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Aaron M Marcella, Adam W Barb
The development of biorenewable chemicals will support green chemistry initiatives and supplement the catalog of starting materials available to the chemical industry. Bacterial fatty acid biosynthesis is being pursued as a source of protein catalysts to synthesize novel reduced carbon molecules in fermentation systems. The availability of methods to measure enzyme catalysis for native and engineered enzymes from this pathway remains a bottleneck because a simple quantitative enzyme assay for numerous enzymes does not exist...
2016: Journal of Biological Methods
David C McKinney, Charles J Eyermann, Rong-Fang Gu, Jun Hu, Steven L Kazmirski, Sushmita D Lahiri, Andrew R McKenzie, Adam B Shapiro, Gloria Breault
Fatty acid biosynthesis is essential to bacterial growth in Gram-negative pathogens. Several small molecules identified through a combination of high-throughput and fragment screening were cocrystallized with FabH (β-ketoacyl-acyl carrier protein synthase III) from Escherichia coli and Streptococcus pneumoniae. Structure-based drug design was used to merge several scaffolds to provide a new class of inhibitors. After optimization for Gram-negative enzyme inhibitory potency, several compounds demonstrated antimicrobial activity against an efflux-negative strain of Haemophilus influenzae...
July 8, 2016: ACS Infectious Diseases
Yong-Hong Yu, Zhe Hu, Hui-Juan Dong, Jin-Cheng Ma, Hai-Hong Wang
Xanthomonas campestris pv. campestris (Xcc), a Gram-negative phytopathogenic bacterium, causes black rot disease of cruciferous vegetables. Although Xcc has a complex fatty acid profile comprised of straight-chain fatty acids and branched-chain fatty acids (BCFAs), and encodes a complete set of genes required for fatty acid synthesis, there is still little known about the mechanism of BCFA synthesis. We reported that expression of Xcc fabH restores the growth of Ralstonia solanacearum fabH mutant, and this allows the R...
2016: Scientific Reports
Katherine A Abrahams, Chun-Wa Chung, Sonja Ghidelli-Disse, Joaquín Rullas, María José Rebollo-López, Sudagar S Gurcha, Jonathan A G Cox, Alfonso Mendoza, Elena Jiménez-Navarro, María Santos Martínez-Martínez, Margarete Neu, Anthony Shillings, Paul Homes, Argyrides Argyrou, Ruth Casanueva, Nicholas J Loman, Patrick J Moynihan, Joël Lelièvre, Carolyn Selenski, Matthew Axtman, Laurent Kremer, Marcus Bantscheff, Iñigo Angulo-Barturen, Mónica Cacho Izquierdo, Nicholas C Cammack, Gerard Drewes, Lluis Ballell, David Barros, Gurdyal S Besra, Robert H Bates
Phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. In this regard, whole-genome sequencing of spontaneous resistant mutants generated against an indazole sulfonamide (GSK3011724A) identifies several specific single-nucleotide polymorphisms in the essential Mycobacterium tuberculosis β-ketoacyl synthase (kas) A gene. Here, this genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution of a KasA-GSK3011724A complex by X-ray crystallography...
2016: Nature Communications
Mohammad Sayed Alam, Sefat Jebin, M Mostafizur Rahman, Md Latiful Bari, Dong-Ung Lee
A series of 15 (E)-N'-benzylidenebenzohydrazide analogues were evaluated for their antimicrobial activities against eleven pathogenic and food-borne microbes, namely, S. aureus (G(+)), L. monocytogenes (G(+)), B. subtilis (G(+)), K. pneumonia (G¯), C. sakazakii (G¯), C. freundii (G¯), S. enterica (G¯), S. enteritidis (G¯), E. coli (G¯), Y. pestis (G¯), and P. aeruginosa (G¯). Most of the compounds exhibited selective activity against some Gram-negative bacterial strains. Of the compounds tested (3a-o), 3b and 3g were most active against C...
2016: EXCLI journal
Natanael D Segretti, Ricardo A M Serafim, Mariana C F Segretti, Marcelo Miyata, Fernando R Coelho, Ohara Augusto, Elizabeth I Ferreira
The development of resistance to antibiotics by microorganisms is a major problem for the treatment of bacterial infections worldwide, and therefore, it is imperative to study new scaffolds that are potentially useful in the development of new antibiotics. In this regard, we propose the design, synthesis and biological evaluation of hybrid sulfonylhydrazone bioisosters/furoxans with potential antibacterial (Escherichia coli) activity. The most active compound of the series, (E)-3-methyl-4-((2-tosylhydrazono)methyl)-1,2,5-oxadiazole 2-oxide, with a MIC=0...
August 15, 2016: Bioorganic & Medicinal Chemistry Letters
Huiya Gu, Robert E Jinkerson, Fiona K Davies, Lyle A Sisson, Philip E Schneider, Matthew C Posewitz
The isolation or engineering of algal cells synthesizing high levels of medium-chain fatty acids (MCFAs) is attractive to mitigate the high clouding point of longer chain fatty acids in algal based biodiesel. To develop a more informed understanding of MCFA synthesis in photosynthetic microorganisms, we isolated several algae from Great Salt Lake and screened this collection for MCFA accumulation to identify strains naturally accumulating high levels of MCFA. A diatom, Chaetoceros sp. GSL56, accumulated particularly high levels of C14 (up to 40%), with the majority of C14 fatty acids allocated in triacylglycerols...
2016: Frontiers in Plant Science
Sarva Santhisudha, Soora Harinath Jayaprakash, Gundluru Mohan, Yellapu Nanda Kumar, Vaithiyanathan Suganthi, Vaithiyalingam Mohanasrinivasan, Cirandur Suresh Reddy
Michael addition of indole derivatives with various substituted nitrostyrenes to yield β- indolylnitroalkanes is accomplished effectively under solvent free conditions using TiO2-SO4(2-) as efficient catalyst at 60 º C. All the synthesized compounds were screened for their antibacterial activity through in silico and in vitro methods. The molecular docking studies against FabH enzyme, a potential drug target of bacterial fatty acid biosynthetic pathway indicated the scope of developing them a new class of antimicrobial agents...
2016: Combinatorial Chemistry & High Throughput Screening
Steffen Lorenz Drees, Chan Li, Fajar Prasetya, Muhammad Saleem, Ingrid Dreveny, Paul Williams, Ulrich Hennecke, Jonas Emsley, Susanne Fetzner
Pseudomonas aeruginosaproduces a number of alkylquinolone-type secondary metabolites best known for their antimicrobial effects and involvement in cell-cell communication. In the alkylquinolone biosynthetic pathway, the β-ketoacyl-(acyl carrier protein) synthase III (FabH)-like enzyme PqsBC catalyzes the condensation of octanoyl-coenzyme A and 2-aminobenzoylacetate (2-ABA) to form the signal molecule 2-heptyl-4(1H)-quinolone. PqsBC, a potential drug target, is unique for its heterodimeric arrangement and an active site different from that of canonical FabH-like enzymes...
March 25, 2016: Journal of Biological Chemistry
Weijia Cao, Weichao Ma, Bowen Zhang, Xin Wang, Kequan Chen, Yan Li, Pingkai Ouyang
The development of efficient microbial processes for pinocembrin production has attracted considerable attention. However, pinocembrin biosynthetic efficiency is greatly limited by the low availability of the malonyl-CoA cofactor in Escherichia coli. Fatty acid biosynthesis is the only metabolic process in E. coli that consumes malonyl-CoA; therefore, we overexpressed the fatty acid biosynthetic pathway enzymes β-ketoacyl-ACP synthase III (FabH) and β-ketoacyl-ACP synthase II (FabF) alone and in combination, and investigated the effect on malonyl-CoA...
April 2016: Journal of Industrial Microbiology & Biotechnology
Kirsten Kuipers, Clement Gallay, Václav Martínek, Manfred Rohde, Markéta Martínková, Samantha L van der Beek, Wouter S P Jong, Hanka Venselaar, Aldert Zomer, Hester Bootsma, Jan-Willem Veening, Marien I de Jonge
Proteins belonging to the DHH family, a member of the phosphoesterase superfamily, are produced by most bacterial species. While some of these proteins are well studied in Bacillus subtilis and Escherichia coli, their functions in Streptococcus pneumoniae remain unclear. Recently, the highly conserved DHH subfamily 1 protein PapP (SP1298) has been reported to play an important role in virulence. Here, we provide a plausible explanation for the attenuated virulence of the papP mutant. Recombinant PapP specifically hydrolyzed nucleotides 3'-phosphoadenosine-5'-phosphate (pAp) and 5'-phosphoadenylyl-(3'->5')-adenosine (pApA)...
July 2016: Molecular Microbiology
Jeffrey D Nanson, Zainab Himiari, Crystall M D Swarbrick, Jade K Forwood
Yersinia pestis, the causative agent of bubonic, pneumonic, and septicaemic plague, remains a major public health threat, with outbreaks of disease occurring in China, Madagascar, and Peru in the last five years. The existence of multidrug resistant Y. pestis and the potential of this bacterium as a bioterrorism agent illustrates the need for new antimicrobials. The β-ketoacyl-acyl carrier protein synthases, FabB, FabF, and FabH, catalyse the elongation of fatty acids as part of the type II fatty acid biosynthesis (FASII) system, to synthesise components of lipoproteins, phospholipids, and lipopolysaccharides essential for bacterial growth and survival...
2015: Scientific Reports
Ruofeng Shang, Jianping Liang, Yunpeng Yi, Yu Liu, Jiatu Wang
Platensimycin and platencin were successively discovered from the strain Streptomyces platensis through systematic screening. These natural products have been defined as promising agents for fighting multidrug resistance in bacteria by targeting type II fatty acid synthesis with slightly different mechanisms. Bioactivity studies have shown that platensimycin and platencin offer great potential to inhibit many resistant bacteria with no cross-resistance or toxicity observed in vivo. This review summarizes the general information on platensimycin and platencin, including antibacterial and self-resistant mechanisms...
2015: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Ya-Hui Mao, Jin-Cheng Ma, Feng Li, Zhe Hu, Hai-Hong Wang
Fatty acid synthesis (FAS), a primary metabolic pathway, is essential for survival of bacteria. Ralstonia solanacearum, a β-proteobacteria member, causes a bacterial wilt affecting more than 200 plant species, including many economically important plants. However, thus far, the fatty acid biosynthesis pathway of R. solanacearum has not been well studied. In this study, we characterized two forms of 3-keto-ACP synthase III, RsFabH and RsFabW, in R. solanacearum. RsFabH, the homologue of Escherichia coli FabH, encoded by the chromosomal RSc1050 gene, catalyzes the condensation of acetyl-CoA with malonyl-ACP in the initiation steps of fatty acid biosynthesis in vitro...
2015: PloS One
Bokyung Lee, Sybille Tachon, Richard A Eigenheer, Brett S Phinney, Maria L Marco
We found that incubation of probiotic Lactobacillus casei BL23 in milk at 4 °C prior to ingestion increased its survival in the mammalian digestive tract. To investigate the specific molecular adaptations of L. casei to milk, we used tandem mass spectrometry to compare proteins produced by L. casei BL23 at 4 °C in milk to those in exponential and stationary phase cells in laboratory culture medium at either 37 or 4 °C. These comparisons revealed a core of expressed L. casei proteins as well as proteins produced in either a growth-phase or temperature-specific manner...
August 7, 2015: Journal of Proteome Research
Ruben Fernandez-Moya, Christopher Leber, Javier Cardenas, Nancy A Da Silva
The native yeast type I fatty acid synthase (FAS) is a complex, rigid enzyme, and challenging to engineer for the production of medium- or short-chain fatty acids. Introduction of a type II FAS is a promising alternative as it allows expression control for each discrete enzyme and the addition of heterologous thioesterases. In this study, the native Saccharomyces cerevisiae FAS was functionally replaced by the Escherichia coli type II FAS (eFAS) system. The E. coli acpS + acpP (together), fabB, fabD, fabG, fabH, fabI, fabZ, and tesA were expressed in individual S...
December 2015: Biotechnology and Bioengineering
Amen Shamim, Sumra Wajid Abbasi, Syed Sikander Azam
β-Ketoacyl-ACP-synthase III (FabH or KAS III) has become an attractive target for the development of new antibacterial agents which can overcome the multidrug resistance. Unraveling the fatty acid biosynthesis (FAB) metabolic pathway and understanding structural coordinates of FabH will provide valuable insights to target Streptococcus gordonii for curing oral infection. In this study, we designed inhibitors against therapeutic target FabH, in order to block the FAB pathway. As compared to other targets, FabH has more interactions with other proteins, located on the leading strand with higher codon adaptation index value and associated with lipid metabolism category of COG...
July 2015: Journal of Molecular Graphics & Modelling
Aaron M Marcella, Fuyuan Jing, Adam W Barb
The fatty acid biosynthetic pathway generates highly reduced carbon based molecules. For this reason fatty acid synthesis is a target of pathway engineering to produce novel specialty or commodity chemicals using renewable techniques to supplant molecules currently derived from petroleum. Malonyl-[acyl carrier protein] (malonyl-ACP) is a key metabolite in the fatty acid pathway and donates two carbon units to the growing fatty acid chain during each step of biosynthesis. Attempts to test engineered fatty acid biosynthesis enzymes in vitro will require malonyl-ACP or malonyl-ACP analogs...
November 2015: Protein Expression and Purification
Yaping Yang, Yuheng Lin, Lingyun Li, Robert J Linhardt, Yajun Yan
Malonyl-CoA is the building block for fatty acid biosynthesis and also a precursor to various pharmaceutically and industrially valuable molecules, such as polyketides and biopolymers. However, intracellular malonyl-CoA is usually maintained at low levels, which poses great challenges to efficient microbial production of malonyl-CoA derived molecules. Inactivation of the malonyl-CoA consumption pathway to increase its intracellular availability is not applicable, since it is usually lethal to microorganisms...
May 2015: Metabolic Engineering
L My, N Ghandour Achkar, J P Viala, E Bouveret
UNLABELLED: In Escherichia coli, the FadR transcriptional regulator represses the expression of fatty acid degradation (fad) genes. However, FadR is also an activator of the expression of fabA and fabB, two genes involved in unsaturated fatty acid synthesis. Therefore, FadR plays an important role in maintaining the balance between saturated and unsaturated fatty acids in the membrane. We recently showed that FadR also activates the promoter upstream of the fabH gene (L. My, B. Rekoske, J...
June 2015: Journal of Bacteriology
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