Senescence marker protein-30 is a unique enzyme that hydrolyzes diisopropyl phosphorofluoridate in the liver.
Senescence marker protein-30 (SMP30) was originally identified as a novel protein in the rat liver, the expression of which decreases androgen-independently with aging. We have now characterized a unique property of SMP30, the hydrolysis of diisopropyl phosphorofluoridate (DFP), which is similar to the chemical warfare nerve agents sarine, soman and tabun. Hydrolysis of DFP was stimulated equally well by 1 mM MgCl2, MnCl2 or CoCl2, to a lesser extent by 1 mM CdCl2 but not at all by 1 mM CaCl2. No 45Ca2+-binding activity was detected for purified SMP30, suggesting that SMP30 is not a calcium-binding protein, as others previously stated. Despite the sequence similarity between SMP30 and a serum paraoxonase (PON), the inability of SMP30 to hydrolyze PON-specific substrates such as paraoxon, dihydrocoumarin, gamma-nonalactone, and delta-dodecanolactone indicate that SMP30 is distinct from the PON family. We previously established SMP30 knockout mice and have now tested DFPase activity in their livers. The livers from wild-type mice contained readily detectable DFPase activity, whereas no such enzyme activity was found in livers from SMP30 knockout mice. Moreover, the hepatocytes of SMP30 knockout mice were far more susceptible to DFP-induced cytotoxicity than those from the wild-type. These results indicate that SMP30 is a unique DFP hydrolyzing enzyme in the liver and has an important detoxification effect on DFP. Consequently, a reduction of SMP30 expression might account for the age-associated deterioration of cellular functions and enhanced susceptibility to harmful stimuli in aged tissue.
Kondo
Yoshitaka
Y
Department of Molecular Pathology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
Ishigami
Akihito
A
Kubo
Sachiho
S
Handa
Setsuko
S
Gomi
Keiko
K
Hirokawa
Kozo
K
Kajiyama
Naoki
N
Chiba
Tsuyoshi
T
Shimokado
Kentaro
K
Maruyama
Naoki
N
D000375:Aging; D000595:Amino Acid Sequence; D000818:Animals; D043303:Aryldialkylphosphatase / Q000097:blood; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000096:biosynthesis* / Q000737:chemistry; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D016923:Cell Death; D002712:Chlorides / Q000494:pharmacology; D003035:Cobalt / Q000494:pharmacology; D003374:Coumarins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D049454:Firefly Luciferin / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006868:Hydrolysis; D047908:Intracellular Signaling Peptides and Proteins; D007531:Isoflurophate / Q000378:metabolism*; D007783:Lactones / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D015636:Magnesium Chloride / Q000494:pharmacology; D008297:Male; D017895:Manganese Compounds / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010261:Paraoxon / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D015238:Sulfotransferases
D002135:Calcium-Binding Proteins; D002712:Chlorides; D003374:Coumarins; D047908:Intracellular Signaling Peptides and Proteins; D007783:Lactones; D017895:Manganese Compounds; C513324:Rgn protein, mouse; D015636:Magnesium Chloride; D007531:Isoflurophate; D003035:Cobalt; C034805:3,4-dihydro-3,4-dibromo-6-bromomethylcoumarin; D049454:Firefly Luciferin; D015238:Sulfotransferases; C028152:alcohol sulfotransferase; D002265:Carboxylic Ester Hydrolases; C019734:arylesterase; D043303:Aryldialkylphosphatase; C018021:cobaltous chloride; D010261:Paraoxon; C025340:manganese chloride; D002118:Calcium