Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.4 (deaminase)
 5,113 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trisubstituted nitrosoureas are very stable in aqueous systems. But they are potent genotoxins in Chinese hamster V79-E cells, if no exogenous metabolizing system is added, and the mechanism of their genotoxic and carcinogenic activity has been largely unknown. This investigation shows that the sister-chromatid-exchange (SCE)-inducing capacity of 1,3-dimethyl-3-phenyl-1-nitrosourea (DMPNU) is eliminated by adding diisopropylflurophosphate (DFP) or porcine liver carboxylesterase to the incubation system. These effects are caused by two different mechanisms: (i) DFP inhibits endogenous amidases existing in V79-E cells, thus preventing the intracellular decomposition, which means an activation; and (ii) exogenous carboxylesterase cleaves DMPNU extracellularly, and the genotoxic decomposition product is obviously too short-lived to reach a critical intracellular target. A second trisubstituted nitrosourea, 3,3-diethyl-1-methyl-1-nitrosourea (DEMNU), which is mainly activated by monooxygenases, but in the absence of an exogenous metabolizing system also induces SCEs in V79-E cells, was studied in the same way. It was found that the 'direct' genotoxicity of DEMNU may be inhibited by DFP as well, but carboxylesterase decomposes this trialklynitrosourea with a much lower efficiency than DMPNU suggesting a low substrate affinity. The SCE-inducing capacity of both compounds is strongly influenced by the presence of calf serum in the culture medium. The nature of the serum factor is still unknown. Pathways for the amidase catalysis of DMPNU and for the activation of DEMNU by monooxygenases and amidases are proposed and discussed with respect to the topical or systemic carcinogenicity of these agents.
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PMID:Serine hydrolases activate/inactivate trisubstituted nitrosoureas in dependence on intra- and extracellular enzyme location: an SCE study in Chinese hamster V79-E cells. 279 Nov 98

Prolyl-beta-naphthylamidase from porcine liver is compared with the two prevalent isoenzymes of pig liver carboxylesterase by isoelectrofocusing experiments and by inhibition studies with phenyl-methyl-sulfonyl fluoride. The results suggest that prolyl-beta-naphthylamidase is identical with the amide-cleaving isoenzyme of carboxylesterase, not with the usually predominant methyl butyrate-hydrolysing isoenzyme. It is questionable whether the recently published sequence of prolyl-beta-naphthylamidase does belong to this enzyme or to the predominant carboxylesterase without amidase activity. Surprisingly, the amide-cleaving carboxylesterase isoenzymes from rat liver have almost no activity with prolyl-beta-naphthylamide.
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PMID:A note on the identity of porcine liver carboxylesterase and prolyl-beta-naphthylamidase. 829 62

Conversion of the biophysically active large surfactant aggregate subtype (LA) of alveolar surfactant into the less surface active small surfactant aggregates (SA) occurs in vivo and is reproduced under conditions of cyclic surface area changes in vitro. A serine-active carboxyl esterase has been suggested as the responsible enzymatic activity, although the exact mechanisms underlying the conversion process are presently unclear. We investigated the influence of exogenous serine proteases and synthetic and natural serine protease inhibitors on the conversion kinetics of natural rabbit surfactant, obtained as bronchoalveolar lavage fluid (BALF). In vitro cycling of BALF was performed for various time periods in the absence or presence of increasing amounts of several serine proteases (trypsin, plasmin, thrombin, tryptase), and one natural (aprotinin) and 25 synthetic serine protease inhibitors (including regular benzamidines [group A], 3-amidinophenylalanine derivatives [group B], bis-benzamidines [group C], and analogs of naphthylsulfonyl-glycyl-4-amidinophenylalanine piperidide [group D]). LA were separated from SA by 48,000 x g centrifugation. Surface activity of the LA fraction was measured by means of the pulsating bubble surfactometer. None of the "classical" serine proteases forwarded any acceleration of the LA-to-SA conversion kinetics. Some of the serine protease inhibitors caused moderate retardation of conversion, but at the same dose range inhibited the surface tension-lowering properties of the LA fraction, which per se explained their inhibitory effect. In contrast, specific dose-dependent inhibition of the LA-to-SA transition was observed for four derivatives of the bis-benzamidine group: full blockage of conversion over 240 min of cycling was noted at doses that did not interfere with the surface activity of the LA fraction. In addition, the prototype of these bis-benzamidines, 1,4-bis-[beta-naphthylsulfonyl-(3-aminophenylalanine)]-piperazide, was found to inhibit the activity of the rabbit liver carboxylesterase ES-2 in two different synthetic substrate assays reflecting the amidase and esterase properties of carboxylesterases. These findings support the hypothesis that the LA-to-SA conversion is an enzymatically-driven process with serine-active carboxyl esterase(s) being centrally involved. Synthetic bis-benzamidine-type serine protease inhibitors may offer specific inhibition of this event.
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PMID:Selective inhibition of large-to-small surfactant aggregate conversion by serine protease inhibitors of the bis-benzamidine type. 1249 37