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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The above-mentioned hypomethylation promotes the malignant degeneration of cells due to favoring a reorganization of chromosomal sections. The most important mechanism of epigenetic regulation is the methylation of DNA by DNA-methyltransferases. It has been found that hypermethylation (methylation of cytosine residues of DNA) of gene-promoter regions, leading to transcriptional repression of tumor suppressor genes the protein products of which such as CDK-inhibitor 2A and RB1 (retinoblastoma protein) decelerate tumor progression, is a common feature of many cancers (Baylin and Jones, 2011). This also holds for global deacetylation. Histone deacetylases (HDACs) class I, II, and IV are Zn2+-dependent amidohydrolases removing an acetyl moiety from a lysine residue at the N-terminus of histone. Class III HDACs (sirturins) are NAD+-dependent. The catalytic action of HDACs enables the histones to wrap the DNA more tightly whereas acetylation of histones by acetyl transferases (HATs) transferring an acetyl group from acetyl-CoA to form ε-N-acetyl lysine normally results in an increase in gene expression, e.g., that of the tumor suppressor p53. Various HAT families are known that differ from each other in their reaction mechanism. The equilibrium of histone acetylation and deacetylation is important for a proper modulation of chromatin topology and regulation of gene transcription. For an excellent review of exploiting the epigenome to control cancer-promoting gene-expression programs, see Brien et al. (2016).
N-Myristoylation as a Novel Molecular Target for the Design of Chemotherapeutic Drugs
Published in Robert I. Glazer, Developments in Cancer Chemotherapy, 2019
Ronald L. Felsted, Colin Goddard, Constance J. Glover
The myristoylation of amino acid terminal glycine appears to be an irreversible reaction. The stability of the N-myristoylglycyl amide bond was indicated in vivo by pulse labeling RSV-infected cells with [3H] myristic acid and observing a constant specific radioactivity in p60src following a chase with nonradioactive fatty acid.41 We have confirmed the stability of the N-myristoylglycyl amide linkage in vitro using [125I]-labeled N-myristoylglycyl peptides homologous to the amino terminal amino acid sequences of p60src or cAMP-dependent protein kinase catalytic subunit. Using these peptides, no significant N-myristoylglycyl peptide amidohydrolase activity was detected in extracts from rat liver and kidney or from Clostridium perfingens which are rich sources of N-acyl amidohydrolase activity.91-94
Glutaminases
Published in Elling Kvamme, Glutamine and Glutamate in Mammals, 1988
Elling Kvamme, Gerd Svenneby, Ingeborg Aasland Torgner
Glutaminase catalyzes the hydrolytic deamidation of glutamine: glutamine + H2O → glutamate + NH3+. The following enzymes are most commonly included in the glutaminase family: Phosphate-activated glutaminase (PAG), phosphate-dependent glutaminase (PDG), and l-glutamine amidohydrolase (EC 3.5.1.2). Since only the kidney, brain, and liver glutaminases have been thoroughly investigated and liver glutaminase is described in Chapter 11, our review will mostly deal with kidney and brain PAG.Maleate-activated glutaminase (MAG), phosphate-independent glutaminase (PIG), and 7-glutamyl transferase (EC 2.3.2.2) (see Chapter 9).Glutaminase II, which is an old term that has been referred to in the literature, is no longer in use. Two enzymes, glutamine aminotransferase (EC 2.6.1.15) and ω-amidase (EC 3.3.1.3) are involved, operating in a sequence (see Chapter 3).
Growth of Porphyromonas gingivalis on human serum albumin triggers programmed cell death
Published in Journal of Oral Microbiology, 2023
Shirin Ghods, M. Fata Moradali, Danielle Duryea, Alejandro R. Walker, Mary E. Davey
Several genes identified by RNA-sequencing as differentially expressed were further examined by quantitative reverse transcription PCR (qRT-PCR) analysis by comparing RNA extracted from strain W83 and W50 at 12.5 h when grown on HSAHK. As shown in Figure 4, PG0144 (agmatine deiminase), was consistently expressed at higher levels in W83 when compared to W50, as well as PG0142, which is predicted to be co-transcribed with PG0139. Surprisingly, RT-qPCR did not detect differential expression of PG0139. The reason for the discrepancy between RNA-sequencing and RT-qPCR analysis is yet unclear and will require further study. Results also indicated a high degree of variability in the expression of PG0143 (amidohydrolase). While this variability was consistent throughout repeat experiments, the expression was consistently higher in strain W83 than W50. Lastly, the analysis confirmed higher levels of expression of the ppGpp synthase/hydrolase-encoding genes (PG1648 and PG1808) in strain W83 as compared to W50.
Fabrication of an improved amperometric creatinine biosensor based on enzymes nanoparticles bound to Au electrode
Published in Biomarkers, 2019
Parveen Kumar, Mohit Kamboj, Ranjana Jaiwal, C.S. Pundir
Creatininase amidohydrolase (EC 3.5.2.10) from Pseudomonas sp. communicated in Flavobacterium sp., and creatinase amidinohydrolase (EC 3.5.3.3) from Pseudomonas sp. expressed in Escherichia coli, sarcosine oxidase (EC 1.5.3.1) from Bacillus sp. were purchased from SISCO Research lab Mumbai, India and Sigma-Aldrich, USA, respectively. Gold electrode (AuE) (2 mm × 20 mm, diameter × height) was purchased from local market, Rohtak were used. All other chemicals utilised in this work were of analytical reagent (AR) grade. All through this study, double distilled (DW) water was used. The blood/serum samples of evidently healthy individuals and persons who suffering from kidney/renal disorders were collected from the hospital of Pt. BDS Post Graduate Institute of Medical Science, Rohtak and kept at −20 °C till use.
A patent update on therapeutic applications of urease inhibitors (2012–2018)
Published in Expert Opinion on Therapeutic Patents, 2019
Abdul Hameed, Mariya Al-Rashida, Maliha Uroos, Syeda Uroos Qazi, Sadia Naz, Marium Ishtiaq, Khalid Mohammed Khan
Urease (urea amidohydrolase; E.C.3.5.1.5) is a metalloenzyme commonly found in a wide variety of plants, algae, fungi, and bacteria. It catalyzes the hydrolysis of urea to ammonia and carbon dioxide [1–5]. The active site of urease contains two nickel (II) ions 3.5–3.7 A° apart. During catalysis, the substrate (urea) directly binds to the two nickel ions via carbonyl oxygen and ammonia group, after displacing water molecule from the active site. This leads to the formation of ammonia and carbamate, and the carbamate then converts into another molecule of ammonia and carbon dioxide (Figure 1) [5–7]. Urease is an important target for the development of drugs against many pathogenic bacteria such as the Helicobacterpylori (responsible for causing gastrointestinal tract infections and peptic/gastric ulcers), as it helps the bacteria to survive the acidic environment of stomach by virtue of its ability to produce ammonia, thereby neutralizing the harsh acidic environment in its vicinity [4,6,8,9]. The pathogenic urease activity also leads to the development of many other diseases such as urinary tract infections, hepatic coma, and infectious kidney stones [10–12]. To control urease activity, an efficacious approach has been the use of urease inhibitors [13,14]. Up to now, a range of urease inhibitors have been reported; however, only a few of them have moved to the advanced stages of drug development as urease inhibitors [15–17].