Nitric oxide biological chemistry in a systems biology context: Influence of biosystems diversity on nitric oxide signal transduction pathways

Nitric oxide (NO) plays roles in numerous biological processes. Due to the myriad NO-reactive molecules present in biological systems, there has been significant debate regarding the ability of NO to transduce highly specific biological signals. Additionally, it is difficult to identify biologically relevant targets of NO-related chemistry. Although numerous hypotheses regarding NO signal transduction mechanisms have been proposed, they have proven difficult to verify due to the low levels of and relatively short half-lives of the signal intermediates. Here we examine biophysical factors that enhance NO signal transduction and facilitate signal transmogrification in the cardiovascular system, and we develop an approach to investigate the interactions of NO with Escherichia coli's genomic program. In particular, we develop a model of supplemental NO delivery, by membrane impermeable NONOates, in resistance vessels. This model identifies three features of blood vessels that will enhance NONOate efficacy: (1) the amount of NO delivered to the abluminal region increases with lumen radius; (2) the presence of a flow-induced RBC-free zone will augment NO delivery; and (3) extravasation of the NONOate into the interstitial space will increase abluminal NO delivery. These results suggest that NONOates may be more effective in larger vessels and that NONOate efficacy can be altered by modifying permeability to the interstitial space. We, also, examine the impact of reactant flux on the reaction of NO with oxygenated Hb (oxyHb). We find that, when the local concentration of oxyHb is in excess, the predominant reaction is oxidative; however, when the local concentration of NO is in excess, the oxyHb is oxidized and subsequently reduced by NO. In order to elucidate how NO-based chemistry interacts with E. coli 's genomic program, we develop a chemogenomic framework designed to deduce the active modes of NO biochemistry, identify the pertinent targets, and construct the chemogenomic response network. This framework implicated dihydroxy-acid dehydratase and isopropylmalate dehydratase as key NO-targets responsible for inducing bacteriostasis.