scholarly journals Studies on 16α-Hydroxylation of Steroid Molecules and Regioselective Binding Mode in Homology-Modeled Cytochrome P450-2C11

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Hamed I. Ali ◽  
Morio Yamada ◽  
Yukihisa Fujita ◽  
Mitsuko Maeda ◽  
Eiichi Akaho
Keyword(s):  
Cytochrome P450 ◽  
Binding Mode ◽  
Heme Iron ◽  
Hydroxyl Group ◽  
Biological Study ◽  
Male Rat ◽  
Ring Configuration ◽  
Effective Inhibition ◽  
Acetyl Group ◽  
Cytochrome P450 2C11

We investigated the 16α-hydroxylation of steroid molecules and regioselective binding mode in homology-modeled cytochrome P450-2C11 to correlate the biological study with the computational molecular modeling. It revealed that there was a positive relationship between the observed inhibitory potencies and the binding free energies. Docking of steroid molecules into this homology-modeled CYP2C11 indicated that 16α-hydroxylation is favored with steroidal molecules possessing the following components, (1) a bent A-B ring configuration (5β-reduced), (2) C-3 α-hydroxyl group, (3) C-17β-acetyl group, and (4) methyl group at both the C-18 and C-19. These respective steroid components requirements were defined as the inhibitory contribution factor. Overall studies of the male rat CYP2C11 metabolism revealed that the above-mentioned steroid components requirements were essential to induce an effective inhibition of [3H]progesterone 16α-hydroxylation. As far as docking of homology-modeled CYP2C11 against investigated steroids is concerned, they are docked at the active site superimposed with flurbiprofen. It was also found that the distance between heme iron and C16α-H was between 4 to 6 Å and that the related angle was in the range of 180±45∘.

scholarly journals The effects of nitrogen-heme-iron coordination on substrate affinities for cytochrome P450 2E1

2011 ◽  
Vol 193 (1) ◽  
pp. 50-56 ◽  
Author(s):  
Jeffrey P. Jones ◽  
Carolyn A. Joswig-Jones ◽  
Michelle Hebner ◽  
Yuzhuo Chu ◽  
Dennis R. Koop
Keyword(s):  
Cytochrome P450 ◽  
Heme Iron ◽  
Cytochrome P450 2E1 ◽  
Iron Coordination ◽  
Substrate Affinities

scholarly journals Oxepinamide F biosynthesis involves enzymatic d-aminoacyl epimerization, 3H-oxepin formation, and hydroxylation induced double bond migration

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Liujuan Zheng ◽  
Haowen Wang ◽  
Aili Fan ◽  
Shu-Ming Li
Keyword(s):  
Cytochrome P450 ◽  
Double Bond ◽  
Biosynthetic Pathway ◽  
Hydroxyl Group ◽  
Cytochrome P450 Enzyme ◽  
Double Bond Migration ◽  
Feeding Experiments ◽  
Aspergillus Ustus ◽  
P450 Enzyme ◽  
Derivatives Of

Abstract Oxepinamides are derivatives of anthranilyl-containing tripeptides and share an oxepin ring and a fused pyrimidinone moiety. To the best of our knowledge, no studies have been reported on the elucidation of an oxepinamide biosynthetic pathway and conversion of a quinazolinone to a pyrimidinone-fused 1H-oxepin framework by a cytochrome P450 enzyme in fungal natural product biosynthesis. Here we report the isolation of oxepinamide F from Aspergillus ustus and identification of its biosynthetic pathway by gene deletion, heterologous expression, feeding experiments, and enzyme assays. The nonribosomal peptide synthase (NRPS) OpaA assembles the quinazolinone core with d-Phe incorporation. The cytochrome P450 enzyme OpaB catalyzes alone the oxepin ring formation. The flavoenzyme OpaC installs subsequently one hydroxyl group at the oxepin ring, accompanied by double bond migration. The epimerase OpaE changes the d-Phe residue back to l-form, which is essential for the final methylation by OpaF.

scholarly journals Discovery of Novel Non-Steroidal Cytochrome P450 17A1 Inhibitors as Potential Prostate Cancer Agents

2020 ◽  
Vol 21 (14) ◽  
pp. 4868
Author(s):  
Tomasz M. Wróbel ◽  
Oksana Rogova ◽  
Kasper L. Andersen ◽  
Rahul Yadav ◽  
Simone Brixius-Anderko ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cytochrome P450 ◽  
Cell Lines ◽  
Antiproliferative Activity ◽  
Enzyme Inhibitors ◽  
Prostate Cancer Cell ◽  
Binding Mode ◽  
Prostate Cancer Cell Lines ◽  
Design Synthesis ◽  
Key Enzyme

The current study presents the design, synthesis, and evaluation of novel cytochrome P450 17A1 (CYP17A1) ligands. CYP17A1 is a key enzyme in the steroidogenic pathway that produces androgens among other steroids, and it is implicated in prostate cancer. The obtained compounds are potent enzyme inhibitors (sub µM) with antiproliferative activity in prostate cancer cell lines. The binding mode of these compounds is also discussed.

scholarly journals Mechanism for APOBEC3G catalytic exclusion of RNA and non-substrate DNA

2019 ◽  
Vol 47 (14) ◽  
pp. 7676-7689 ◽  
Author(s):  
William C Solomon ◽  
Wazo Myint ◽  
Shurong Hou ◽  
Tapan Kanai ◽  
Rashmi Tripathi ◽  
...  
Keyword(s):  
Md Simulation ◽  
Catalytic Domain ◽  
Simulation Analysis ◽  
Binding Mode ◽  
Hydroxyl Group ◽  
Hiv Replication ◽  
Ssdna Binding ◽  
Dna And Rna ◽  
Multiple Substrate ◽  
Sugar Conformation

Abstract The potent antiretroviral protein APOBEC3G (A3G) specifically targets and deaminates deoxycytidine nucleotides, generating deoxyuridine, in single stranded DNA (ssDNA) intermediates produced during HIV replication. A non-catalytic domain in A3G binds strongly to RNA, an interaction crucial for recruitment of A3G to the virion; yet, A3G displays no deamination activity for cytidines in viral RNA. Here, we report NMR and molecular dynamics (MD) simulation analysis for interactions between A3Gctd and multiple substrate or non-substrate DNA and RNA, in combination with deamination assays. NMR ssDNA-binding experiments revealed that the interaction with residues in helix1 and loop1 (T201-L220) distinguishes the binding mode of substrate ssDNA from non-substrate. Using 2′-deoxy-2′-fluorine substituted cytidines, we show that a 2′-endo sugar conformation of the target deoxycytidine is favored for substrate binding and deamination. Trajectories of the MD simulation indicate that a ribose 2′-hydroxyl group destabilizes the π-π stacking of the target cytosine and H257, resulting in dislocation of the target cytosine base from the catalytic position. Interestingly, APOBEC3A, which can deaminate ribocytidines, retains the ribocytidine in the catalytic position throughout the MD simulation. Our results indicate that A3Gctd catalytic selectivity against RNA is dictated by both the sugar conformation and 2′-hydroxyl group.

Alternative splicing events in the coding region of the cytochrome P450 aromatase gene in male rat germ cells

1998 ◽  
Vol 20 (3) ◽  
pp. 305-312 ◽  
Author(s):  
J Levallet ◽  
H Mittre ◽  
B Delarue ◽  
S Carreau
Keyword(s):  
Cytochrome P450 ◽  
Alternative Splicing ◽  
Germ Cells ◽  
Binding Domain ◽  
Biologically Active ◽  
Male Rat ◽  
Heme Binding ◽  
Coding Region ◽  
P450 Aromatase ◽  
Alternative Splicing Events

Expression of cytochrome P450 mRNA in rat germ cells was characterized by reverse transcription PCR with various primers located at the 3'-end of the coding region. At least two unusual isoforms (Ex10-S and INT) of P450 aromatase (P450arom) mRNA were expressed. Analysis of their sequences demonstrated that an alternative splicing event occurred first at the exon-intron boundary of the GT consensus sequence of the last coding exon, and second in the internal 5' donor inside exon 9 used as a minor cryptic splicing site. These isoforms lacked the last coding exon which contained the heme-binding domain; in addition, for the Ex10-S transcript, the catalytic domain was also absent because of a frameshift in the open reading frame. The deduced amino acid sequences led to truncated P450arom polypeptides without the heme-binding domain, which were probably unable to convert androgens into estrogens. Adult rat germ cells are able to express P450arom mRNA, which is then translated into a biologically active enzyme which is involved in estrogen production. Moreover, for the first time, we report the existence of alternative splicing events of P45Oarom mRNA in pachytene spermatocytes and round spermatids, which probably cannot encode functional aromatase molecules.

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