**6. Regulation of free radicals with nonenzymatic small endogenous (synthetic/physiological) antioxidants**

### **6.1 Uric acid**

Uric acid (UA) is a hydrophilic antioxidant generated during the metabolism of purine nucleotides and accounts nearly for 66% of the total oxygen scavenging activity in the blood serum. Mammals and humans are capable of producing UA, making it the most predominant aqueous antioxidant present in humans [65, 66] with an approximate blood level of 3.5–7.5 mg/dL. UA is a strong electron donor and a selective scavenger of peroxynitrite (ONOO<sup>−</sup> ), requiring the participation of ascorbic acid and thiols in its cycle for complete scavenging of such species [67, 68]. Peroxynitrite is formed by the reaction between nitric oxide (·NO) and superoxide radical (O2 **.−**) (**Figure 1**) and has been implicated in many pathologies. Besides scavenging peroxynitrite, UA reacts with hydroxyl radicals, singlet oxygen, lipid peroxides, and hypochlorous acid, itself getting converted to innocuous chemical species like urea and allantoin. Furthermore, it has been implicated in scavenging carbonate ions (CO3 **.−**) and nitrogen dioxide (NO2 **.** ) [69], and in complexation with copper and iron ions, resulting in the inhibition of deleterious free radical reactions like the Fenton and the Haber-Weiss reactions [65]. Some have suggested that UA

does not directly scavenge peroxynitrite since UA cannot compete for the reaction of peroxynitrite with CO2. The antioxidant effect of uric acid may thus be related to the scavenging of the radicals CO3**·−** and NO2**.** which are formed from the reaction of peroxynitrite with CO2 [67]. As shown in **Figure 13**, UA displays a keto-enol tautomerism where the enol form predominantly exists as the monobasic urate anion at physiological pH [70]. The complete scavenging of peroxynitrite requires the presence of ascorbic acid and thiols whereby the urate anion is regenerated following reduction of the urate free radical with ascorbate (AscH− ). ESR studies on UA radical production by hydrogen atom abstraction provided evidence that the unpaired electron resides primarily on the five-membered ring of the purine structure. The radical was described as a delocalized π radical as the odd electron showed spin density on all four nitrogen atoms [71].

**Figure 13.** *Chemical structure and radical scavenging mechanism of uric acid.*
