**Acknowledgements**

*Free Radical Medicine and Biology*

[85, 86] especially against peroxyl radicals [87].

*Enzymatic degradation of hemoglobin heme to bilirubin.*

Bilirubin (BIL) is an endogenous antioxidant produced from the enzymatic degradation of hemoglobin and other heme proteins (**Figure 16**). The process involves oxidative cleavage, catalyzed by the enzyme heme oxygenase, of one porphyrin exocyclic double bond of a heme residue of hemoglobin to generate biliverdin. Subsequent enzymatic reduction of biliverdin by biliverdin reductase yields bilirubin. This process is reversible and the oxidation of bilirubin by lipophilic ROS results in the formation of biliverdin. Notable structural features of bilirubin include an open chain of four connected pyrrole rings and a *Z*,*Z*-double bond geometry. In biological systems, bilirubin shows potent antioxidant properties

Putrescine (H2N-(CH2)4-NH2), spermidine ([H2N-(CH2)3]2-NH), and spermine (H2N-(CH2)3-NH-(CH2)4-NH-(CH2)3-NH2) are biogenic unbranched polyamines (PAs) that exhibit antioxidant activities [88–90]. These amines are present in minute quantities in virtually all living species. While putrescine (1,4-diaminobutane) bears two primary amine groups at both terminal carbons, spermidine (triamine) and spermine (tetraamine) contain one and two additional secondary amine moieties, respectively. As antioxidants, PAs mediate protection of DNA against oxidative damage induced by hydrogen peroxide [90], scavenge free radicals [88], and reduce oxidative haemolysis of erythrocytes [90]. The amines also function as positive modulators of antioxidant genes under conditions of strong oxidative stress [88]. The protective effect of PAs is related to the stabilization of polyunsaturated phospholipids in cell membranes from peroxyl radicals, superoxides, and hydrogen peroxide [89]. In regard to their role in DNA protection against ROS, PAs are positively charged at physiological pH, enabling them to remain in proximity to negatively charged macromolecules, thus protecting them against oxidative damage [90]. Biosynthetically, the three polyamines are biosynthesized from L-ornithine, known to supply C4N building block, and L-methionine [91]. In animals, L-ornithine undergoes a pyridoxal phosphate (PLP)-dependent decarboxylation to generate putrescine. Thereafter, aminopropylation of putrescine by the enzyme spermidine synthase and decarboxy-S-adenosyl methionine produces spermidine. Repetition of the same sequence of reactions in the presence of the enzyme spermine synthase generates spermine.

In addition to the oxidative damage that reactive oxygen and nitrogen species inflict on macromolecules, they also participate in damage caused by microbial

**6.4 Bilirubin**

**6.5 Polyamines**

**Figure 16.**

**108**

**7. Conclusions**

Dr. Ziad Moussa is grateful to the United Arab Emirates University (UAEU) of Al-Ain and to the Research Office for supporting the research developed in his laboratory (Project 852).
