期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 291, 期 21, 页码 11083-11093出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.711895
关键词
bacteria; cancer therapy; chemical biology; DNA repair; DNA-protein interaction; enzyme inhibitor; enzyme structure
资金
- National Natural Science Foundation of China [21372237, 91313303]
- National Basic Research Program [2015CB910603]
- National Science and Technology Major Project Key New Drug Creation and Manufacturing Program Grant [2014ZX09507009-01]
The AlkB repair enzymes, including Escherichia coli AlkB and two human homologues, ALKBH2 and ALKBH3, are iron(II)- and 2-oxoglutarate-dependent dioxygenases that efficiently repair N-1-methyladenine and N-3-methylcytosine methylated DNA damages. The development of small molecule inhibitors of these enzymes has seen less success. Here we have characterized a previously discovered natural product rhein and tested its ability to inhibit AlkB repair enzymes in vitro and to sensitize cells to methyl methane sulfonate that mainly produces N-1-methyladenine and N-3-methylcytosine lesions. Our investigation of the mechanism of rhein inhibition reveals that rhein binds to AlkB repair enzymes in vitro and promotes thermal stability in vivo. In addition, we have determined a new structural complex of rhein bound to AlkB, which shows that rhein binds to a different part of the active site in AlkB than it binds to in fat mass and obesity-associated protein (FTO). With the support of these observations, we put forth the hypothesis that AlkB repair enzymes would be effective pharmacological targets for cancer treatment.
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