Biomaterial Database

Inactivation of O6-methylguanine-DNA methyltransferase in vivo by SN2 alkylating agents. 1995

E Sledziewska-Gójska

Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw.

The cellular level of O6-methylguanine-DNA methyltransferase (MGMT) is important in mutagenic, carcinogenic and therapeutic effects of alkylating agents. I have investigated how SN2 alkylating agents affect the activity of MGMT in vivo. As a model, adapted cultures of E. coli K12 strain AB2497 containing 2400 +/- 430 molecules of MGMT per cell were used. MGMT activity was assayed in the cell extracts of adapted cultures challenged with various doses of MMS, DMS and for comparison the SN1 alkylating agents, MNNG and MNU. In control non-adapted cultures, with low constitutive levels of MGMT, the mutagenic potential of various doses of different alkylating agents was estimated to correlate with the O6-methylguanine content produced in DNA by various treatments. Inactivation of MGMT by MNNG or MNU occurs only in doses able to produce a highly mutagenic level of O6-methylguanine in DNA, which is consistent with the consumption of MGMT activity in the DNA repair process. In contrast, non-mutagenic doses of MMS or DMS are sufficient to inactivate MGMT in adapted E. coli cells. It may be concluded that SN2 alkylating agents can block the main pathway of O6-methylguanine-DNA repair in vivo.

UI	MeSH Term	Description	Entries
D008769	Methylnitronitrosoguanidine	A nitrosoguanidine derivative with potent mutagenic and carcinogenic properties.	Methylnitrosonitroguanidine,Nitrosomethylnitroguanidine,Nitrosonitromethylguanidine,MNNG,N-Methyl-N'-nitro-N-nitrosoguanidine,N Methyl N' nitro N nitrosoguanidine
D008770	Methylnitrosourea	A nitrosourea compound with alkylating, carcinogenic, and mutagenic properties.	Nitrosomethylurea,N-Methyl-N-nitrosourea,NSC-23909,N Methyl N nitrosourea,NSC 23909,NSC23909
D008780	Methyltransferases	A subclass of enzymes of the transferase class that catalyze the transfer of a methyl group from one compound to another. (Dorland, 28th ed) EC 2.1.1.	Methyltransferase
D004260	DNA Repair	The removal of DNA LESIONS and/or restoration of intact DNA strands without BASE PAIR MISMATCHES, intrastrand or interstrand crosslinks, or discontinuities in the DNA sugar-phosphate backbones.	DNA Damage Response
D004926	Escherichia coli	A species of gram-negative, facultatively anaerobic, rod-shaped bacteria (GRAM-NEGATIVE FACULTATIVELY ANAEROBIC RODS) commonly found in the lower part of the intestine of warm-blooded animals. It is usually nonpathogenic, but some strains are known to produce DIARRHEA and pyogenic infections. Pathogenic strains (virotypes) are classified by their specific pathogenic mechanisms such as toxins (ENTEROTOXIGENIC ESCHERICHIA COLI), etc.	Alkalescens-Dispar Group,Bacillus coli,Bacterium coli,Bacterium coli commune,Diffusely Adherent Escherichia coli,E coli,EAggEC,Enteroaggregative Escherichia coli,Enterococcus coli,Diffusely Adherent E. coli,Enteroaggregative E. coli,Enteroinvasive E. coli,Enteroinvasive Escherichia coli
D016296	Mutagenesis	Process of generating a genetic MUTATION. It may occur spontaneously or be induced by MUTAGENS.	Mutageneses
D019853	O(6)-Methylguanine-DNA Methyltransferase	An enzyme that transfers methyl groups from O(6)-methylguanine, and other methylated moieties of DNA, to a cysteine residue in itself, thus repairing alkylated DNA in a single-step reaction. EC 2.1.1.63.	Methylated-DNA-Protein-Cysteine S-Methyltransferase,O(6)-AGT,O(6)-Methylguanine Methyltransferase,DNA Repair Methyltransferase I,DNA Repair Methyltransferase II,Guanine-O(6)-Alkyltransferase,O(6)-Alkylguanine-DNA Alkyltransferase,O(6)-MeG-DNA Methyltransferase,O(6)-Methylguanine DNA Transmethylase,Methylated DNA Protein Cysteine S Methyltransferase,S-Methyltransferase, Methylated-DNA-Protein-Cysteine