human cyp1a2
Recently Published Documents


TOTAL DOCUMENTS

52
(FIVE YEARS 3)

H-INDEX

19
(FIVE YEARS 0)

2020 ◽  
Vol 10 (11) ◽  
pp. 3929-3947
Author(s):  
Nick St. John ◽  
Julian Freedland ◽  
Henri Baldino ◽  
Francis Doyle ◽  
Cinzia Cera ◽  
...  

Exposure to the mycotoxin aflatoxin B1 (AFB1) strongly correlates with hepatocellular carcinoma (HCC). P450 enzymes convert AFB1 into a highly reactive epoxide that forms unstable 8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 (AFB1-N7-Gua) DNA adducts, which convert to stable mutagenic AFB1 formamidopyrimidine (FAPY) DNA adducts. In CYP1A2-expressing budding yeast, AFB1 is a weak mutagen but a potent recombinagen. However, few genes have been identified that confer AFB1 resistance. Here, we profiled the yeast genome for AFB1 resistance. We introduced the human CYP1A2 into ∼90% of the diploid deletion library, and pooled samples from CYP1A2-expressing libraries and the original library were exposed to 50 μM AFB1 for 20 hs. By using next generation sequencing (NGS) to count molecular barcodes, we initially identified 86 genes from the CYP1A2-expressing libraries, of which 79 were confirmed to confer AFB1 resistance. While functionally diverse genes, including those that function in proteolysis, actin reorganization, and tRNA modification, were identified, those that function in postreplication DNA repair and encode proteins that bind to DNA damage were over-represented, compared to the yeast genome, at large. DNA metabolism genes also included those functioning in checkpoint recovery and replication fork maintenance, emphasizing the potency of the mycotoxin to trigger replication stress. Among genes involved in postreplication repair, we observed that CSM2, a member of the CSM2(SHU) complex, functioned in AFB1-associated sister chromatid recombination while suppressing AFB1-associated mutations. These studies thus broaden the number of AFB1 resistance genes and have elucidated a mechanism of error-free bypass of AFB1-associated DNA adducts.


2019 ◽  
Author(s):  
Beili Ying ◽  
Yang Zhong ◽  
Jingfang Wang

AbstractAs an important member of cytochrome P450 (CYP) enzymes, human CYP1A2 is associated with the metabolism of caffeine and melatonin and the activation of precarcinogens. Besides, this CYP protein also involves in metabolizing 5-10% of clinical medicines. Some peripheral mutations in CYP1A2 (P42R, I386F, R431W, and R456H) significantly decrease the enzyme activities, resulting in a vital reduction in substrate metabolisms. To explore the effects of these peripheral mutations, we constructed a membrane-binding model for the full-length human CYP1A2 and studied their dynamic behaviors on lipid membranes. Free energy calculations indicate that the peripheral mutations donot influence substrate binding. P42R is located in the N-terminal anchor, and its positive charged sidechain is adverse to membrane binding. I386F enhances the van der Waals contacts of the water channel bottleneck and R456H breaks the hydrogen bonding interactions that function to position the BC loop, both of which result in a significant inhibition on the water channel. R431W causes a sidechain conformational rearrangement for aromatic residues around the substrate channel, making it in a closed state in most cases. Our computational simulations demonstrate that pi-pi stacking interactions are essential for substrate binding and channel opening. We hope that these findings may be of general relevance to the mutation-induced activity changes for CYP proteins, providing useful information for understanding the CYP-mediated drug metabolism.


2018 ◽  
Vol 8 (1) ◽  
pp. 384-389 ◽  
Author(s):  
T. I. Madzhidov ◽  
A. A. Khakimova ◽  
R. I. Nugmanov ◽  
C. Muller ◽  
G. Marcou ◽  
...  

2016 ◽  
Vol 208 ◽  
pp. 506-511 ◽  
Author(s):  
Xiaoli Duan ◽  
Guofeng Shen ◽  
Hongbiao Yang ◽  
George Lambert ◽  
Fusheng Wei ◽  
...  

2014 ◽  
Vol 88 (2) ◽  
pp. 245-252 ◽  
Author(s):  
Rui Gu ◽  
David E. Hibbs ◽  
Jennifer A. Ong ◽  
Robert J. Edwards ◽  
Michael Murray

Sign in / Sign up

Export Citation Format

Share Document