- Deconins A-E: Cuparenic and mevalonic or propionic acid conjugates from the basidiomycete Deconica sp. 471
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Bioassay-guided fractionation of antibacterial extracts from cultures of a basidiomycete from Northern Thailand, which represents a new species of the genus Deconica, yielded the terpenoid deconin A (1), whose structure was elucidated by spectral methods (NMR, HRMS) as a cuparenic/mevalonic acid conjugate. The absolute configuration of 1 was determined after saponification and comparison of specific rotations of the resulting cuparenic acid and mevalonolactone with authentic standards and literature data. Six minor congeners (2-7) were isolated and identified, and their antimicrobial and cytotoxic effects are reported. Compounds 1-4 are the first natural products featuring an unmodified mevalonic acid residue as a building block.
- Surup, Frank,Thongbai, Benjarong,Kuhnert, Eric,Sudarman, Enge,Hyde, Kevin D.,Stadler, Marc
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Read Online
- Donor Promiscuity of a Thermostable Transketolase by Directed Evolution: Efficient Complementation of 1-Deoxy-d-xylulose-5-phosphate Synthase Activity
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Enzymes catalyzing asymmetric carboligation reactions typically show very high substrate specificity for their nucleophilic donor substrate components. Structure-guided engineering of the thermostable transketolase from Geobacillus stearothermophilus by directed in vitro evolution yielded new enzyme variants that are able to utilize pyruvate and higher aliphatic homologues as nucleophilic components for acyl transfer instead of the natural polyhydroxylated ketose phosphates or hydroxypyruvate. The single mutant H102T proved the best hit toward 3-methyl-2-oxobutyrate as donor, while the double variant H102L/H474S showed highest catalytic efficiency toward pyruvate as donor. The latter variant was able to complement the auxotrophic deficiency of Escherichia coli cells arising from a deletion of the dxs gene, which encodes for activity of the first committed step into the terpenoid biosynthesis, offering the chance to employ a growth selection test for further enzyme optimization.
- Saravanan, Thangavelu,Junker, Sebastian,Kickstein, Michael,Hein, Sascha,Link, Marie-Kristin,Ranglack, Jan,Witt, Samantha,Lorillière, Marion,Hecquet, Laurence,Fessner, Wolf-Dieter
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supporting information
p. 5358 - 5362
(2017/04/27)
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- Synthesis of mevalonate- and fluorinated mevalonate prodrugs and their in vitro human plasma stability
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The mevalonate pathway is essential for the production of many important molecules in lipid biosynthesis. Inhibition of this pathway is the mechanism of statin cholesterol-lowering drugs, as well as the target of drugs to treat osteoporosis, to combat parasites, and to inhibit tumor cell growth. Unlike the human mevalonate pathway, the bacterial pathway appears to be regulated by diphosphomevalonate (DPM). Enzymes in the mevalonate pathway act to produce isopentenyl diphosphate, the product of the DPM decarboxylase reaction, utilize phosphorylated (charged) intermediates, which are poorly bioavailable. It has been shown that fluorinated DPMs (6-fluoro- and 6,6,6-trifluoro-5-diphosphomevalonate) are excellent inhibitors of the bacterial pathway; however, highly charged DPM and analogs are not bioavailable. To increase cellular permeability of mevalonate analogs, we have synthesized various prodrugs of mevalonate and 6-fluoro- and 6,6,6-trifluoromevalonate that can be enzymatically transformed to the corresponding DPM or fluorinated DPM analogs by esterases or amidases. To probe the required stabilities as potentially bioavailable prodrugs, we measured the half-lives of esters, amides, carbonates, acetals, and ketal promoieties of mevalonate and the fluorinated mevalonate analogs in human blood plasma. Stability studies showed that the prodrugs are converted to the mevalonates in human plasma with a wide range of half-lives. These studies provide stability data for a variety of prodrug options having varying stabilities and should be very useful in the design of appropriate prodrugs of mevalonate and fluorinated mevalonates.
- Kang, Soosung,Watanabe, Mizuki,Jacobs,Yamaguchi, Masaya,Dahesh, Samira,Nizet, Victor,Leyh, Thomas S.,Silverman, Richard B.
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p. 448 - 461
(2015/04/16)
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- Process For The Production Of Isoprenol From Mevalonate Employing a Diphosphomevalonate Decarboxylae
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Described is a method for the enzymatic production of isoprenol using mevalonate as a substrate and enzymatically converting it by a decarboxylation step into isoprenol as well as the use of an enzyme which is capable of catalyzing the decarboxylation of mevalonate for the production of isoprenol from mevalonate. Furthermore described is the use of mevalonate as a starting material for the production of isoprenol in an enzymatically catalysed reaction. Also disclosed is a method for the production of isoprene comprising the method for the production of isoprenol using mevalonate as a substrate and enzymatically converting it by a decarboxylation step into isoprenol and further comprising the step of converting the produced isoprenol into isoprene as well as a method for the production of isoamyl alcohol comprising the method for the production of isoprenol using mevalonate as a substrate and enzymatically converting it by a decarboxylation step into isoprenol and further comprising the step of converting the produced isoprenol into isoamyl alcohol.
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Paragraph 0103
(2016/03/04)
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- Synthesis of mevalonate-and fluorinated mevalonate prodrugs and their in vitro human plasma stability
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The mevalonate pathway is essential for the production of many important molecules in lipid biosynthesis. Inhibition of this pathway is the mechanism of statin cholesterol-lowering drugs, as well as the target of drugs to treat osteoporosis, to combat parasites, and to inhibit tumor cell growth. Unlike the human mevalonate pathway, the bacterial pathway appears to be regulated by diphosphomevalonate (DPM). Enzymes in the mevalonate pathway act to produce isopentenyl diphosphate, the product of the DPM decarboxylase reaction, utilize phosphorylated (charged) intermediates, which are poorly bioavailable. It has been shown that fluorinated DPMs (6-fluoro-and 6,6,6-trifluoro-5-diphosphomevalonate) are excellent inhibitors of the bacterial pathway; however, highly charged DPM and analogs are not bioavailable. To increase cellular permeability of mevalonate analogs, we have synthesized various prodrugs of mevalonate and 6-fluoro-and 6,6,6-trifluoromevalonate that can be enzymatically transformed to the corresponding DPM or fluorinated DPM analogs by esterases or amidases. To probe the required stabilities as potentially bioavailable prodrugs, we measured the half-lives of esters, amides, carbonates, acetals, and ketal promoieties of mevalonate and the fluorinated mevalonate analogs in human blood plasma. Stability studies showed that the prodrugs are converted to the mevalonates in human plasma with a wide range of half-lives. These studies provide stability data for a variety of prodrug options having varying stabilities and should be very useful in the design of appropriate prodrugs of mevalonate and fluorinated mevalonates.
- Kang, Soosung,Watanabe, Mizuki,Jacobs,Yamaguchi, Masaya,Dahesh, Samira,Nizet, Victor,Leyh, Thomas S.,Silverman, Richard B.
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p. 448 - 461
(2016/10/19)
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- COMPOSITIONS AND METHODS FOR PRODUCING ISOPRENE FREE OF C5 HYDROCARBONS UNDER DECOUPLING CONDITIONS AND/OR SAFE OPERATING RANGES
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The invention features methods for producing isoprene from cultured cells wherein the cells in the stationary phase. The invention also provides compositions that include these cultured cells and/or increased amount of isoprene. The invention also provides for systems that include a non-flammable concentration of isoprene in the gas phase. Additionally, the invention provides isoprene compositions, such as compositions with increased amount of isoprene or increased purity.
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- CONVERSION OF PRENYL DERIVATIVES TO ISOPRENE
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The present invention provides methods for producing derivatives from cultured cells. In addition, the present invention provides methods for conversion of prenyl deerivatives, obtained from biological or petrochemical sources, to isoprene by employing chemical or biological catalysts. The present invention also provides compositions that include the cultured cells or isoprene or prenyl derivatives produced there from.
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- 3-Trehalosamine compounds
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Novel antibiotic 3-trehalosamine (U-59,834) producible in a fermentation under controlled conditions using the new microorganism Nocardiopsis trehalosei sp. nov., NRRL 12026. This antibiotic is active against Gram-positive bacteria, for example, Staphylococcus aureus, Bacillus subtilis, and Diplococcus pneumoniae. Thus, 3-trehalosamine can be used in various environments to eradicate or control such bacteria. Antibiotic 3-trehalosamine can be shown by the following structural formula: STR1
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- Antibiotic 354 and process for producing same
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Novel antibiotic 354 (U-54,703) producible in a fermentation under controlled conditions using the new microorganism Streptomyces puniceus subsp. doliceus, NRRL 11160. This antibiotic is active against Gram-negative bacteria, for example, Pseudomonas and Proteus species. Thus, antibiotic 354 can be used in various environments to eradicate or control such bacteria.
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- Composition of matter and process
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Novel antibiotic formulations of antibiotic 354 (U-54,703) and their use in treating susceptible infectious disease in humans and animals.
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- Aminoglycoside antibiotics
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6-0- AND 3'-0-D-glycosyl analogs of 4-0-(α-D-glycosyl)-2-deoxystreptamine, 6-0- and 3'-0-D-glycosyl ortho esters of 4-0-(α-D-glycosyl)-2-deoxystreptamine, novel aminoglycoside antibiotics, and novel intermediates are prepared by a new chemical process. The compounds have utility as antibacterial agents or as intermediates to make antibacterially-active compounds.
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