14. However, the acyl selection mechanism of TE has not been thoroughly elucidated to date. In this study, the crystal structure of the C12-specific thioesterase FatB from Umbellularia californica, which consists of two independent hotdog domains, was determined...
November 17, 2017: ACS Chemical Biology
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