scholarly journals Conversion of 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine to cidofovir by an intracellular cyclic CMP phosphodiesterase.

1997 ◽  
Vol 41 (3) ◽  
pp. 641-646 ◽  
Author(s):  
D B Mendel ◽  
T Cihlar ◽  
K Moon ◽  
M S Chen
Keyword(s):  
Parent Compound ◽  
Catalytic Efficiency ◽  
Cyclic Monophosphate ◽  
Nucleotide Analog ◽  
Target Organs ◽  
Hcmv Disease ◽  
Methyl Cytosine ◽  
Reduced Toxicity ◽  
Hydrolysis Of ◽  
Cyclic Cmp

Cidofovir (HPMPC) [1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]-cytosine] is an acyclic nucleotide analog with potent and selective activity against herpesviruses. The prodrug, cyclic HPMPC (cHPMPC) [1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl) methyl]cytosine], has antiviral activity similar to that of the parent compound but exhibits reduced toxicity in animal models. cHPMPC is converted to cidofovir by a cellular cyclic CMP phosphodiesterase (EC 3.1.4.37) which hydrolyzes a variety of substrates, including adenosine 3',5'-cyclic monophosphate (cAMP) and cytidine 3',5'-cyclic monophosphate (cCMP). The K(m) and Vmax values for hydrolysis of cHPMPC by cCMP phosphodiesterase purified from human liver are 250 microM and 0.66 nmol.min-1.unit-1, respectively. These values are similar to the K(m) and Vmax values for cAMP (23 microM and 1.16 nmol.min-1.unit-1, respectively) and cCMP (75 microM and 2.32 nmol.min-1.unit of enzyme-1, respectively). The catalytic efficiency (Vmax/K(m) ratio) of this enzyme for the cHPMPC substrate is only 10- to 20-fold lower than those for the natural cyclic nucleotides, indicating that cHPMPC is a viable intracellular substrate for the human enzyme. Kinetic analysis indicates that cHPMPC, cAMP, and cCMP are competitive with respect to each other and that they are hydrolyzed by the same enzyme. cHPMPC is hydrolyzed to cidofovir in all primary human cell systems tested, including those derived from target organs that might be infected in patients with human cytomegalovirus (HCMV) disease. Importantly, hydrolysis of cHPMPC is not diminished in cells infected with HCMV.

Synthesis and Tautomerism of Curcumin Derivatives and Related Compounds

2015 ◽  
Vol 68 (2) ◽  
pp. 224 ◽  
Author(s):  
Hiroyasu Taguchi ◽  
Daijiro Yanagisawa ◽  
Shigehiro Morikawa ◽  
Koichi Hirao ◽  
Nobuaki Shirai ◽  
...  
Keyword(s):  
Parent Compound ◽  
Amyloid Plaques ◽  
Enol Form ◽  
19F Nmr ◽  
Enolic Form ◽  
Curcumin Derivatives ◽  
Alkyl Groups ◽  
Alzheimer Brain ◽  
Hydrolysis Of ◽  
Related Compounds

1,7-Bis(4′-hydroxy-3′-trifluoromethoxyphenyl)-1,6-heptadiene-3,5-dione (2a), related to curcumin, and thirteen 4-substituted derivatives were prepared and their keto/enol ratio in DMSO[D6] was determined by 19F NMR because the enolic form of these related curcumins had been shown to bind to amyloid plaques in the Alzheimer brain. The parent compound and the 4-ethoxycarbonyl derivative were almost 100 % in the enolic form that contains a conjugated hepta-1,4,6-trien-3-on-5-ol backbone. Enolisation decreased to varying amounts in the derivatives that had 4-substituted alkyl groups. Attempts to prepare the 4-hydroxypropyl derivative by hydrolysis of O-methoxymethyl 2m or O-tetrahydropyranyloxy 2n protected derivatives led to cyclised products. A related pyrimidine compound 6b that mimicked a fixed enol form was also prepared.

scholarly journals Cover Feature: Distance between Metal Centres Affects Catalytic Efficiency of Dinuclear CoIII Complexes in the Hydrolysis of a Phosphate Diester (Eur. J. Org. Chem. 39/2018)

2018 ◽  
Vol 2018 (39) ◽  
pp. 5335-5335
Author(s):  
Eva Szusanna Bencze ◽  
Cristiano Zonta ◽  
Fabrizio Mancin ◽  
Leonard J. Prins ◽  
Paolo Scrimin
Keyword(s):  
Catalytic Efficiency ◽  
Phosphate Diester ◽  
Hydrolysis Of

scholarly journals Application of β-glucosidase Immobilized on Chitosan microspheres in Degradation of Polydatin in Polygonum cuspidatum

2021 ◽  
Vol 233 ◽  
pp. 02034
Author(s):  
Wei Zong ◽  
Shan Liu ◽  
Jeonyun Yun ◽  
Xiong Xiao ◽  
Zujun Deng ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Cost Reduction ◽  
Degradation Rate ◽  
Temperature Stability ◽  
Catalytic Efficiency ◽  
Efficient Production ◽  
Polygonum Cuspidatum ◽  
Optimum Temperature ◽  
Preparation Conditions ◽  
Hydrolysis Of

Resveratrol in Polygonum cuspidatum is a β-glycoside, which can be hydrolyzed to resveratrol by β-glucosidase. it is an efficient production process to degrade polydatin from Polygonum cuspidatum extract by immobilized β-glucosidase. It is of great significance to explore suitable immobilization conditions to improve the catalytic efficiency and reusability of β-glucosidase for polydatin degradation and cost reduction. In this paper, the recombinant Escherichia coli bgl2238, which was screened and constructed from corn soil of Heilongjiang Province in the early laboratory, was immobilized by chitosan adsorption and glutaraldehyde crosslinking. The preparation conditions and immobilization process of bgl2238 were determined by single factor method: the optimal crosslinking time was 1 h, the optimal crosslinking temperature was 20 °C, the recovery rate of enzyme activity of bgl2238 was 87 %, and the enzyme activity was 859.65 mU/g. The optimum temperature of the immobilized bgl2238 is 50 °C, which is 6 °C higher than that of the free bgl2238, and the temperature stability and pH stability are improved. After six consecutive hydrolysis of Polygonum cuspidatum, the degradation rate of polydatin is still over 70 %, which proves that the immobilized bgl2238 has good reusability. This will be helpful to evaluate the application prospect of β - glucosidase immobilized in this system and determine the best conditions for its production.

scholarly journals Biochemistry and metabolism of vitamin D / Biohemija i metabolizam vitamina D

2012 ◽  
Vol 31 (4) ◽  
pp. 309-315 ◽  
Author(s):  
Snežana Jovičić ◽  
Svetlana Ignjatović ◽  
Nada Majkić-Singh
Keyword(s):  
Vitamin D ◽  
Cytochrome P450 ◽  
Vitamin D3 ◽  
Mammalian Cells ◽  
Parent Compound ◽  
Endocrine System ◽  
Target Cells ◽  
Plasma Vitamin ◽  
Endocrine Gland ◽  
Target Organs

Summary Vitamin D is not technically a vitamin, since it is not an essential dietary factor. It is rather a prohormone produced photochemically in the skin from 7-dehydrocholesterol. Vitamin D and its metabolites may be categorized as either cholecalciferols or ergocalciferols. Cholecalciferol (vi - tamin D3) is the parent compound of the naturally occurring family and is produced in the skin from 7-dehydrocholesterol on exposure to the ultraviolet B portion of sunlight. Vitamin D2 (ergocalciferol), the parent compound of the other family, is manufactured by irradiation of ergosterol produced by yeasts and its potency is less than one-third of vitamin D3’s potency. The steps in the vitamin D endocrine system include the following: 1) the photoconversion of 7- dehydrocholesterol to vitamin D3 in the skin or dietary intake of vitamin D3; 2) metabolism of vitamin D3 by the liver to 25-hydroxyvitamin-D3 [25(OH)D3 ], the major form of vitamin D circulating in the blood compartment; 3) conversion of 25(OH)D3 by the kidney (functioning as an endocrine gland) to the hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3 ]; 4) systemic transport of the dihydroxylated metabolite 1,25(OH)2D3 to distal target organs; and 5) binding of 1,25(OH)2D3 to a nuclear receptor (VDR) at target organs, followed by generation of appropriate biological responses. The activation of vitamin D to its hormonal form is mediated by cytochrome P450 enzymes. Six cytochrome P450 (CYP) isoforms have been shown to hydroxylate vitamin D. Four of these, CYP27A1, CYP2R1, CYP3A4 and CYP2J3, are candidates for the enzyme vitamin D 25-hy - droxylase that is involved in the first step of activation. The highly regulated, renal enzyme 25-hydroxyvitamin D-1a-hy - dro xylase contains the component CYP27B1, which completes the activation pathway to the hormonal form 1,25(OH)2D3. A five-step inactivation pathway from 1,25(OH)2D3 to calcitroic acid is attributed to a single multifunctional CYP, CYP24A1, which is transcriptionally in du - ced in vitamin D target cells by the action of 1,25(OH)2D3. An additional key component in the operation of the vitamin D endocrine system is the plasma vitamin D binding protein (DBP), which carries vitamin D3 and its metabolites to their metabolism and target organs. DBP is a specific, high-affinity transport protein. It is synthesized by the liver and circulates in great excess, with fewer than 5% of the binding sites normally occupied. 1,25(OH)2D3, acts as a ligand for a nuclear transcription factor, vitamin D receptor - VDR, which like all other nuclear receptors, regulates gene transcription and cell function. The widespread presence of VDR, and the key activating (1a-hydroxylase, CYP27B1) and inactivating (24-hydroxylase, CYP24A1) en - zy mes in most mammalian cells means that the cells in these tissues have the potential to produce biological res pon ses, depending on the availability of appropriate amounts of vi - tamin D3. Thanks to this widespread presence of elements of vitamin D endocrine system, its biological features are being recognized outside bone tissue, i.e. calcium and pho - sphate metabolism.

scholarly journals Mutational Effects on Carbapenem Hydrolysis of YEM-1, a New Subclass B2 Metallo-β-Lactamase from Yersinia mollaretii

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Paola Sandra Mercuri ◽  
Roberto Esposito ◽  
Sylvie Blétard ◽  
Stefano Di Costanzo ◽  
Mariagrazia Perilli ◽  
...  
Keyword(s):  
Genome Sequence ◽  
Catalytic Efficiency ◽  
The Other ◽  
Kinetic Characterization ◽  
Activity Profile ◽  
Gene Encoding ◽  
Content Type ◽  
Hydrolysis Of

ABSTRACT Analysis of the genome sequence of Yersinia mollaretii ATCC 43969 identified the blaYEM gene, encoding YEM-1, a putative subclass B2 metallo-β-lactamase. The objectives of our work were to produce and purify YEM-1 and to complete its kinetic characterization. YEM-1 displayed the narrowest substrate range among known subclass B2 metallo-β-lactamases, since it can hydrolyze imipenem, but not other carbapenems, such as biapenem, meropenem, doripenem, and ertapenem, with high catalytic efficiency. A possible explanation of this activity profile is the presence of tyrosine at residue 67 (loop L1), threonine at residue 156 (loop L2), and serine at residue 236 (loop L3). We showed that replacement of Y67 broadened the activity profile of the enzyme for all carbapenems but still resulted in poor activity toward the other β-lactam classes.

scholarly journals Comparative gonadotoxicity of the chemotherapy drugs cisplatin and carboplatin on prepubertal mouse gonads

2020 ◽  
Vol 26 (3) ◽  
pp. 129-140 ◽  
Author(s):  
Caroline M Allen ◽  
Federica Lopes ◽  
Rod T Mitchell ◽  
Norah Spears
Keyword(s):  
Animal Model ◽  
Cell Population ◽  
Parent Compound ◽  
Chemotherapy Drugs ◽  
Model Study ◽  
Concomitant Reduction ◽  
Animal Model Study ◽  
Potential Benefits ◽  
Reduced Toxicity

Abstract The treatment of childhood cancer with chemotherapy drugs can result in infertility in adulthood. Newer generations of drugs are developed to replace parent drugs, with the potential benefits of less toxic side effects. For platinum alkylating-like drugs, in contrast to the parent compound cisplatin, the newer-generation drug carboplatin is reported to have reduced toxicity in some respects, despite being administered at 5–15 times higher than the cisplatin dose. Whether carboplatin is also less toxic than cisplatin to the reproductive system is unknown. Here we compare the gonadotoxic impact of cisplatin and carboplatin on female and male mouse prepubertal gonads. In vitro cultured CD1 mouse ovaries or testis fragments were exposed to either cisplatin or carboplatin for 24 h on Day 2 of culture and analysed by Day 6. A dose response for each drug was determined for the ovary (0.5, 1 & 5 μg/ml cisplatin and 1, 5 & 10 μg/ml carboplatin) and the testis (0.01, 0.05 & 0.1 μg/ml cisplatin and 0.1, 0.5 & 1 μg/ml carboplatin). For the ovary, unhealthy follicles were evident from 1 μg/ml cisplatin (73% unhealthy, P = 0.001) and 5 μg/ml carboplatin (84% unhealthy, P = 0.001), with a concomitant reduction in follicle number (P = 0.001). For the testis, the proliferating germ cell population was significantly reduced from 0.05 μg/ml cisplatin (73% reduction, P = 0.001) and 0.5 μg/ml carboplatin (75% reduction, P = 0.001), with no significant impact on the Sertoli cell population. Overall, results from this in vitro animal model study indicate that, at patient equivalent concentrations, carboplatin is no less gonadotoxic than cisplatin.

scholarly journals Further evidence for an allosteric model for ribonuclease

1976 ◽  
Vol 153 (2) ◽  
pp. 329-337 ◽  
Author(s):  
E J Walker ◽  
G B Ralston ◽  
I G Darvey
Keyword(s):  
Conformational Change ◽  
Equilibrium Dialysis ◽  
Kinetic Studies ◽  
Experimental Systems ◽  
Substrate Analogues ◽  
Multiple Binding ◽  
Rate Of Hydrolysis ◽  
Hydrolysis Of ◽  
Cyclic Cmp ◽  
Allosteric Model

Evidence is presented from three experimental systems to support the allosteric model of Walker et al. (1975) (Biochem. J. 147, 425-433) which explains the substrate-concentration-dependent transition observed in the RNAase (ribonuclease)-catalysed hydrolysis of 2‘:3’-cyclic CMP (cytidine 2‘:3’-cyclic monophosphate). 1. Kinetic studies of the initial rate of hydrolysis of 2‘:3’-cyclic CMP show that the midpoint of the transition shifts to lower concentrations of 2‘:3’-cyclic CMP in the presence of the substrate analogues 3′-CMP, 5′-CMP, 3′-AMP, 3′-UMP and Pi; 2′-CMP and 2′-UMP do not cause such a shift. 2. Trypsin-digestion studies show that a conformational change in RNAase to a form less susceptible to tryptic inactivation is induced in the presence of the substrate analogues 3′-CMP, 5′-CMP, 3′-AMP, and 3′-UMP. 2′-CMP, 2′-AMP and 2′-UMP do not induce this conformational change. 3. Equilibrium-dialysis experiments demonstrate the multiple binding of molecules of 3′-CMP, 3′-AMP and 5′-AMP to a molecule of RNAase. 2′-CMP binds the ratio 1:1 over the analogue concentration range studied.

scholarly journals Pharmacokinetics, Safety, and Hydrolysis of Oral Pyrroloquinazolinediamines Administered in Single and Multiple Doses in Rats

2007 ◽  
Vol 51 (8) ◽  
pp. 2898-2904 ◽  
Author(s):  
Qigui Li ◽  
Michael P. Kozar ◽  
Todd W. Shearer ◽  
Lisa H. Xie ◽  
Ai J. Lin ◽  
...  
Keyword(s):  
Parent Compound ◽  
Parent Drug ◽  
Therapeutic Index ◽  
High Dose ◽  
Time Curve ◽  
Safety Margins ◽  
Intermediate Metabolites ◽  
Active Intermediate ◽  
Multiple Treatments ◽  
Hydrolysis Of

ABSTRACT Pyrroloquinazolinediamine (PQD) derivatives such as tetra-acetamide PQD (PQD-A4) and bis-ethylcarbamyl PQD (PQD-BE) were much safer (with therapeutic indices of 80 and 32, respectively) than their parent compound, PQD (therapeutic index, 10). Further evaluation of PQD-A4 and PQD-BE in single and multiple pharmacokinetic (PK) studies as well as corresponding toxicity studies was conducted with rats. PQD-A4 could be converted to two intermediate metabolites (monoacetamide PQD and bisacetamide PQD) first and then to the final metabolite, PQD, while PQD-BE was directly hydrolyzed to PQD without precursor and intermediate metabolites. Maximum tolerant doses showed that PQD-A4 and PQD-BE have only 1/12 and 1/6, respectively, of the toxicity of PQD after a single oral dose. Compared to the area under the concentration-time curve for PQD alone (2,965 ng·h/ml), values measured in animals treated with PQD-A4 and PQD-BE were one-third (1,047 ng·h/ml) and one-half (1,381 ng·h/ml) as high, respectively, after an equimolar dosage, suggesting that PQD was the only agent to induce the toxicity. Similar results were also shown in multiple treatments; PQD-A4 and PQD-BE generated two-fifths and three-fifths, respectively, of PQD concentrations, with 8.8-fold and 3.8-fold safety margins, respectively, over the parent drug. PK data indicated that the bioavailability of oral PQD-A4 was greatly limited at high dose levels, that PQD-A4 was slowly converted to PQD via a sequential three-step process of conversion, and that PQD-A4 was significantly less toxic than the one-step hydrolysis drug, PQD-BE. It was concluded that the slow and smaller release of PQD was the main reason for the reduction in toxicity and that the active intermediate metabolites can still maintain antimalarial potency. Therefore, the candidate with multiple-step hydrolysis of PQD could be developed as a safer potential agent for malaria treatment.

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