Nitric oxide synthase NOS is
Nitric oxide synthase (NOS) is a predominant enzyme of immune system, which elaborates nitric oxide (NO) from the amino endothelin receptor antagonist arginine (Arg). NO mediates vasodilatation, blood pressure regulation, neurotransmission, host defense, and macrophage-mediated immunity, among an array of other functions (Vannini et al., 2015). The enzyme occurs in several forms, depending on the tissue which expresses it. In stress conditions, activated macrophages hyper-express or constitutively elaborate the isoform iNOS (Connelly et al., 2003). High level of NO has been linked to tumor angiogenesis by upregulation of VEGF (Choudhari et al., 2013). ATP synthase is the enzyme required for the generation of ATP from ADP and Pi. This cell surface-embedded F1F0 enzyme mediates a broad array of functions, including innate immunity, angiogenesis, proliferation, apoptosis etc. Up regulation of α-subunit of F1 moiety has been consistently observed in several cancers (Pan et al., 2011, Wang et al., 2013). Stress-activated phospholipase D (PLD) is associated with cell migration. This enzyme-driven cell invasion is mediated by phosphatidic acid, an intracellular signaling molecule, along with a number of other proteins, which collaborate to manipulate vesicular trafficking, exocytosis, autophagy, and actin polymerization (Henkels et al., 2013, Bruntz et al., 2014). Autophagy is a cellular process that delivers misfolded proteins or impaired organelles to lysosomes for degradation, ensuring genomic stability and cytoplasmic homeostasis. Its perturbations initiate malignancy as damaged components pool in the cytosol (Levine and Kroemer, 2008, Glick et al., 2010, Yang et al., 2011). Actin, an essential protein for cellular ionic balance (calcium influx), motility, chromatin structure, and gene expression, among other vital functions require transition between monomeric (G-actin) and filamentous (F-actin) states (Dominguez and Holmes, 2011, von der Ecken et al., 2015). Extracellular acidity activates proton-sensing proteins which hamper the actin polymerization/depolymerization process (Damaghi et al., 2013). Urease, a Ni2+-containing hydrolase is elaborated by gut pathogens as Helicobacter pylori. Excess urease is associated with gastric cancers, mechanism of which has been explained as the gastric mucosal hyperproliferation induced by the enzyme. Autoantibodies formed against this immunogenic enzyme lead to tissue injuries (Wu et al., 2007, Konieczna et al., 2012). Urease-mediated ileal or colonic mucosa lesion is characteristic of Crohn\'s disease, a chronic inflammatory bowel disease (Papamichael et al., 2014). Together these activated proteases MMPs and cathepsins, along with other enzymes (as mentioned above) in their pathways start the pathologic cascades, causing epigenetic changes and tissue remodeling, setting the stage for tumorigenesis (Page-McCaw et al., 2007). There are numerous other known and unknown enzymes participating in the pathologies. Fig. 2 illustrates the mechanism. Several cancer-associated receptor proteins, the G-protein-coupled receptor (GPCR) such as ovarian cancer G-protein-coupled receptor 1 (OGR1), and GPR4, promote the inflammatory enzyme expression, and T-cell death-associated gene 8 (TDAG8) act as a proton-sensing receptor (Ihara et al., 2010, de Vallière et al., 2015). In acidic conditions, these enzymes are activated. Transcription factors are activated with change in pH, which modulates their activity via p38 MAPK activity (Riemann et al., 2011). Cancer-associated transcription factors involved in the enzyme activation include AP-1 (activator protein 1), Nuclear factor κappa B (NF-κB), hypoxia inducible factor (HIF), p53, STAT, GATA3, FOXA1, FOXA2, SOX17, NFE2L2, SOX2, TP63, SP1, BCLAF1, E2F4, and NFATc2 (Gerlach et al., 2012, Paquin et al., 2013, Liu et al., 2015, Yao et al., 2015). DNA methylation, DNA binding, cell cycle progression, T-cell activation, apoptosis, and autophagy are the mechanisms intervened (Gerlach et al., 2012, Paquin et al., 2013). The transcription factor p53 accumulates in hypoxic condition. However, its transrepression activity is enhanced, which inhibits a series of genes (Zhao et al., 2009). In this regard, p53 antagonizes HIF genes, which normally are involved in metastasis (Zhao et al., 2009, Rankin and Giaccia, 2016).