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3240373 
Journal Article 
Integrated network analysis identifies nitric oxide response networks and dihydroxyacid dehydratase as a crucial target in Escherichia coli 
Hyduke, DR; Jarboe, LR; Tran, LM; Chou, KJY; Liao, JC 
2007 
1 
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
EISSN: 1091-6490 
104 
20 
8484-8489 
WOS:000246599900053 
Nitric oxide (NO) is used by mammalian immune systems to
counter microbial invasions and is produced by bacteria during denitrification. As a defense,
microorganisms possess a complex network to cope with NO. Here we report a combined
transcriptomic, chemical, and phenotypic approach to identify direct NO targets and construct the
biochemical response network. In particular, network component analysis was used to identify
transcription factors that are perturbed by NO. Such information was screened with potential NO
reaction mechanisms and phenotypic data from genetic knockouts to identify active chemistry and
direct NO targets in Escherichia coli. This approach identified the comprehensive E. coli NO
response network and evinced that NO halts bacterial growth via inhibition of the branched-chain
amino acid biosynthesis enzyme dihydroxyacid dehydratase. Because mammals do not synthesize
branched-chain amino acids, inhibition of dihydroxyacid dehydratase may have served to foster the
role of NO in the immune arsenal. 
systems biology; chemoinformatics