Integrated network analysis identifies nitric oxide response networks and dihydroxyacid dehydratase as a crucial target in Escherichia coli.
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.
Hyduke
Daniel R
DR
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, CA 90095, USA.
Jarboe
Laura R
LR
Tran
Linh M
LM
Chou
Katherine J Y
KJ
Liao
James C
JC
D000222:Adaptation, Physiological / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D053263:Gene Regulatory Networks; D006836:Hydro-Lyases / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D008954:Models, Biological; D009569:Nitric Oxide / Q000494:pharmacology*; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D007506:Iron-Sulfur Proteins; D014157:Transcription Factors; D009569:Nitric Oxide; D006836:Hydro-Lyases; C020052:dihydroxyacid dehydratase