# Nutrient Sensing and Biofilm Modulation: The Example of L-arginine in _Pseudomonas_
## 3 L-arginine as a Pleiotropic Nutrient
This second regulator is a heme-based sensor able to bind to NO (nitrate-derived) and, in turn, to transcriptionally activate the denitrification pathway, the anaerobic respiratory chain where nitrate is the final electron acceptor to be sequentially reduced to dinitrogen [39, 40]. Deni-trification induction leads to a nitrate-dependent (partial) repression of the ADI pathway to favour the more efficient respiratory process instead of the fermentative one [41]. The relevance and functionality of the ADI pathway in other _Pseudomonas_ remains to be fully characterised, particularly in those species considered to be strict aerobes, such as _P. putida_. From a metabolic point of view, L-arginine catabolism allows this amino acid to act as a key precursor of many other nutrients and modulators, including in other organisms; urea, creatine and L-glutamate homeostasis are directly linked to L-arginine degradation, while its biosynthesis may sustain L-glutamate and pyrimidine biosynthesis by also sharing the regulatory strategy [42]. Among the modulating molecules, L-arginine is responsible for the synthesis of polyamines, a group of (multi)aminic metabolites able to affect cell division and proliferation by controlling gene expression, DNA replication and protein biosynthesis [43]. Arginine and polyamines have also been described to modulate siderophore-mediated iron acquisition and tolerance to oxidative stress in _P. putida_[44]. Moreover, in the late 1980's, it was discovered that the endothelium-derived relaxing factor, a signal molecule crucial in the mammals' vascular biology, corresponds to NO [45] and originates from L-arginine thanks to the nitric oxide synthase activity (NOS) [46, 47]. L-arginine-derived NO is one of the strategies of the host immune system to tackle bacterial infections; for this reason, L-arginine supplementation may represent a therapeutic approach for cardiovascular disorders [48], wound healing [49] and immunostimulation [50]. Nevertheless, it may represent a Janus molecule in cancer therapy, being both an immunutrient and an onconutrient [51, 52]. In this way, pathogens such as _P. aeruginosa_, compete with immune cells for nutrients (see below for details). Although the large part of NO in bacteria originates from inorganic sources including nitrates and nitrites [53], a bacterial counterpart of eukaryotic NOS, bNOS, has been reported in certain species; bNOS-derived NO can play different roles, including toxin biosynthesis, protection against oxidative stress, a growth factor in response to stress and an environmental signal to trigger the target tissue growth [54]. Given the large repertoire of metabolic pathways involving L-arginine, their study has been conducted to improve the industrial production of L-arginine (and its derivatives) by engineered overproducing strains [34, 55]. Moreover, engineering of proteins involved in L-arginine recognition has been useful to develop a biosensor for L-arginine detection in biological fluids, up to now possible through HPLC and derivatization [56]. L-arginine is one of the few nutrients used to tackle oral biofilms, which also includes _P. aeruginosa_[57], as a strategy to target pathogens without destroying the physiologically present microbial flora, which contributes to controlling the development of oral infectious diseases [58]. The current approach aims at defining nutrient-based solutions to antagonise biofilm virulence by preventing microbial dysbiosis.