1190-73-4Relevant academic research and scientific papers
Synthesis of HIV-1 capsid protein assembly inhibitor (CAP-1) and its analogues based on a biomass approach
Romashov, Leonid V.,Ananikov, Valentine P.
, p. 10593 - 10598 (2016)
A biomass-derived platform chemical was utilized to access a demanded pharmaceutical substance with anti-HIV activity (HIV, human immunodeficiency virus) and a variety of structural analogues. Step economy in the synthesis of the drug core (single stage from cellulose) is studied including flexible variability of four structural units. The first synthesis and X-ray structure of the inhibitor of HIV-1 capsid protein assembly (CAP-1) is described.
Coenzyme A hemithioacetals as easily prepared inhibitors of CoA ester-utilizing enzymes
Schwartz, Benjamin,Vogel, Kurt W.,Drueckhammer, Dale G.
, p. 9356 - 9361 (1996)
Hemithioacetals are formed by reactions of coenzyme A (CoA) with aldehydes in aqueous solution. Equilibria for hemithioacetal formation with four commercially available aldehydes and rate constants for hemithioacetal dissociation have been studied. The hemithioacetals are viewed as acyl-CoA analogs having a tetrahedral center in place of the planar trigonal thioester carbonyl carbon. These compounds may serve as mimics of the tetrahedral intermediate or transition state in the reactions of acyl-CoA dependent acyltransferase enzymes. The hemithioacetal generated by reaction of CoA with formaldehyde is a poor inhibitor of chloramphenicol acetyltransferase, with a K(i) more than 6-fold higher than the K(m) for the substrate acetyl-CoA. The hemithioacetals formed by reaction of CoA with acetaldehyde and trifluroacetaldehyde are substantially better inhibitors, with K(i) values approximately 2.4-fold and 10-fold lower than the K(m) values for acetyl-CoA, respectively. The hemithioacetal formed by reaction of CoA with succinic semialdehyde inhibits succinic thiokinase, with a K(i) 4-fold lower than the K(m) for the substrate succinyl-CoA. The CoA hemithioacetals provide a novel readily accessible new class of acyl-CoA analogs for use in mechanistic and structural studies of CoA ester-utilizing enzymes.
Formicins, N-Acetylcysteamine-Bearing Indenone Thioesters from a Wood Ant-Associated Bacterium
Byun, Woong Sub,Du, Young Eun,Hong, Suckchang,Hwang, Sunghoon,Jang, Yong-Joon,Lee, Sang Kook,Lee, Seok Beom,Oh, Dong-Chan,Shin, Bora,Shin, Jongheon,Shin, Yern-Hyerk
, (2020)
Formicins A-C (1-3) were discovered from Streptomyces sp. associated with wood ants. The structures of 1 and 2 were elucidated as indenone thioesters bearing N-acetylcysteamine based on spectroscopic analysis. The configurations of 1-3 were determined by the analysis of ROESY correlations, the phenylglycine methyl ester method, and chemical derivatization from 3 to 2. Formicin A inhibited the growth of human triple-negative breast cancer cells by regulating the liver kinase B1-mediated AMPK signaling pathway.
Step-Economic Synthesis of Biomimetic β-Ketopolyene Thioesters and Demonstration of Their Usefulness in Enzymatic Biosynthesis Studies
Hahn, Frank,Ro?, Theresa,Schr?der, Marius,Wunderlich, Johannes
, (2020)
Studies on the biosynthetic processing of polyene thioester intermediates are complicated by limited access to appropriate substrate surrogates. We present a step-economic synthetic access to biomimetic β-ketopolyene thioesters that is based on an Ir-catalyzed reductive Horner-Wadsworth-Emmons olefination. New β-ketotriene and pentaenethioates of pantetheine and N-acetylcysteamine were exemplarily synthesized via short and concise routes. The usefulness of these compounds was demonstrated in an in vitro assay with the ketoreductase domain MycKRB from mycolactone biosynthesis.
Biosynthetic Studies of Brevetoxins, Potent Neurotoxins Produced by the Dinoflagellate Gymnodinium breve
Lee, Min S.,Qin, Guo-wei,Nakanishi, Koji,Zagorski, Michael G.
, p. 6234 - 6241 (1989)
Blooms of the dinoflegellate Gymnodinium breve (Ptychodiscus brevis) commonly known as "red tide" have led to massive fish kills, mollusk contamination, and human food intoxications along the Florida coast and the Gulf of Mexico.The toxins from G. breve responsible for these phenomena are the brevetoxins (BTX's), a group of potent neurotoxins with polycyclic trans-fused ether rings which presumably depolarize the sodium channels of the excitable membranes.BTX-B, C50H70O14, the first of these neurotoxins whose structure was elucidated, has an unprecedented structure consisting of 6/6/6/7/7/6/6/8/6/6/6 ether rings trans-fused in a ladder-like manner.Another member of these toxins, BTX-A, C49H70O13, has another remarkable structure consisting of trans-fused 5/8/6/7/9/6/6/6 ether rings.Although the carbon skeletons of BTX-B and BTX-A are different, both consist of a single carbon chain that is polyoxygenated with methyl substituent groups.This is consistent with polyketide biosynthesis, i.e., condensation of acetate units with the methyl groups originating from either S-adenosylmethionine or propionate.Labeling experiments using sodium - and acetate and methionine demonstrate that the labeling patterns of BTX-B and BTX-A are similar and that the biosynthesis of brevetoxins is not of simple polyketide origin.These labeling studies suggest that the citric acid cycle is involved in the biosynthetis of BTX-B and BTX-A, the degree of its involvement being unusually high.Furthermore, CO2 participates in a unique manner in the biosynthesis of C-1 of BTX-B and BTX-A.
Identification of crucial bottlenecks in engineered polyketide biosynthesis
Grote, Marius,Kushnir, Susanna,Pryk, Niclas,M?ller, David,Erver, Julian,Ismail-Ali, Ahmed,Schulz, Frank
, p. 6374 - 6385 (2019)
The concept of combinatorial biosynthesis promises access to compound libraries based on privileged natural scaffolds. Ever since the elucidation of the biosynthetic pathway towards the antibiotic erythromycin A in 1990, the predictable manipulation of type I polyketide synthase megaenzymes was investigated. However, this goal was rarely reached beyond simplified model systems. In this study, we identify the intermediates in the biosynthesis of the polyether monensin and numerous mutated variants using a targeted metabolomics approach. We investigate the biosynthetic flow of intermediates and use the experimental setup to reveal the presence of selectivity filters in polyketide synthases. These obstruct the processing of non-native intermediates in the enzymatic assembly line. Thereby we question the concept of a truly modular organization of polyketide synthases and highlight obstacles in substrate channeling along the cascade. In the search for the molecular origin of a selectivity filter, we investigate the role of different thioesterases in the monensin gene cluster and the connection between ketosynthase sequence motifs and incoming substrate structures. Furthermore, we demonstrate that the selectivity filters do not apply to new-to-nature side-chains in nascent polyketides, showing that the acceptance of these is not generally limited by downstream modules.
Functional characterization of an NADPH dependent 2-alkyl-3-ketoalkanoic acid reductase involved in olefin biosynthesis in stenotrophomonas maltophilia
Bonnett, Shilah A.,Papireddy, Kancharla,Higgins, Samuel,Del Cardayre, Stephen,Reynolds, Kevin A.
, p. 9633 - 9640 (2011)
OleD is shown to play a key reductive role in the generation of alkenes (olefins) from acyl thioesters in Stenotrophomonas maltophilia. The gene coding for OleD clusters with three other genes, oleABC, and all appear to be transcribed in the same direction as an operon in various olefin producing bacteria. In this study, a series of substrates varying in chain length and stereochemistry were synthesized and used to elucidate the functional role and substrate specificity of OleD. We demonstrated that OleD, which is an NADP(H) dependent reductase, is a homodimer which catalyzes the reversible stereospecific reduction of 2-alkyl-3-ketoalkanoic acids. Maximal catalytic efficiency was observed with syn-2-decyl-3-hydroxytetradecanoic acid, with a kcat/Km 5- and 8-fold higher than for syn-2-octyl-3- hydroxydodecanoic acid and syn-2-hexyl-3-hydroxydecanoic acid, respectively. OleD activity was not observed with syn-2-butyl-3-hydroxyoctanoic acid and compounds lacking a 2-alkyl group such as 3-ketodecanoic and 3-hydroxydecanoic acids, suggesting the necessity of the 2-alkyl chain for enzyme recognition and catalysis. Using diastereomeric pairs of substrates and 4 enantiopure isomers of 2-hexyl-3-hydroxydecanoic acid of known stereochemistry, OleD was shown to have a marked stereochemical preference for the (2R,3S)-isomer. Finally, experiments involving OleA and OleD demonstrate the first 3 steps and stereochemical course in olefin formation from acyl thioesters; condensation to form a 2-alkyl-3-ketoacyl thioester, subsequent thioester hydrolysis, and ketone reduction.
Preprogramming Complex Hydrogel Responses using Enzymatic Reaction Networks
Postma, Sjoerd G. J.,Vialshin, Ilia N.,Gerritsen, Casper Y.,Bao, Min,Huck, Wilhelm T. S.
, p. 1794 - 1798 (2017)
The creation of adaptive matter is heavily inspired by biological systems. However, it remains challenging to design complex material responses that are governed by reaction networks, which lie at the heart of cellular complexity. The main reason for this slow progress is the lack of a general strategy to integrate reaction networks with materials. Herein we use a systematic approach to preprogram the response of a hydrogel to a trigger, in this case the enzyme trypsin, which activates a reaction network embedded within the hydrogel. A full characterization of all the kinetic rate constants in the system enabled the construction of a computational model, which predicted different hydrogel responses depending on the input concentration of the trigger. The results of the simulation are in good agreement with experimental findings. Our methodology can be used to design new, adaptive materials of which the properties are governed by reaction networks of arbitrary complexity.
The biosynthesis of pramanicin in Stagonospom sp. ATCC 74235: A modified acyltetramic acid
Harrison, Paul H.M.,Duspara, Petar A.,Jenkins, Stephen I.,Kassam, Salima A.,Liscombe, David K.,Hughes, Donald W.
, p. 4390 - 4402 (2000)
Biosynthetic incorporations of acetate, malonate and serine precursors which had been isotopically labelled with 2H, 13C, 15N and 18O into pramanicin 1 in Stagonospora sp. ATCC 74235 were demonstrated. Intact incorporation of a starter acetate and six extender malonates generates the acyclic, hydrophobic tail. A further intact acetate, in preference to malonate, and a serine entity which is incorporated only as the L-enantiomer and with the O=C-CH(N)-CH2 entity intact, provide the pyrrolidone ring and hydroxymethyl group of 1. The results are fully consistent with a biosynthetic pathway involving an acyltetramic acid (2). The olefinic precursor 3 of the epoxide in 1 is described, and is also shown to co-occur in the cultures. The ratio of 1:3 can be controlled by addition of precursors. The Royal Society of Chemistry 2000.
Enzymatic extender unit generation for in vitro polyketide synthase reactions: Structural and functional showcasing of Streptomyces coelicolor MatB
Hughes, Amanda J.,Keatinge-Clay, Adrian
, p. 165 - 176 (2011)
In vitro experiments with modular polyketide synthases (PKSs) are often limited by the availability of polyketide extender units. To determine the polyketide extender units that can be biocatalytically accessed via promiscuous malonyl-CoA ligases, structural and functional studies were conducted on Streptomyces coelicolor MatB. We demonstrate that this adenylate-forming enzyme is capable of producing most CoA-linked polyketide extender units as well as pantetheine- and N-acetylcysteamine-linked analogs useful for in vitro PKS studies. Two ternary product complex structures, one containing malonyl-CoA and AMP and the other containing (2R)-methylmalonyl-CoA and AMP, were solved to 1.45 A and 1.43 A resolution, respectively. MatB crystallized in the thioester-forming conformation, making extensive interactions with the bound extender unit products. This first structural characterization of an adenylate-forming enzyme that activates diacids reveals the molecular details for how malonate and its derivatives are accepted. The orientation of the α-methyl group of bound (2R)-methylmalonyl-CoA, indicates that it is necessary to epimerize α-substituted extender units formed by MatB before they can be accepted by PKS acyltransferase domains. We demonstrate the in vitro incorporation of methylmalonyl groups ligated by MatB to CoA, pantetheine, or N-acetylcysteamine into a triketide pyrone by the terminal module of the 6-deoxyerythronolide B synthase. Additionally, a means for quantitatively monitoring certain in vitro PKS reactions using MatB is presented.
