The metabolism of 2-methyladenosine in Mycobacterium smegmatis.
2-Methyladenosine (methyl-ado) has demonstrated selective activity against Mycobacterium tuberculosis, which indicates that differences in the substrate preferences between mycobacterial and human purine metabolic enzymes can be exploited to develop novel drugs for the treatment of mycobacterial diseases. Therefore, in an effort to better understand the reasons for the anti-mycobacterial activity of methyl-ado, its metabolism has been characterized in Mycobacterium smegmatis. In a wild-type strain, methyl-ado was phosphorylated by adenosine kinase to methyl-AMP, which was further converted to methyl-ATP and incorporated into RNA. In contrast, a mutant strain of M. smegmatis was isolated that was resistant to methyl-ado, deficient in adenosine kinase activity and was not able to generate methyl-ado metabolites in cells treated with methyl-ado. These results indicated that phosphorylated metabolites of methyl-ado were responsible for the cytotoxic activity of this compound. Methyl-ado was not a substrate for either adenosine deaminase or purine-nucleoside phosphorylase from M. smegmatis. Treatment of M. smegmatis with methyl-ado resulted in the inhibition of ATP synthesis, which indicated that a metabolite of methyl-ado inhibited one of the enzymes involved in de novo purine synthesis. These studies demonstrated the importance of adenosine kinase in the activation of methyl-ado to toxic metabolites in M. smegmatis.
Chen
Chih-Kuang
CK
Biochemistry Department, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA1.
Barrow
Esther W
EW
Biochemistry Department, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA1.
Allan
Paula W
PW
Biochemistry Department, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA1.
Bansal
Namita
N
Biochemistry Department, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA1.
Maddry
Joseph A
JA
Biochemistry Department, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA1.
Suling
William J
WJ
Biochemistry Department, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA1.
Barrow
William W
WW
Biochemistry Department, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA1.
Parker
William B
WB
Biochemistry Department, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA1.
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D000248:Adenosine Kinase / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D003470:Culture Media; D024881:Drug Resistance, Bacterial; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*
D003470:Culture Media; C031088:2-methyladenosine; D000255:Adenosine Triphosphate; D000248:Adenosine Kinase; D000241:Adenosine