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Jiangyong Gu, Li Li, Dongmei Wang, Wei Zhu, Ling Han, Ruizhi Zhao, Xiaojie Xu, Chuanjian Lu
Psoriasis vulgaris is a chronic inflammatory and immune-mediated skin disease. 44 metabonomics biomarkers were identified by high-throughput liquid chromatography coupled to mass spectrometry in our previous work. To further explore the roles of metabonomics biomarkers in the pathogenesis of psoriasis, the metabonomics biomarker-enzyme network was constructed. The key metabonomics biomarkers and enzymes were screened out by network analysis. Long-chain fatty acids, phospholipids, Estradiol and NADH were the most important metabonomics biomarkers...
March 14, 2018: Annals of Medicine
Fuyuan Jing, Le Zhao, Marna D Yandeau-Nelson, Basil J Nikolau
The substrate specificity of acyl-ACP thioesterase (TE) plays an essential role in controlling the fatty acid profile produced by type II fatty acid synthases. Here we identify two groups of residues that synergistically determine different substrate specificities of two acyl-ACP TEs from Cuphea viscosissima (CvFatB1 and CvFatB2). One group (V194, V217, N223, R226, R227, and I268 in CvFatB2) is critical in determining the structure and depth of a hydrophobic cavity in the N-terminal hotdog domain that binds the substrate's acyl moiety...
February 28, 2018: Nature Communications
Yanbin Feng, Yunxiu Zhang, Yayue Wang, Jiao Liu, Yinghui Liu, Xupeng Cao, Song Xue
Medium-chain fatty acids have attracted significant attention as sources of biofuels in recent years. Acyl-ACP thioesterase, which is considered as the key enzyme to determine the carbon chain length, catalyzes the termination of de novo fatty acid synthesis. Although recombinant medium-chain acyl-ACP thioesterase (TE) affects the fatty acid profile in heterologous cells, tailoring of the fatty acid composition merely by engineering a specific TE is still intractable. In this study, the activity of a C8-C10-specific thioesterase FatB2 from Cuphea hookeriana on C10-ACP was quantified twice as high as that on C8-ACP based on a synthetic C8-C16 acyl-ACP pool in vitro...
February 22, 2018: Applied Microbiology and Biotechnology
Kang Xiao, Xiu-Hong Yue, Wen-Chao Chen, Xue-Rong Zhou, Lian Wang, Lin Xu, Feng-Hong Huang, Xia Wan
Medium chain hydroxy fatty acids (HFAs) at ω-1, 2, or 3 positions (ω-1/2/3) are rare in nature but are attractive due to their potential applications in industry. They can be metabolically engineered in Escherichia coli , however, the current yield is low. In this study, metabolic engineering with P450BM3 monooxygenase was applied to regulate both the chain length and sub-terminal position of HFA products in E. coli , leading to increased yield. Five acyl-acyl carrier protein thioesterases from plants and bacteria were first evaluated for regulating the chain length of fatty acids...
2018: Frontiers in Microbiology
Amy M Weeks, Ningkun Wang, Jeffrey G Pelton, Michelle C Y Chang
Fluorinated small molecules play an important role in the design of bioactive compounds for a broad range of applications. As such, there is strong interest in developing a deeper understanding of how fluorine affects the interaction of these ligands with their targets. Given the small number of fluorinated metabolites identified to date, insights into fluorine recognition have been provided almost entirely by synthetic systems. The fluoroacetyl-CoA thioesterase (FlK) from Streptomyces cattleya thus provides a unique opportunity to study an enzyme-ligand pair that has been evolutionarily optimized for a surprisingly high 10 6 selectivity for a single fluorine substituent...
February 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
Jing Guo, Haiqin Chen, Bo Yang, Hao Zhang, Wei Chen, Yong Q Chen
Thioesterases (TEs) play an essential role in the metabolism of fatty acids (FAs). To explore the role of TEs in mediating intracellular lipid metabolism in the oleaginous fungus Mortierella alpina, the acyl-CoA thioesterase ACOT8I was overexpressed. The contents of total fatty acids (TFAs) were the same in the recombinant strains as in the wild-type M. alpina, whilst the production of free fatty acids (FFAs) was enhanced from about 0.9% (wild-type) to 2.8% (recombinant), a roughly threefold increase. Linoleic acid content in FFA form constituted about 9% of the TFAs in the FFA fraction in the recombinant strains but only about 1...
February 13, 2018: Journal of Industrial Microbiology & Biotechnology
Michael C Nicastri, Vito W Rebecca, Ravi K Amaravadi, Jeffrey D Winkler
DQ661 is a novel dimeric quinacrine that affects multiple lysosomal functions (autophagy and macropinocytosis) and mTORC1 (mechanistic target of rapamycin) activity by specifically targeting protein-palmitoyl thioesterase 1 (PPT1). DQ661 has in vivo activity in immunocompetent mouse models of cancer, and constitutes a new tool compound for the study of lysosomal function in cancer and therapeutic resistance.
2018: Molecular & Cellular Oncology
Takumi Okamoto, Kosuke Kawaguchi, Shiro Watanabe, Rina Agustina, Toshiki Ikejima, Keisuke Ikeda, Minoru Nakano, Masashi Morita, Tsuneo Imanaka
In mammals, four ATP-binding cassette (ABC) proteins belonging to subfamily D have been identified. ABCD1‒3 are located on peroxisomal membrane and play an important role in the transportation of various fatty acid-CoA derivatives, including very long chain fatty acid-CoA, into peroxisomes. ABCD4 is located on lysosomal membrane and is suggested to be involved in the transport of vitamin B12 from lysosomes to the cytosol. However, the precise transport mechanism by which these ABC transporters facilitate the import or export of substrate has yet to be well elucidated...
February 1, 2018: Biochemical and Biophysical Research Communications
Hui Li, Xiaoxuan Yu, Xiao Liu, Po Hu, Le Shen, Yuxin Zhou, Yu Zhu, Zhiyu Li, Hui Hui, Qinglong Guo, Jingyan Xu
Acute myeloid leukaemia (AML) comprises a range of disparate genetic subtypes, involving complex gene mutations and specific molecular alterations. Post-translational modifications of specific proteins influence their translocation, stability, aggregation and even leading disease progression. Therapies that target to post-translational modification of specific proteins in cancer cells represent a novel treatment strategy. Non-homogenous subcellular distribution of PLSCR1 is involved in the primary AML cell differentiation...
January 29, 2018: Journal of Cellular and Molecular Medicine
Matthew J Grisewood, Néstor J Hernandez Lozada, James B Thoden, Nathanael P Gifford, Daniel Mendez-Perez, Haley A Schoenberger, Matthew F Allan, Martha E Floy, Rung-Yi Lai, Hazel M Holden, Brian F Pfleger, Costas D Maranas
Enzyme and metabolic engineering offer the potential to develop biocatalysts for converting natural resources into a wide range of chemicals. To broaden the scope of potential products beyond natural metabolites, methods of engineering enzymes to accept alternative substrates and/or perform novel chemistries must be developed. DNA synthesis can create large libraries of enzyme-coding sequences, but most biochemistries lack a simple assay to screen for promising enzyme variants. Our solution to this challenge is structure-guided mutagenesis in which optimization algorithms select the best sequences from libraries based on specified criteria (i...
June 2, 2017: ACS Catalysis
Megan Garland, Christopher J Schulze, Ian T Foe, Wouter A van der Linden, Matthew A Child, Matthew Bogyo
Protein palmitoylation is a dynamic post-translational modification (PTM) important for cellular functions such as protein stability, trafficking, localization, and protein-protein interactions. S-palmitoylation occurs via the addition of palmitate to cysteine residues via a thioester linkage, catalyzed by palmitoyl acyl transferases (PATs), with removal of the palmitate catalyzed by acyl protein thioesterases (APTs) and palmitoyl-protein thioesterases (PPTs). Tools that target the regulators of palmitoylation-PATs, APTs and PPTs-will improve understanding of this essential PTM...
2018: PloS One
Rahul S Kathayat, Yang Cao, Pablo D Elvira, Patrick A Sandoz, María-Eugenia Zaballa, Maya Z Springer, Lauren E Drake, Kay F Macleod, F Gisou van der Goot, Bryan C Dickinson
The reversible modification of cysteine residues by thioester formation with palmitate (S-palmitoylation) is an abundant lipid post-translational modification (PTM) in mammalian systems. S-palmitoylation has been observed on mitochondrial proteins, providing an intriguing potential connection between metabolic lipids and mitochondrial regulation. However, it is unknown whether and/or how mitochondrial S-palmitoylation is regulated. Here we report the development of mitoDPPs, targeted fluorescent probes that measure the activity levels of "erasers" of S-palmitoylation, acyl-protein thioesterases (APTs), within mitochondria of live cells...
January 23, 2018: Nature Communications
Dhanaraju Mandalapu, Xinjian Ji, Jinfeng Chen, Chuchu Guo, Wan-Qiu Liu, Wei Ding, Jiahai Zhou, Qi Zhang
A chemoenzymatic approach for the synthesis of teixobactin analogues has been established by using the tandem thioesterase (TE) of the non-ribosomal peptide synthase (NRPS) Txo2. We show that, unlike the closely-related counterparts involved in lysobactin biosynthesis (in which the N-terminal TE is solely responsible for the lactonization reaction), the two teixobactin TE domains are functionally exchangeable and likely act synergistically, representing an unprecedented off-loading mechanism in NRPS enzymology...
January 23, 2018: Journal of Organic Chemistry
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
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