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Substrate specificity and catalytic ...

Dick, Ryan Andrew.

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Substrate specificity and catalytic mechanism of NADPH-dependent alkenal/one oxidoreductase.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Substrate specificity and catalytic mechanism of NADPH-dependent alkenal/one oxidoreductase./
作者:	Dick, Ryan Andrew.
面頁冊數:	142 p.
附註:	Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 4878.
Contained By:	Dissertation Abstracts International64-10B.
標題:	Health Sciences, Pharmacology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3107496

Substrate specificity and catalytic mechanism of NADPH-dependent alkenal/one oxidoreductase.
Dick, Ryan Andrew.

Substrate specificity and catalytic mechanism of NADPH-dependent alkenal/one oxidoreductase. - 142 p.

Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 4878.

Thesis (Ph.D.)--The Johns Hopkins University, 2004.

NADPH-dependent alkenal/one oxidoreductase (AOR) was identified in a screen for novel dithiolethione inducible genes of the rat liver. Via its leukotriene B4 12-hydroxydehydrogenase activity, it is capable of inactivating this potent neutrophil chemoattractant. However, its ability to reduce the carbon-carbon double bond of α,β-unsaturated carbonyls proved much more robust. The substrate specificity of this activity was therefore investigated. Several α,β-unsaturated aldehydes and ketones, including cytotoxic aldehydic products of lipid peroxidation, were found to be substrates. Experiments were completed to verify that AOR did not reduce the carbonyl double bond. Overexpression of AOR was found to confer protection from 4-hydroxy-2-nonenal (4HNE), the most prominent and cytotoxic lipid peroxidation product, to 293 cells.Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Substrate specificity and catalytic mechanism of NADPH-dependent alkenal/one oxidoreductase.
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100 1 $a Dick, Ryan Andrew. $3 1947066
245 1 0 $a Substrate specificity and catalytic mechanism of NADPH-dependent alkenal/one oxidoreductase.
300 $a 142 p.
500 $a Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 4878.
500 $a Adviser: Thomas W. Kensler.
502 $a Thesis (Ph.D.)--The Johns Hopkins University, 2004.
520 $a NADPH-dependent alkenal/one oxidoreductase (AOR) was identified in a screen for novel dithiolethione inducible genes of the rat liver. Via its leukotriene B4 12-hydroxydehydrogenase activity, it is capable of inactivating this potent neutrophil chemoattractant. However, its ability to reduce the carbon-carbon double bond of α,β-unsaturated carbonyls proved much more robust. The substrate specificity of this activity was therefore investigated. Several α,β-unsaturated aldehydes and ketones, including cytotoxic aldehydic products of lipid peroxidation, were found to be substrates. Experiments were completed to verify that AOR did not reduce the carbonyl double bond. Overexpression of AOR was found to confer protection from 4-hydroxy-2-nonenal (4HNE), the most prominent and cytotoxic lipid peroxidation product, to 293 cells.
520 $a Studies of the catalytic and kinetic mechanism of the reductase activity of AOR were completed to validate its classification as a medium-chain dehydrogenase/reductase. Consistent with horse liver alcohol dehydrogenase, AOR exhibited a sequential ordered binding kinetic mechanism with dinucleotide cofactor binding first and leaving last. However, metabolism of <italic>trans</italic>-2-nonen-3-one by AOR displayed a Theorell-Chance mechanism. AOR was also found to transfer the pro-<italic>R</italic> hydride of NADPH to what will become the <italic> R</italic> position of the unsaturated substrate. The pKa of this activity was determined to be 9.2.
520 $a The mycotoxin illudins and investigational anticancer alkylating drug, irofulven, were also found to be excellent substrates of AOR. Each compound contains an α,β-unsaturated ketone, whose reduction leads to the activation of a strained cyclopropyl group. Activation of this group through reduction of the 8,9-double bonds of these compounds by AOR was postulated to account for their toxicity. However AOR overexpression experiments confirmed that only the activation of irofulven by AOR is biologically relevant. This was confirmed in a panel of 60-human tumor cell lines by a positive correlation between AOR activity levels and irofulven sensitivity. Irofulven was also found to irreversibly inhibit AOR in both NADPH-dependent and independent manners. NADPH-dependent inactivation was interpreted as being mechanism-based, while the labile 15-hydroxyl group was hypothesized to account for NADPH-independent inactivation. Interestingly, irofulven was also found to induce cross-linking of AOR monomers in a NADPH-independent manner.
590 $a School code: 0098.
650 4 $a Health Sciences, Pharmacology. $3 1017717
690 $a 0419
710 2 0 $a The Johns Hopkins University. $3 1017431
773 0 $t Dissertation Abstracts International $g 64-10B.
790 1 0 $a Kensler, Thomas W., $e advisor
790 $a 0098
791 $a Ph.D.
792 $a 2004
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3107496