scholarly journals Synthesis, In Silico Prediction and In Vitro Evaluation of Antimicrobial Activity, DFT Calculation and Theoretical Investigation of Novel Xanthines and Uracil Containing Imidazolone Derivatives

2021 ◽  
Vol 22 (20) ◽  
pp. 10979
Author(s):  
Samar El-Kalyoubi ◽  
Fatimah Agili ◽  
Wael A. Zordok ◽  
Ashraf S. A. El-Sayed
Keyword(s):  
Acetic Acid ◽  
Theoretical Investigation ◽  
Polyketide Synthase ◽  
Dft Calculation ◽  
Acyl Carrier Protein ◽  
Docking Study ◽  
Antibacterial Activities ◽  
Protein Domain ◽  
Type I

Novel xanthine and imidazolone derivatives were synthesized based on oxazolone derivatives 2a-c as a key intermediate. The corresponding xanthine 3-5 and imidazolone derivatives 6-13 were obtained via reaction of oxazolone derivative 2a-c with 5,6-diaminouracils 1a-e under various conditions. Xanthine compounds 3-5 were obtained by cyclocondensation of 5,6-diaminouracils 1a-c with different oxazolones in glacial acetic acid. Moreover, 5, 6-diaminouracils 1a-e were reacted with oxazolones 2a-c in presence of drops of acetic acid under fused condition yielding the imidazolone derivatives 6-13. Furthermore, Schiff base of compounds 14-16 were obtained by condensing 5, 6-diaminouracils 1a,b,e with 4-dimethylaminobenzaldehyde in acetic acid. The structural identity of the resulting compounds was resolved by IR, 1H-, 13C-NMR and Mass spectral analyses. The novel synthesized compounds were screened for their antifungal and antibacterial activities. Compounds 3, 6, 13 and 16 displayed the highest activity against Escherichia coli as revealed from the IC50 values (1.8–1.9 µg/mL). The compound 16 displayed a significant antifungal activity against Candia albicans (0.82 µg/mL), Aspergillus flavus (1.2 µg/mL) comparing to authentic antibiotics. From the TEM microgram, the compounds 3, 12, 13 and 16 exhibited a strong deformation to the cellular entities, by interfering with the cell membrane components, causing cytosol leakage, cellular shrinkage and irregularity to the cell shape. In addition, docking study for the most promising antimicrobial tested compounds depicted high binding affinity against acyl carrier protein domain from a fungal type I polyketide synthase (ACP), and Baumannii penicillin- binding protein (PBP). Moreover, compound 12 showed high drug- likeness, and excellent pharmacokinetics, which needs to be in focus for further antimicrobial drug development. The most promising antimicrobial compounds underwent theoretical investigation using DFT calculation.

Solution Structure of an Acyl Carrier Protein Domain from a Fungal Type I Polyketide Synthase,

Biochemistry ◽  
2010 ◽  
Vol 49 (10) ◽  
pp. 2186-2193 ◽  
Author(s):  
Pakorn Wattana-amorn ◽  
Christopher Williams ◽  
Eliza Płoskoń ◽  
Russell J. Cox ◽  
Thomas J. Simpson ◽  
...  
Keyword(s):  
Solution Structure ◽  
Polyketide Synthase ◽  
Acyl Carrier Protein ◽  
Protein Domain ◽  
Carrier Protein ◽  
Type I

scholarly journals Solution Structures of the Acyl Carrier Protein Domain from the Highly Reducing Type I Iterative Polyketide Synthase CalE8

PLoS ONE ◽  
2011 ◽  
Vol 6 (6) ◽  
pp. e20549 ◽  
Author(s):  
Jackwee Lim ◽  
Rong Kong ◽  
Elavazhagan Murugan ◽  
Chun Loong Ho ◽  
Zhao-Xun Liang ◽  
...  
Keyword(s):  
Polyketide Synthase ◽  
Acyl Carrier Protein ◽  
Protein Domain ◽  
Carrier Protein ◽  
Type I ◽  
Solution Structures ◽  
Iterative Polyketide Synthase

scholarly journals De Novo Design and Implementation of a Tandem Acyl Carrier Protein Domain in a Type I Modular Polyketide Synthase

2018 ◽  
Vol 13 (11) ◽  
pp. 3072-3077 ◽  
Author(s):  
Zilong Wang ◽  
Saket R. Bagde ◽  
Gerardo Zavala ◽  
Tsutomu Matsui ◽  
Xi Chen ◽  
...  
Keyword(s):  
Polyketide Synthase ◽  
De Novo ◽  
Acyl Carrier Protein ◽  
De Novo Design ◽  
Protein Domain ◽  
Carrier Protein ◽  
Type I ◽  
Design And Implementation ◽  
Modular Polyketide Synthase

scholarly journals Sticky swinging arm dynamics: studies of an acyl carrier protein domain from the mycolactone polyketide synthase

2016 ◽  
Vol 473 (8) ◽  
pp. 1097-1110 ◽  
Author(s):  
Steven Vance ◽  
Olga Tkachenko ◽  
Ben Thomas ◽  
Mona Bassuni ◽  
Hui Hong ◽  
...  
Keyword(s):  
Polyketide Synthase ◽  
Acyl Carrier Protein ◽  
Protein Domain ◽  
Carrier Protein ◽  
Protein Surface ◽  
Prosthetic Group ◽  
Polyketide Biosynthesis ◽  
Covalently Linked

When covalently linked to an acyl carrier protein (ACP) and loaded with acyl substrate-mimics, some 4′-phosphopantetheine prosthetic group arms swing freely, whereas others stick to the protein surface, suggesting a possible mode of interaction with enzyme domains during polyketide biosynthesis.

scholarly journals Modular type I polyketide synthase acyl carrier protein domains share a common N-terminally extended fold

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Luisa Moretto ◽  
Rachel Heylen ◽  
Natalie Holroyd ◽  
Steven Vance ◽  
R. William Broadhurst
Keyword(s):  
Polyketide Synthase ◽  
Acyl Carrier Protein ◽  
Protein Domains ◽  
Carrier Protein ◽  
Type I

scholarly journals Genetic Determinants of Reutericyclin Biosynthesis in Lactobacillus reuteri

2015 ◽  
Vol 81 (6) ◽  
pp. 2032-2041 ◽  
Author(s):  
Xiaoxi B. Lin ◽  
Christopher T. Lohans ◽  
Rebbeca Duar ◽  
Jinshui Zheng ◽  
John C. Vederas ◽  
...  
Keyword(s):  
Polyketide Synthase ◽  
Genomic Island ◽  
Lactobacillus Reuteri ◽  
Acyl Carrier Protein ◽  
Open Reading Frames ◽  
Protein Domain ◽  
Regulatory Proteins ◽  
Tetramic Acid ◽  
Genetic Determinants ◽  
Content Type

ABSTRACTReutericyclin is a unique antimicrobial tetramic acid produced by some strains ofLactobacillus reuteri. This study aimed to identify the genetic determinants of reutericyclin biosynthesis. Comparisons of the genomes of reutericyclin-producingL. reuteristrains with those of non-reutericyclin-producing strains identified a genomic island of 14 open reading frames (ORFs) including genes coding for a nonribosomal peptide synthetase (NRPS), a polyketide synthase (PKS), homologues of PhlA, PhlB, and PhlC, and putative transport and regulatory proteins. The protein encoded byrtcNis composed of a condensation domain, an adenylation domain likely specific ford-leucine, and a thiolation domain.rtcKcodes for a PKS that is composed of a ketosynthase domain, an acyl-carrier protein domain, and a thioesterase domain. The products ofrtcA,rtcB, andrtcCare homologous to the diacetylphloroglucinol-biosynthetic proteins PhlABC and may acetylate the tetramic acid moiety produced by RtcN and RtcK, forming reutericyclin. Deletion ofrtcNorrtcABCinL. reuteriTMW1.656 abrogated reutericyclin production but did not affect resistance to reutericyclin. Genes coding for transport and regulatory proteins could be deleted only in the reutericyclin-negativeL. reuteristrain TMW1.656ΔrtcN, and these deletions eliminated reutericyclin resistance. The genomic analyses suggest that the reutericyclin genomic island was horizontally acquired from an unknown source during a unique event. The combination of PhlABC homologues with both an NRPS and a PKS has also been identified in the lactic acid bacteriaStreptococcus mutansandLactobacillus plantarum, suggesting that the genes in these organisms and those inL. reuterishare an evolutionary origin.

scholarly journals A Mammalian Type I Fatty Acid Synthase Acyl Carrier Protein Domain Does Not Sequester Acyl Chains

2007 ◽  
Vol 283 (1) ◽  
pp. 518-528 ◽  
Author(s):  
Eliza Ploskoń ◽  
Christopher J. Arthur ◽  
Simon E. Evans ◽  
Christopher Williams ◽  
John Crosby ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Acyl Carrier Protein ◽  
Protein Domain ◽  
Carrier Protein ◽  
Type I ◽  
Acyl Chains

scholarly journals Structural and evolutionary relationships of “AT-less” type I polyketide synthase ketosynthases

2015 ◽  
Vol 112 (41) ◽  
pp. 12693-12698 ◽  
Author(s):  
Jeremy R. Lohman ◽  
Ming Ma ◽  
Jerzy Osipiuk ◽  
Boguslaw Nocek ◽  
Youngchang Kim ◽  
...  
Keyword(s):  
Amino Acid ◽  
Substrate Specificity ◽  
Polyketide Synthase ◽  
Acyl Carrier Protein ◽  
Structural Diversity ◽  
Type I ◽  
Substrate Specificities ◽  
In Trans ◽  
Canonical Type ◽  
Insight Into

Acyltransferase (AT)-less type I polyketide synthases (PKSs) break the type I PKS paradigm. They lack the integrated AT domains within their modules and instead use a discrete AT that acts in trans, whereas a type I PKS module minimally contains AT, acyl carrier protein (ACP), and ketosynthase (KS) domains. Structures of canonical type I PKS KS-AT didomains reveal structured linkers that connect the two domains. AT-less type I PKS KSs have remnants of these linkers, which have been hypothesized to be AT docking domains. Natural products produced by AT-less type I PKSs are very complex because of an increased representation of unique modifying domains. AT-less type I PKS KSs possess substrate specificity and fall into phylogenetic clades that correlate with their substrates, whereas canonical type I PKS KSs are monophyletic. We have solved crystal structures of seven AT-less type I PKS KS domains that represent various sequence clusters, revealing insight into the large structural and subtle amino acid residue differences that lead to unique active site topologies and substrate specificities. One set of structures represents a larger group of KS domains from both canonical and AT-less type I PKSs that accept amino acid-containing substrates. One structure has a partial AT-domain, revealing the structural consequences of a type I PKS KS evolving into an AT-less type I PKS KS. These structures highlight the structural diversity within the AT-less type I PKS KS family, and most important, provide a unique opportunity to study the molecular evolution of substrate specificity within the type I PKSs.

Acyl carrier protein: structure–function relationships in a conserved multifunctional protein family

2007 ◽  
Vol 85 (6) ◽  
pp. 649-662 ◽  
Author(s):  
David M. Byers ◽  
Huansheng Gong
Keyword(s):  
Fatty Acid ◽  
Active Sites ◽  
Fatty Acid Synthase ◽  
Acyl Carrier Protein ◽  
Divalent Cations ◽  
Structural Features ◽  
Carrier Protein ◽  
Type I ◽  
Prosthetic Group

Acyl carrier protein (ACP) is a universal and highly conserved carrier of acyl intermediates during fatty acid synthesis. In yeast and mammals, ACP exists as a separate domain within a large multifunctional fatty acid synthase polyprotein (type I FAS), whereas it is a small monomeric protein in bacteria and plastids (type II FAS). Bacterial ACPs are also acyl donors for synthesis of a variety of products, including endotoxin and acylated homoserine lactones involved in quorum sensing; the distinct and essential nature of these processes in growth and pathogenesis make ACP-dependent enzymes attractive antimicrobial drug targets. Additionally, ACP homologues are key components in the production of secondary metabolites such as polyketides and nonribosomal peptides. Many ACPs exhibit characteristic structural features of natively unfolded proteins in vitro, with a dynamic and flexible conformation dominated by 3 parallel α helices that enclose the thioester-linked acyl group attached to a phosphopantetheine prosthetic group. ACP conformation may also be influenced by divalent cations and interaction with partner enzymes through its “recognition” helix II, properties that are key to its ability to alternately sequester acyl groups and deliver them to the active sites of ACP-dependent enzymes. This review highlights recent progress in defining how the structural features of ACP are related to its multiple carrier roles in fatty acid metabolism.

scholarly journals Antibacterial Activities and Molecular Docking of Novel Sulfone Biscompound Containing Bioactive 1,2,3-Triazole Moiety

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4817
Author(s):  
Huda R. M. Rashdan ◽  
Ihsan A. Shehadi ◽  
Mohamad T. Abdelrahman ◽  
Bahaa A. Hemdan
Keyword(s):  
Molecular Docking ◽  
Pathogenic Bacteria ◽  
Analytical Data ◽  
Docking Study ◽  
Antibacterial Activities ◽  
Bactericidal Effect ◽  
Bacterial Strains ◽  
Molecular Docking Study ◽  
Synthetic Compound

In this study, a new synthetic 1,2,3-triazole-containing disulfone compound was derived from dapsone. Its chemical structure was confirmed using microchemical and analytical data, and it was tested for its in vitro antibacterial potential. Six different pathogenic bacteria were selected. MICs values and ATP levels were determined. Further, toxicity performance was measured using MicroTox Analyzer. In addition, a molecular docking study was performed against two vital enzymes: DNA gyrase and Dihydropteroate synthase. The results of antibacterial abilities showed that the studied synthetic compound had a strong bactericidal effect against all tested bacterial strains, as Gram-negative species were more susceptible to the compound than Gram-positive species. Toxicity results showed that the compound is biocompatible and safe without toxic impact. The molecular docking of the compound showed interactions within the pocket of two enzymes, which are able to stabilize the compound and reveal its antimicrobial activity. Hence, from these results, this study recommends that the established compound could be an outstanding candidate for fighting a broad spectrum of pathogenic bacterial strains, and it might therefore be used for biomedical and pharmaceutical applications.

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