How Does Pyridoxamine Inhibit the Formation of Advanced Glycation End Products? The Role of Its Primary Antioxidant Activity

Abstract

Pyridoxamine, one of the natural forms of vitamin B 6 , is known to be an effective inhibitor of the formation of advanced glycation end products (AGEs), which are closely related to various human diseases. Pyridoxamine forms stable complexes with metal ions that catalyze the oxidative reactions taking place in the advanced stages of the protein glycation cascade. It also reacts with reactive carbonyl compounds generated as byproducts of protein glycation, thereby preventing further protein damage. We applied Density Functional Theory to study the primary antioxidant activity of pyridoxamine towards three oxygen-centered radicals (•OOH, •OOCH 3 and •OCH 3 ) to find out whether this activity may also play a crucial role in the context of protein glycation inhibition. Our results show that, at physiological pH, pyridoxamine can trap the •OCH 3 radical, in both aqueous and lipidic media, with rate constants in the diffusion limit (>1.0 × 10 8 M −1 s −1 ). The quickest pathways involve the transfer of the hydrogen atoms from the protonated pyridine nitrogen, the protonated amino group or the phenolic group. Its reactivity towards •OOH and •OOCH 3 is smaller, but pyridoxamine can still scavenge them with moderate rate constants in aqueous media. Since reactive oxygen species are also involved in the formation of AGEs, these results highlight that the antioxidant capacity of pyridoxamine is also relevant to explain its inhibitory role on the glycation process.Given the pathological implications of protein glycation, the design of molecules with the ability to attenuate its effects is a matter of utmost concern. The three main mechanisms by which these molecules, known as protein glycation inhibitors, prevent the formation of AGEs are: (i) the complexation of metal ions that catalyze the secondary reactions of protein glycation; (ii) the scavenging of RCS; and (iii) ROS generated as byproducts of those secondary reactions. In 1999, it was discovered that pyridoxamine (PM) had the ability of inhibiting the oxidation of Amadori compounds to form AGEs [10]. PM is one of the three natural forms of vitamin B 6 , together with pyridoxal (PL) and pyridoxine (PN). By that time, it was known that PM was very reactive towards carbonyl groups, since it acted as a coenzyme in transamination reactions between carbonyl compounds and amino groups [11], and this led to consider that it could be an effective AGE inhibitor. Thus far, several studies in both animal and human models have shown its therapeutic effects on diabetic kidney disease [12,13], as well as on retinopathies [14] and vascular diseases [15].Concerning its mechanism of action, it has been suggested that PM could be effective as a metal chelating agent, a RCS scavenger and/or a ROS scavenger. It can form stable complexes with Cu 2+ and Fe 3+ [16,17] and stable adducts with several dicarbonyl compounds [18][19][20][21], as well as inhibit the production of the hydroxyl radical from the Fenton reaction or directly react with it [22][23][24]. Some studies also suggest that ...

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