© 2001 American Heart Association, Inc.
Editorial |
Is Paraoxonase-3 Another HDL-Associated Protein Protective Against Atherosclerosis?
From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor.
Correspondence to Bert N. La Du, MD, PhD, Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-0632.
Key Words: paraoxonase • high density lipoproteins • atherosclerosis
The article by Reddy et al1 in the present issue of Arteriosclerosis, Thrombosis, and Vascular Biology is the first report of expression of human paraoxonase-3 (PON3) and its ability to prevent the formation of mildly oxidized LDL and also to inactivate preformed mildly oxidized LDL.
Investigations on mammalian serum paraoxonase (PON),
now called PON1, started nearly 50 years ago by
Aldridge2 3
with the study of its hydrolytic activity with paraoxon and other
organophosphates. More recently, 
5 years ago, it was established
that PON1 is a member multigene family in
mammals.4 There are 3 PON
genes closely aligned on human chromosome 7 and mouse chromosome
6.
Research efforts on possible physiological functions of the PON family of enzymes have probably been hindered to some degree by their inappropriate designation as PONs (PON1, PON2, and PON3) and by the fact that most of our present knowledge of this homologous group of proteins has been limited to PON1, which does involve PON and arylesterase activities (reviewed by Durrington et al5 in the present issue of Arteriosclerosis, Thrombosis, and Vascular Biology). However, other members of the PON family (PON2 and PON3) from human and rabbit sources have recently been examined in our laboratory (Draganov et al;6 D.I. Draganov, personal communication), and these all completely lack PON activity and have very little, if any, arylesterase activity. Thus, PON activity of PON1 appears now to be a distinctive marker of its more recent evolutionary origin than the other PONs, but this eliminates PON activity as being a common enzymatic feature shared generally by members of the PON family.
Kobayashi et
al7 pointed out that a fungal
lactonase of Fusarium oxysporum
has appreciable structural homology with human PON1. The fungal
lactonase was earlier shown by this same group to hydrolyze aldonate
lactones, D-pantoyl
lactone, dihydrocoumarin, and homogentisic
acid8 but not
paraoxon.7 Recently, the
lactonase activities of purified human serum PON1 Q and R isozymes were
investigated in our
laboratory.9 Both PON1
isozymes can hydrolyze many aliphatic and several aromatic lactones,
including 2-coumaranone, dihydrocoumarin, and homogentisic acid
lactone. In addition, human PON1 hydrolyzes a number of the statin
drugs (eg, lovastatin and simvastatin) as well
as spironolactone and 
-hydroxybutyric acid lactone. Some of these
new lactone substrates have been used in purifying and characterizing
PON3 from rabbit serum, which has unusually high lactonase activity
with
lovastatin.6
Of further cardiovascular interest is the finding that rabbit serum PON3 is closely associated with the HDL fraction, and it is even more effective than rabbit PON1 in protecting LDL from copper-induced oxidation.6 The human serum PON3 enzyme was also been found to be closely associated with the HDL fraction by Reddy et al.1 Thus, several common features have recently emerged suggesting that the hydrolytic capacity and the ability to protect against oxidative damage by LDL may be important clues involving some common physiological functions of the PON proteins.
Interestingly, the lactonase activity and the protection against oxidative damage of LDL require the free cysteine at position 284, but this residue is not essential for either PON or arylesterase activity. So far, lactonase activity with several of the lactone substrates tested does not directly predict the degree of protection against oxidative damage, but the 2 activities are clearly related. It may turn out that the mechanism by which protection is achieved is the hydrolysis of a potentially toxic endogenous lactone that would otherwise produce vascular damage. Unfortunately, neither arylesterase activity nor PON activity has predictive value concerning the degree of protection against oxidative damage. In any case, lactonase activity appears, at this time, to be a common property shared by the evolved PON enzymes.
The observations by Shih et al10 that knockout mice lacking PON1 develop atherosclerosis only when fed an atherogenic diet suggest that this enzyme is a protector but perhaps not a major protector against this disease. An alternative explanation, however, is that the other PONs still present in the knockout mice are able to compensate to some degree for the PON1 deficiency, and this redundancy accounts for the less than expected clinical effect. The other PON enzymes have tissue levels and distributions different from those of PON1, and possibly different substrate specificity, but they may also be important protectors against tissue damage from oxidized HDL and LDL and may be able to inactivate chemical mediators of cardiovascular damage. As we learn more about the properties of these other PON proteins in the future, these questions will be answered, and the relationship between the PON family of enzymes and cardiovascular disease should become clear.
Footnotes
From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor.
References
1.
Reddy ST,
Wadleigh DJ, Grijalva V, Ng C, Hama S, Gangopahyay A, Shih DM, Lusis
AJ, Navab M, Fogelman AM. Human paraoxonase-3 is an HDL-associated
enzyme with biological activity similar to paraoxonase-1 protein but is
not regulated by oxidized lipids.
Arterioscler Thromb Vasc Biol. 2001;21:542–547.
2. Aldridge WN. Serum esterases, I: two types of esterase (A and B) hydrolyzing p-nitrophenyl acetate propionate and butyrate and a method for their determination. Biochem J. 1953;53:110–117.[Medline] [Order article via Infotrieve]
3. Aldridge WN. Serum esterases, II: an enzyme hydrolyzing diethyl aranitrophenyl phosphate (E600) and its identity with A-esterase of mammalian sera. Biochem J. 1953;53:117–124.[Medline] [Order article via Infotrieve]
4. Primo-Parmo SL, Sorenson RS, Teiber J, La Du BN. The human serum paraoxonase-arylesterase gene (PON1) is one member of a multigene family. Genomics. 1996;33:498–507.[Medline] [Order article via Infotrieve]
5.
Durrington PN,
Mackness B, Mackness MI. Paraoxonase and
atherosclerosis.
Arterioscler Thromb Vasc Biol. 2001;21:471–472.
6.
Draganov DI, Stetson
PL, Watson CE, Billecke SS, La Du BN. Rabbit serum paraoxonase 3 (PON3)
is a high density lipoprotein-associated lactonase and protects low
density lipoprotein against oxidation.
J Biol Chem. 2000;275:33435–33442.
7. Kobayashi M, Shinohara M, Sakoh C, Kataoka M, Shimizu S. Lactone-ring-cleaving enzyme: genetic analysis, novel RNA editing, and evolutionary implications. Proc Natl Acad Sci U S A. 1999;95:2787–12792.
8. Shimizu S, Kataoka M, Shimizu K, Hirakata M, Sakamoto K, Yamada H. Purification and characterization of a novel lactonohydrolase, catalyzing the hydrolysis of aldonate lactones and aromatic lactones, from Fusarium oxysporum. Eur J Biochem. 1992;209:383–390.[Medline] [Order article via Infotrieve]
9.
Billecke S, Draganov
D, Counsell R, Stetson P, Watson C, Hsu C, La Du BN. Human serum
paraoxonase (PON1) isozymes Q and R hydrolyze lactones and cyclic
carbonate esters. Drug Metab
Dispos. 2000;28:1335–1342.
10. Shih DM, Gu L, Xia YR, Navab M, Li WF, Hama S, Castellani LW, Furlong CE, Costa LG, Fogelman AM, et al. Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature. 1998;394:284–287.[Medline] [Order article via Infotrieve]
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