| Literature References | 1. PRIMO-PARMO, S.L., SORENSON, R.C., TEIBER, J. AND LA DU, B.N.
The human serum paraoxonase/arylesterase gene (PON1) is one member of a
multigene family.
GENOMICS 33 498-507 (1996).
2. ALDRIDGE, W.N.
Serum esterases: II. An enzyme hydrolyzing diethyl p-nitrophenyl phosphate
BIOCHEM.J. 53 117-124 (1953).
3. LA DU, B.N.
Human serum paraoxonase/arylesterase.
IN PHARMACOGENETICS OF DRUG METABOLISM, KALOW, W., ED., PERGAMON PRESS,
NEW YORK, 1992, PP.51-91.
4. BREALEY, C.J., WALKER, C.H. AND BALDWIN, B.C.
A-esterase activities in relation to the differential toxicity of
pirimiphosmethyl to birds and mammals.
PESTICIDES SCI. 11 546-554 (1980).
5. SCOTT, D.L., WHITE, S.P., OTWINOWSKI, Z., YUAN, W., GELB, M.H. AND
SIGLER, P.B.
Interfacial catalysis: the mechanism of phospholipase A2.
SCIENCE 250 1541-1546 (2000).
6. REDDY, S.T., WADLEIGH, D.J., GRIJALVA, V., NG, C., HAMA, S.,
GANGOPADHYAY, A., SHIH, D.M., LUSIS, A.J., NAVAB, M. AND FOGELMAN, A.M.
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. 21 542-547 (2001).
7. NG, C.J., WADLEIGH, D.J., GANGOPADHYAY, A., HAMA, S., GRIJALVA, V.R.,
NAVAB, M., FOGELMAN, A.M. AND REDDY, S.T.
Paraoxonase-2 is a ubiquitously expressed protein with antioxidant
properties and is capable of preventing cell-mediated oxidative modification
of low density lipoprotein.
J.BIOL.CHEM. 276 44444-44449 (2001).
8. BORIGHT, A.P, CONNELLY, P.W., BRUNT, J.H., SCHERER, S.W.,
TSUI, L.C. AND HEGELE, R.A.
Genetic variation in paraoxonase-1 and paraoxonase-2 is associated with
variation in plasma lipoproteins in Alberta Hutterites.
ATHEROSCLEROSIS 139 131-136 (1998).
9. MACKNESS, B., DURRINGTON, P.N., ABUASHIA, B., BOULTON, A.J. AND
MACKNESS, M.I.
Low paraoxonase activity in type II diabetes mellitus complicated by
retinopathy.
CLIN.SCI. (LONDON) 98 355-363 (2000).
10. BUSCH, C.P., RAMDATH, D.D., RAMSEWAK, S. AND HEGELE, R A.
Association of PON2 variation with birth weight in Trinidadian neonates of
South Asian ancestry.
PHARMACOGENETICS 9 351-356 (1999).
11. SANGHERA, D.K., ASTON, C.E., SAHA, N. AND KAMBOH, M.I.
DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated
with the risk of coronary heart disease.
AM.J.HUM.GENET. 62 36-44 (1998).
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| Documentation | The serum paraoxonases/arylesterases are enzymes that catalyse the hydrolysis
of the toxic metabolites of a variety of organophosphorus insecticides. The
enzymes hydrolyse a broad spectrum of organophosphate substrates, including
paraoxon and a number of aromatic carboxylic acid esters (e.g., phenly
acetate), and hence confer resistance to organophosphate toxicity [1].
Mammals have 3 distinct paraoxonase types, termed PON1-3 [1]. In mice and
humans, the PON genes are found on the same chromosome in close proximity.
PON activity has been found in variety of tissues, with highest levels in
liver and serum [2] - the source of serum PON is thought to be the liver
[3]. Unlike mammals, fish and avian species lack paraoxonase activity [4].
The absence of this activity in chicken and turkey indicates that PON2 does
not hydrolyse paraoxon [1].
Human and rabbit PONs appear to have two distinct Ca2+ binding sites, one
required for stability and one required for catalytic activity. The Ca2+
dependency of PONs suggests a mechanism of hydrolysis where Ca2+ acts as the
electrophilic catalyst, like that proposed for phospholipase A2 [5]. The
paraoxonase enzymes, PON1 and PON3, are high density lipoprotein (HDL)-
associated proteins capable of preventing oxidative modification of low
density lipoproteins (LPL) [6]. Although PON2 has oxidative properties, the
enzyme does not associate with HDL [7].
Within a given species, PON1, PON2 and PON3 share ~60% amino acid sequence
identity, whereas between mammalian species particular PONs (1,2 or 3) share
79-90% identity at the amino acid level. Human PON1 and PON3 share numerous
conserved phosphorylation and N-glycosylation sites; however, it is not
known whether the PON proteins are modified at these sites, or whether
modification at these sites is required for activity in vivo [6].
The PON2 enzyme is able to lower the intracellular oxidative stress of a
cell and prevent cell-mediated oxidation of LDL [7]. Polymorphisms in human
PON2 are associated with numerous pathophysiological indicators, including
variations in plasma lipoprotein [8], glucose levels in fasting type II
diabetics [9], neonatal birth weight [10], and the risk of coronary heart
disease [11]. Although genetic associations between PON2 and these
conditions have been shown, the exact function of PON2 in humans is unknown.
PARAOXONASE2 is a 3-element fingerprint that provides a signature for the
paraoxonase 2 enzymes. The fingerprint was derived from an initial alignment
of 4 sequences: the motifs were drawn from conserved regions spanning the
full alignment length, focusing on those sections that characterise the type
2 enzymes but distinguish them from the rest of the paraoxonase family. Two
iterations on SPTR40_20f were required to reach convergence, at which point
a true set comprising 5 sequences was identified.
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