scholarly journals Tri-Cyclic Nucleobase Analogs and their Ribosides as Substrates of Purine-Nucleoside Phosphorylases. II Guanine and Isoguanine Derivatives

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1493 ◽  
Author(s):  
Stachelska-Wierzchowska ◽  
Wierzchowski ◽  
Górka ◽  
Bzowska ◽  
Wielgus-Kutrowska
Keyword(s):  
Nucleoside Analogs ◽  
Purine Nucleoside ◽  
Moderate Activity ◽  
Wild Type ◽  
E Coli ◽  
Single Compound ◽  
Neutral Aqueous Medium ◽  
Nucleoside Phosphorylases ◽  
Derivatives Of ◽  
Modest Activity

Etheno-derivatives of guanine, O6-methylguanine, and isoguanine were prepared and purified using standard methods. The title compounds were examined as potential substrates of purine-nucleoside phosphorylases from various sources in the reverse (synthetic) pathway. It was found that 1,N2-etheno-guanine and 1,N6-etheno-isoguanine are excellent substrates for purine-nucleoside phosphorylase (PNP) from E. coli, while O6-methyl-N2,3-etheno-guanine exhibited moderate activity vs. this enzyme. The latter two compounds displayed intense fluorescence in neutral aqueous medium, and so did the corresponding ribosylation products. By contrast, PNP from calf spleens exhibited only modest activity towards 1,N6-etheno-isoguanine; the remaining compounds were not ribosylated by this enzyme. The enzymatic ribosylation of 1,N6-etheno-isoguanine using two forms of calf PNP (wild type and N243D) and E. coli PNP (wild type and D204N) gave three different products, which were identified on the basis of NMR analysis and comparison with the product of the isoguanosine reaction with chloroacetic aldehyde, which gave an essentially single compound, identified unequivocally as N9-riboside. With the wild-type E. coli enzyme as a catalyst, N9--d- and N7--d-ribosides are obtained in proportion ~1:3, while calf PNP produced another riboside, tentatively identified as N6--d-riboside. The potential application of various forms of PNP for synthesis of the tri-cyclic nucleoside analogs is discussed.

scholarly journals Tricyclic Nucleobase Analogs and Their Ribosides as Substrates and Inhibitors of Purine-Nucleoside Phosphorylases III. Aminopurine Derivatives

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 681 ◽  
Author(s):  
Alicja Stachelska-Wierzchowska ◽  
Jacek Wierzchowski ◽  
Michał Górka ◽  
Agnieszka Bzowska ◽  
Ryszard Stolarski ◽  
...  
Keyword(s):  
Enzymatic Synthesis ◽  
Purine Nucleoside Phosphorylase ◽  
Major Product ◽  
Purine Nucleoside ◽  
Fluorescent Product ◽  
E Coli ◽  
Purine Analogs ◽  
Mammalian Enzyme ◽  
Nucleoside Phosphorylases ◽  
Derivatives Of

Etheno-derivatives of 2-aminopurine, 2-aminopurine riboside, and 7-deazaadenosine (tubercidine) were prepared and purified using standard methods. 2-Aminopurine reacted with aqueous chloroacetaldehyde to give two products, both exhibiting substrate activity towards bacterial (E. coli) purine-nucleoside phosphorylase (PNP) in the reverse (synthetic) pathway. The major product of the chemical synthesis, identified as 1,N2-etheno-2-aminopurine, reacted slowly, while the second, minor, but highly fluorescent product, reacted rapidly. NMR analysis allowed identification of the minor product as N2,3-etheno-2-aminopurine, and its ribosylation product as N2,3-etheno-2-aminopurine-N2-β-d-riboside. Ribosylation of 1,N2-etheno-2-aminopurine led to analogous N2-β-d-riboside of this base. Both enzymatically produced ribosides were readily phosphorolysed by bacterial PNP to the respective bases. The reaction of 2-aminopurine-N9-β -d-riboside with chloroacetaldehyde gave one major product, clearly distinct from that obtained from the enzymatic synthesis, which was not a substrate for PNP. A tri-cyclic 7-deazaadenosine (tubercidine) derivative was prepared in an analogous way and shown to be an effective inhibitor of the E. coli, but not of the mammalian enzyme. Fluorescent complexes of amino-purine analogs with E. coli PNP were observed.

scholarly journals Enzymatic synthesis and phosphorolysis of 4(2)-thioxo- and 6(5)-azapyrimidine nucleosides by E. coli nucleoside phosphorylases

2016 ◽  
Vol 12 ◽  
pp. 2588-2601 ◽  
Author(s):  
Vladimir A Stepchenko ◽  
Anatoly I Miroshnikov ◽  
Frank Seela ◽  
Igor A Mikhailopulo
Keyword(s):  
Purine Nucleoside Phosphorylase ◽  
Reaction Conditions ◽  
E Coli ◽  
No Formation ◽  
Structural Peculiarities ◽  
Substrate Properties ◽  
Nucleoside Phosphorylases ◽  
Derivatives Of

The trans-2-deoxyribosylation of 4-thiouracil (4SUra) and 2-thiouracil (2SUra), as well as 6-azauracil, 6-azathymine and 6-aza-2-thiothymine was studied using dG and E. coli purine nucleoside phosphorylase (PNP) for the in situ generation of 2-deoxy-α-D-ribofuranose-1-phosphate (dRib-1P) followed by its coupling with the bases catalyzed by either E. coli thymidine (TP) or uridine (UP) phosphorylases. 4SUra revealed satisfactory substrate activity for UP and, unexpectedly, complete inertness for TP; no formation of 2’-deoxy-2-thiouridine (2SUd) was observed under analogous reaction conditions in the presence of UP and TP. On the contrary, 2SU, 2SUd, 4STd and 2STd are good substrates for both UP and TP; moreover, 2SU, 4STd and 2’-deoxy-5-azacytidine (Decitabine) are substrates for PNP and the phosphorolysis of the latter is reversible. Condensation of 2SUra and 5-azacytosine with dRib-1P (Ba salt) catalyzed by the accordant UP and PNP in Tris∙HCl buffer gave 2SUd and 2’-deoxy-5-azacytidine in 27% and 15% yields, respectively. 6-Azauracil and 6-azathymine showed good substrate properties for both TP and UP, whereas only TP recognizes 2-thio-6-azathymine as a substrate. 5-Phenyl and 5-tert-butyl derivatives of 6-azauracil and its 2-thioxo derivative were tested as substrates for UP and TP, and only 5-phenyl- and 5-tert-butyl-6-azauracils displayed very low substrate activity. The role of structural peculiarities and electronic properties in the substrate recognition by E. coli nucleoside phosphorylases is discussed.

scholarly journals MurF Inhibitors with Antibacterial Activity: Effect on Muropeptide Levels

2009 ◽  
Vol 53 (8) ◽  
pp. 3240-3247 ◽  
Author(s):  
Ellen Z. Baum ◽  
Steven M. Crespo-Carbone ◽  
Barbara D. Foleno ◽  
Lee D. Simon ◽  
Jerome Guillemont ◽  
...  
Keyword(s):  
Cell Wall ◽  
Pharmacophore Model ◽  
Polymyxin B ◽  
Bacterial Survival ◽  
Wild Type ◽  
E Coli ◽  
Gram Positive Bacteria ◽  
Activity Effect ◽  
Modest Activity

ABSTRACT MurF catalyzes the last cytoplasmic step of bacterial cell wall synthesis and is essential for bacterial survival. Our previous studies used a pharmacophore model of a MurF inhibitor to identify additional inhibitors with improved properties. We now present the characterization of two such inhibitors, the diarylquinolines DQ1 and DQ2. DQ1 inhibited Escherichia coli MurF (50% inhibitory concentration, 24 μM) and had modest activity (MICs, 8 to 16 μg/ml) against lipopolysaccharide (LPS)-defective E. coli and wild-type E. coli rendered permeable with polymyxin B nonapeptide. DQ2 additionally displayed activity against gram-positive bacteria (MICs, 8 to 16 μg/ml), including methicillin (meticillin)-susceptible and -resistant Staphylococcus aureus isolates and vancomycin-susceptible and -resistant Enterococcus faecalis and Enterococcus faecium isolates. Treatment of LPS-defective E. coli cells with ≥2× MIC of DQ1 resulted in a 75-fold-greater accumulation of the MurF substrate compared to the control, a 70% decline in the amount of the MurF product, and eventual cell lysis, consistent with the inhibition of MurF within bacteria. DQ2 treatment of S. aureus resulted in similar effects on the MurF substrate and product quantities. At lower levels of DQ1 (≤1× MIC), the level of accumulation of the substrate was less pronounced (15-fold greater compared to the amount for the control). However, a 50% increase in the amount of the MurF product compared to the control was reproducibly observed, consistent with the possible upregulation of muropeptide biosynthesis upon partial inhibition of this pathway. The overexpression of cloned MurF appeared to partly alleviate the DQ1-mediated inhibition of muropeptide synthesis. The identification of MurF inhibitors such as DQ1 and DQ2 that disrupt cell wall biosynthesis suggests that MurF remains a viable target for an antibacterial agent.

scholarly journals SYNTHESIS CHARACTERIZATION AND ANTIMICROBIAL ACTIVITIES STUDIES OF N-{2-(4-CHLOROPHENYL) ACETYL} AMINO ALCOHOLS DERIVED FROM α-AMINO ACIDS

2020 ◽  
pp. 11-16
Author(s):  
G. Venkateshappa ◽  
G. Shivaraju ◽  
P. Raghavendra Kumar
Keyword(s):  
Amino Acids ◽  
Amino Alcohols ◽  
Antimicrobial Activities ◽  
Docking Studies ◽  
Moderate Activity ◽  
E Coli ◽  
Synthetic Drugs ◽  
Antimicrobial Studies ◽  
Ft Ir ◽  
Derivatives Of

Amino acids play important roles in organisms to sustain in living state and perform as body constituents, enzymes and antibodies. At insalubrious situations, use of amino acids derivatives as drugs in the maintenance of normal health is better choice than common unnatural synthetic drugs. This is due to the fact that the amino acids derivatives may be more bio-compatible, biodegradable and eliminate easily than others.  In this sense we have made an effort and report herein the synthesis of N-{2-(4-chlorophenyl) acetyl} amino alcohols synthesised by reduction of N-{2-(4-chlorophenyl)acetyl} derivatives of (S)-amino acids such as (S)-phenylalanine, (S)-alanine, (S)-methionine, (S)-leucine, (S)-tryptophan and (S)-proline. These newly synthesized amino acids derivatives were analysed by proton, carbon-13 NMR and FT-IR spectroscopy. The composition of solid derivatives was determined by elemental analysis. Further, antimicrobial activities of these derivatives were assessed on usual bacteria K. aerogenes, E. coli, S. aureus and P. desmolyticum and fungi A. flavus and C. albicans. The compounds were witnessed moderate activity than authorised antibacterial and fungal agents Ciprofloxacin and Fluconazole respectively. The antimicrobial studies also revealed that, these derivatives could be better antifungal agents than antibacterial agents. Finally we compared the experimental results of antimicrobial activities with docking studies.  

scholarly journals Structure of E. coli 5′-methylthioadenosine/S-adenosylhomocysteine Nucleosidase Reveals Similarity to the Purine Nucleoside Phosphorylases

Structure ◽  
2001 ◽  
Vol 9 (10) ◽  
pp. 941-953 ◽  
Author(s):  
Jeffrey E. Lee ◽  
Kenneth A. Cornell ◽  
Michael K. Riscoe ◽  
P.Lynne Howell
Keyword(s):  
Purine Nucleoside ◽  
E Coli ◽  
Nucleoside Phosphorylases

DESIGN AND EVALUATION OF 5′-MODIFIED NUCLEOSIDE ANALOGS AS PRODRUGS FOR AN E. COLI PURINE NUCLEOSIDE PHOSPHORYLASE MUTANT

2005 ◽  
Vol 24 (5-7) ◽  
pp. 387-392 ◽  
Author(s):  
William B. Parker ◽  
Paula W. Allan ◽  
Steve E. Ealick ◽  
Eric J. Sorscher ◽  
Abdalla E. A. Hassan ◽  
...  
Keyword(s):  
Purine Nucleoside Phosphorylase ◽  
Nucleoside Analogs ◽  
Purine Nucleoside ◽  
Nucleoside Phosphorylase ◽  
E Coli ◽  
Modified Nucleoside

Haloanilino Derivatives of Pyrimidines, Purines, and Purine Nucleoside Analogs: Synthesis and Activity against Human Cytomegalovirus

1995 ◽  
Vol 38 (10) ◽  
pp. 1811-1819 ◽  
Author(s):  
Maria Medveczky ◽  
Te-Fang Yang ◽  
Joseph Gambino ◽  
Peter Medveczky ◽  
George E. Wright
Keyword(s):  
Human Cytomegalovirus ◽  
Nucleoside Analogs ◽  
Purine Nucleoside ◽  
Derivatives Of

scholarly journals Efficient Synthesis of Purine Nucleoside Analogs by a New Trimeric Purine Nucleoside Phosphorylase from Aneurinibacillus migulanus AM007

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 100
Author(s):  
Gaofei Liu ◽  
Tiantong Cheng ◽  
Jianlin Chu ◽  
Sui Li ◽  
Bingfang He
Keyword(s):  
Purine Nucleoside Phosphorylase ◽  
Nucleoside Analogs ◽  
Industrial Applications ◽  
Purine Nucleoside ◽  
Initial Activity ◽  
One Pot ◽  
Purine Base ◽  
Nucleoside Phosphorylase ◽  
Pyrimidine Nucleoside Phosphorylase ◽  
Nucleoside Phosphorylases

Purine nucleoside phosphorylases (PNPs) are promising biocatalysts for the synthesis of purine nucleoside analogs. Although a number of PNPs have been reported, the development of highly efficient enzymes for industrial applications is still in high demand. Herein, a new trimeric purine nucleoside phosphorylase (AmPNP) from Aneurinibacillus migulanus AM007 was cloned and heterologously expressed in Escherichia coli BL21(DE3). The AmPNP showed good thermostability and a broad range of pH stability. The enzyme was thermostable below 55 °C for 12 h (retaining nearly 100% of its initial activity), and retained nearly 100% of the initial activity in alkaline buffer systems (pH 7.0–9.0) at 60 °C for 2 h. Then, a one-pot, two-enzyme mode of transglycosylation reaction was successfully constructed by combining pyrimidine nucleoside phosphorylase (BbPyNP) derived from Brevibacillus borstelensis LK01 and AmPNP for the production of purine nucleoside analogs. Conversions of 2,6-diaminopurine ribonucleoside (1), 2-amino-6-chloropurine ribonucleoside (2), and 6-thioguanine ribonucleoside (3) synthesized still reached >90% on the higher concentrations of substrates (pentofuranosyl donor: purine base; 20:10 mM) with a low enzyme ratio of BbPyNP: AmPNP (2:20 μg/mL). Thus, the new trimeric AmPNP is a promising biocatalyst for industrial production of purine nucleoside analogs.

scholarly journals Crystal structures of a new class of pyrimidine/purine nucleoside phosphorylase (ppnP) revealed a Cupin fold

2021 ◽  
Author(s):  
Yan Wen ◽  
Xiaojia Li ◽  
Wenting Guo ◽  
Baixing Wu
Keyword(s):  
Crystal Structures ◽  
Purine Nucleoside Phosphorylase ◽  
Binding Pocket ◽  
Purine Nucleoside ◽  
Structural Basis ◽  
Nucleoside Phosphorylase ◽  
E Coli ◽  
New Class ◽  
Nucleoside Phosphorylases ◽  
Pocket Formation

Nucleotides metabolism is a fundamental process in all organisms. Two families of nucleoside phosphorylases (NP) that catalyze the phosphorolytic cleavage of the glycosidic bond in nucleosides have been found, including the trimeric or hexameric NP-I and dimeric NP-II family enzymes. Recently studies revealed another class of NP protein in E. coli named Pyrimidine/purine nucleoside phosphorylase (ppnP), which can catalyze the phosphorolysis of diverse nucleosides and yield D-ribose 1-phosphate and the respective free bases. Here, we solve the crystal structures of ppnP from E. coli and the other three species. Our studies revealed that the structure of ppnP belongs to the Rlmc-like cupin fold and showed as a rigid dimeric conformation. Detail analysis revealed a potential nucleoside binding pocket full of hydrophobic residues. And the residues involved in the dimer and pocket formation are all well conserved in bacteria. Since the cupin fold is a large superfamily in the biosynthesis of natural products, our studies provide the structural basis for understanding and the directed evolution of NP proteins.

Sign in / Sign up

Export Citation Format

Share Document