Abstract
Serum paraoxonase-1 (PON1) is the most studied member of the group of paraoxonases (PONs). This enzyme possesses three enzymatic activities: lactonase, arylesterase, and paraoxonase activity. PON1 and its isoforms play an important role in drug metabolism as well as in the prevention of cardiovascular and neurodegenerative diseases. Although all three members of the PON family have the same origin and very similar amino acid sequences, they have different functions and are found in different locations. PONs exhibit substrate promiscuity, and their true physiological substrates are still not known. However, possible substrates include homocysteine thiolactone, an analogue of natural quorum-sensing molecules, and the recently discovered derivatives of arachidonic acid—bioactive δ-lactones. Directed evolution, site-directed mutagenesis, and kinetic studies provide comprehensive insights into the active site and catalytic mechanism of PON1. However, there is still a whole world of mystery waiting to be discovered, which would elucidate the substrate promiscuity of a group of enzymes that are so similar in their evolution and sequence yet so distinct in their function.
Highlights
Paraoxonases are a group of three identified enzymes: paraoxonase-1 (PON1, EC 3.1.1.2, 3.1.1.81, 3.1.8.1), paraoxonase-2 (PON2, EC 3.1.1.2, 3.1.1.81), and paraoxonase-3 (PON3, EC 3.1.1.2, 3.1.1.81, 3.1.8.1)
PON1 and PON3 reside in high-density lipoproteins (HDLs) in the blood system and exclusively hydrolyze organophosphates and bulky statin lactones, respectively, whereas PON2 is found in many tissues and mainly acts as an intracellular protector against oxidative stress
PON1 have suggested the following: (i) the rate-limiting step is the nucleophilic attack of the water molecule on the carbonyl group of phenyl acetate (PA); (ii) the induced fit of the active site does not play an important role for arylesterase activity; (iii) the calcium ion bound to the active site is necessary for stabilizing the substrates and transition states [33]
Summary
Paraoxonases are a group of three identified enzymes: paraoxonase-1 (PON1, EC 3.1.1.2, 3.1.1.81, 3.1.8.1), paraoxonase-2 (PON2, EC 3.1.1.2, 3.1.1.81), and paraoxonase-3 (PON3, EC 3.1.1.2, 3.1.1.81, 3.1.8.1). The most studied among them is PON1. It is not necessarily considered the most important. The oldest member appears to be PON2, from which first PON3 and PON1 evolved. PON1 and PON3 reside in high-density lipoproteins (HDLs) in the blood system and exclusively hydrolyze organophosphates and bulky statin lactones, respectively, whereas PON2 is found in many tissues and mainly acts as an intracellular protector against oxidative stress. PON1 isoforms play an important role in drug metabolism and the prevention of cardiovascular and neurodegenerative diseases. All three PONs exhibit a broad range of enzymatic activities towards various types of substrates in a single active site. PON2 exhibits lactonase and very low arylesterase activity. PON3 exhibits high lactonase, weak arylesterase, and almost no paraoxonase activity.
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