**3. Arginine catabolic pathways**

There are enumerating pathways and enzymes to degrade arginine into other biomolecules and intermediates. Five main pathways including; arginine succinyltransferase (AST) (**Figure 2A**), arginine decarboxylase (ADC) (**Figure 2B**), Arginase1 (**Figure 2C**), citrulline- NO ((**Figure 2D**) and arginine deiminase (ADI) (**Figure 3**) were found to degrade arginine. These pathways are mainly focused by the researchers to study arginine degradation and find out its role in different cellular activities and ADI pathway has higher affinity for arginine among all of these pathways [22]. The essential site for arginine degradation in ureotelic organisms is the liver and second main site is the kidney where arginine is major converted into the polyamines, urea, creatine phosphate and NO and transported through bloodstream into the cells by cationic amino acid transporters (Melis et al, 2008). In bacteria arginine is degraded via three key pathways; (i) ADC pathway, here, arginine degradation is initiated by decarboxylation of arginine and form agmatine which further converted into putrescine by enzyme agmatine ureohydrolase. Putrescine is converted into γ- aminobutyric acid by putrescine transaminase and pyrroline dehydrogenase and ultimately converted into glutamate and succinate [23].

#### **Figure 2.**

*Arginine biosynthesis by different metabolic pathways such as AST pathway (A), ADC pathway (B), arginase1 pathway (C) and citrulline-NO pathway (D).*

**157**

**Figure 3.**

*Arginine Metabolism: An Enlightening Therapeutic Attribute for Cancer Treatment*

The enzyme arginine decarboxylase (ADC) is also considered as an important enzyme in bacteria [24], plants [25] and in mammalian systems [26]. The infusion of agmatine in the cerebral ventricles increases blood pressure and regulates the angiogenic activities [27]. (ii) AST pathway; here, arginine is degraded into glutamate, succinate and other intermediates. AST pathway is mainly activated for arginine degradation when nitrogen is limited for growth and contributes into the production of amino acids [28]. (iii) Arginase1 pathway; this pathway is activated when arginine concentration is excess in the media and urea and ornithine are produced by enzyme arginase1 during first enzymatic reaction [29]. Here, urea does not metabolize further and rapidly excreted into the medium. In arginase1 pathway, arginine used as the nitrogen and carbon sole sources and less than 3% of consumed arginine results in the formation of urea and 36% consumed by the route of putrescine and polyamine synthesis [30]. Polyamines produced by this pathway are polycations and interact with negatively charged molecules, such as DNA, RNA and also with proteins and involved in cellular growth, survival and proliferation [31]. Polyamines such as putrescine, spermidine and spermine are very tightly regulated by polyamine metabolic pathway [32]. These metabolites used by *H. pylori* to retard the expression of pro-inflammatory cytokines and prevent the immune response in stimulated macrophages [33] and also maintain the microenvironment around their cell in acidic condition for their survival using arginine [34]. Cancer and proliferative cells show high levels of polyamines and with this feature cancer cells maintain their proliferative properties [32] and high levels of polyamines were observed in cancerous cells [35]. It is proposed that both Gram negative and positive bacterial cells which contain unusually high AST and ADI level grow anaerobically in a complex acidic medium and both the enzymes help to raise the pH for the cell survival in the acidic environment [36]. Last but not least, arginine deiminase (ADI) pathway degrades arginine to ornithine, ammonia, and carbon dioxide and generates one mol of ATP by utilization of per mol of arginine [37]. A variety of bacterial cells; both gram positive and gram negative can catabolized arginine through ADI pathway [18]. Enzyme activity of ADI has been detected

*degradation of arginine through ADI pathway in the bacterial system.*

*DOI: http://dx.doi.org/10.5772/intechopen.97254*

*Arginine Metabolism: An Enlightening Therapeutic Attribute for Cancer Treatment DOI: http://dx.doi.org/10.5772/intechopen.97254*

**Figure 3.** *degradation of arginine through ADI pathway in the bacterial system.*

The enzyme arginine decarboxylase (ADC) is also considered as an important enzyme in bacteria [24], plants [25] and in mammalian systems [26]. The infusion of agmatine in the cerebral ventricles increases blood pressure and regulates the angiogenic activities [27]. (ii) AST pathway; here, arginine is degraded into glutamate, succinate and other intermediates. AST pathway is mainly activated for arginine degradation when nitrogen is limited for growth and contributes into the production of amino acids [28]. (iii) Arginase1 pathway; this pathway is activated when arginine concentration is excess in the media and urea and ornithine are produced by enzyme arginase1 during first enzymatic reaction [29]. Here, urea does not metabolize further and rapidly excreted into the medium. In arginase1 pathway, arginine used as the nitrogen and carbon sole sources and less than 3% of consumed arginine results in the formation of urea and 36% consumed by the route of putrescine and polyamine synthesis [30]. Polyamines produced by this pathway are polycations and interact with negatively charged molecules, such as DNA, RNA and also with proteins and involved in cellular growth, survival and proliferation [31]. Polyamines such as putrescine, spermidine and spermine are very tightly regulated by polyamine metabolic pathway [32]. These metabolites used by *H. pylori* to retard the expression of pro-inflammatory cytokines and prevent the immune response in stimulated macrophages [33] and also maintain the microenvironment around their cell in acidic condition for their survival using arginine [34]. Cancer and proliferative cells show high levels of polyamines and with this feature cancer cells maintain their proliferative properties [32] and high levels of polyamines were observed in cancerous cells [35]. It is proposed that both Gram negative and positive bacterial cells which contain unusually high AST and ADI level grow anaerobically in a complex acidic medium and both the enzymes help to raise the pH for the cell survival in the acidic environment [36]. Last but not least, arginine deiminase (ADI) pathway degrades arginine to ornithine, ammonia, and carbon dioxide and generates one mol of ATP by utilization of per mol of arginine [37]. A variety of bacterial cells; both gram positive and gram negative can catabolized arginine through ADI pathway [18]. Enzyme activity of ADI has been detected

*Bioactive Compounds - Biosynthesis, Characterization and Applications*

sources [21].

**3. Arginine catabolic pathways**

Enzyme ASS1 catalyzes the conversion of citrulline to aspartate and argininosuccinate which is further converted into arginine and fumarate by ASL [16, 17]. Ornithine can also be converted back to citrulline by arginine deiminase (ADI) pathway in bacteria [18] and by arginase1 pathway in mammals [19]. In both the cases citrulline is recycled back to arginine by ASS enzyme [15]. The ability to generate arginine from citrulline depends on the activity of ASS and ASL [20]. These two enzymes are tightly coupled for sensitivity of cells to arginine deprivation and their activity depends on their ability to regenerate arginine from the alternative

There are enumerating pathways and enzymes to degrade arginine into other biomolecules and intermediates. Five main pathways including; arginine succinyltransferase (AST) (**Figure 2A**), arginine decarboxylase (ADC) (**Figure 2B**), Arginase1 (**Figure 2C**), citrulline- NO ((**Figure 2D**) and arginine deiminase (ADI) (**Figure 3**) were found to degrade arginine. These pathways are mainly focused by the researchers to study arginine degradation and find out its role in different cellular activities and ADI pathway has higher affinity for arginine among all of these pathways [22]. The essential site for arginine degradation in ureotelic organisms is the liver and second main site is the kidney where arginine is major converted into the polyamines, urea, creatine phosphate and NO and transported through bloodstream into the cells by cationic amino acid transporters (Melis et al, 2008). In bacteria arginine is degraded via three key pathways; (i) ADC pathway, here, arginine degradation is initiated by decarboxylation of arginine and form agmatine which further converted into putrescine by enzyme agmatine ureohydrolase. Putrescine is converted into γ- aminobutyric acid by putrescine transaminase and pyrroline dehydrogenase and ultimately converted into glutamate and succinate [23].

*Arginine biosynthesis by different metabolic pathways such as AST pathway (A), ADC pathway (B), arginase1* 

**156**

**Figure 2.**

*pathway (C) and citrulline-NO pathway (D).*

in several lactic acid bacteria (LAB), *bacilli, clostridia, pseudomonads, aeromonads, mycoplasmas, halobacteria, and cyanobacteria* [36]. ADI pathway is completed by three key enzymes: arginine deiminase (ADI), ornithine transcarbamoylase (OTC), and carbamate kinase (CK) as shown in **Figure 3**. Moreover, in *Pseudomonas aeruginosa*, a fourth gene that encodes a transport protein to exchange arginine and ornithine for this pathway has been identified [37]. ADI pathway is most important for the bacterial cell survival in the acidic environmental condition because arginine degradation by ADI pathway produced ammonia that raises the cytoplasmic and extracellular pH and produced ATP use as the energy source for cell survival. In the absence of carbohydrate bacteria preferred arginine and utilize it by ADI pathway as an alternate energy source to engender energy for cellular growth [20, 38]. ADI pathway is regulated at transcriptional level and regulated by transcriptional regulator ArgR [3, 37]. Moreover, carbon catabolite repression (CCR) has also been confirmed for the expression of ADI pathway in various bacteria. CCR regulates the expression of arc operon with glucose and catabolite control protein A (CcpA) [39]. CcpA is a transcriptional regulators belonging to the Crp/Fnr family and regulates the expression by the binding with regulatory proteins to the cis-acting catabolite response elements (cre) located in the promoter regions [20].
