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.
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8. BILLECKE, S., DRAGANOV, D., COUNSELL, R., STETSON, P., WATSON, C., HSU,
C. AND LA DU, B.N.
Human serum paraoxonase (PON1) isozymes Q and R hydrolyze lactones and
cyclic carbonate esters.
DRUG METAB.DISPOS. 28 1335-1342 (2000).
9. HUMBERT, R., ADLER, D.A., DISTECHE, C.M., HASSETT, C., OMIECINSKI, C.J.
AND FURLONG, C.E.
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A polymorphism of the paraoxonase gene associated with variation in plasma
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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].
Rabbit and human serum PON1 also hydrolyse a variety of lactones and cyclic
carbonate esters, including naturally occurring lactones and pharmacological
agents [8]. Humans have 2 common PON1 allozymes, determined by the presence
of either arginine or glutamine at position 191. The A-type allozyme
(glutamine at position 191) causes low paraoxonase activity [9]; this
polymorphism is associated with variations in cholesterol and lipoprotein
levels [10].
PARAOXONASE1 is a 3-element fingerprint that provides a signature for the
paraoxonase 1 enzymes. The fingerprint was derived from an initial alignment
of 4 sequences: the motifs were drawn from conserved regions spanning the
N-terminal portion of the alignment, focusing on those sections that
characterise the type 1 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 7 sequences was identified.
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