Hydroxamates as Substrates and Inhibitors for FMN-Dependent 2-Hydroxy Acid Dehydrogenases

Amar, David; North, Paul; Miškinienė, Vanda; Čėnas, Narimantas; Lederer, Florence

doi:10.1006/bioo.2002.1237

Cited by 3 publications

(3 citation statements)

References 67 publications

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“…However, to date, they have been known to primarily oxidize hydroxyacid anions to ketoacid anions. The only exceptions so far are the long-chain hydroxyacid oxidase from rat kidney, which can oxidize R-(S)-amino acids as well as an ionized form of 2-hydroxyphenylacetohydroxamic acid, and (L)-pantoyllactone dehydrogenase from Nocardia asteroides, which is able to oxidize a hydroxylactone to a ketolactone (8,11,12). In the present study, we identify methyl and ethyl esters of (S)-mandelic acid as substrates for MDH.…”

mentioning

confidence: 65%

“…The only exception was (L)-pantoyllactone dehydrogenase from N. asteroides, which can utilize a cyclic hydroxyester as a substrate but not a hydroxyacid (12). In another study, long-chain hydroxyacid oxidase was shown to use 2hydroxyphenylacetohydroxamate, with 10-100-fold less efficiency relative to the best substrate, mandelate; the authors concluded that an ionized form of this hydroxamic acid was the actual substrate (11).…”

Section: Discussionmentioning

confidence: 99%

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Esters of Mandelic Acid as Substrates for (S)-Mandelate Dehydrogenase from Pseudomonas putida: Implications for the Reaction Mechanism

Dewanti

Mitra

2004

Biochemistry

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(S)-Mandelate dehydrogenase (MDH) from Pseudomonas putida is a flavin mononucleotide (FMN)-dependent enzyme that oxidizes (S)-mandelate to benzoylformate. In this work, we show that the ethyl and methyl esters of (S)-mandelic acid are substrates for MDH. Although the binding affinity of the neutral esters is 25-50-fold lower relative to the negatively charged (S)-mandelate, they are oxidized with comparable k(cat)s. Substrate analogues in which the carbonyl group on the C-1 carbon is replaced by other electron-withdrawing groups were not substrates. The requirement of a carbonyl group on the C-1 carbon in a substrate suggests that the negative charge developed during the reaction is stabilized by delocalization to the carbonyl oxygen. Arg277, a residue that is important in both binding and transition state stabilization for the activity with (S)-mandelate, is also critical for transition state stabilization for the esters, but not for their binding affinity. We previously showed that the substrate oxidation half-reaction with (S)-mandelate has two rate-limiting steps of similar activation energies and proceeds through the formation of a charge-transfer complex of an electron-rich donor and oxidized FMN [Dewanti, A. R., and Mitra, B. (2003) Biochemistry 42, 12893-12901]. This charge-transfer intermediate was observed with the neutral esters as well. The observation of this electron-rich intermediate for the oxidation of an uncharged substrate to an uncharged product, as well as the critical role of Arg277 in the reaction with the esters, provides further evidence that the MDH reaction mechanism is not a concerted transfer of a hydride ion from the substrate to the FMN, but involves the transient formation of a carbanion/ene(di)olate intermediate.

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confidence: 65%

Section: Discussionmentioning

confidence: 99%

Esters of Mandelic Acid as Substrates for (S)-Mandelate Dehydrogenase from Pseudomonas putida: Implications for the Reaction Mechanism

Dewanti

Mitra

2004

Biochemistry

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“…Flavoenzymes catalyze oxidation of α‐hydroxy acids to form the corresponding α‐keto acids belong to the family of α‐hydroxy acid oxidases [26a,41] . Selective members of the first subclass of α‐hydroxy acid oxidases such as lactate monooxygenase (LaMO) can catalyze oxidative decarboxylation, while lactate oxidase (LaOX) catalyzes oxidation of lactate to form pyruvate.…”

Section: Lactate Monooxygenase Versus Lactate Oxidase (α‐Hydroxy Acid...mentioning

confidence: 99%

Dual Activities of Oxidation and Oxidative Decarboxylation by Flavoenzymes

et al. 2022

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Specific flavoenzyme oxidases catalyze oxidative decarboxylation in addition to their classical oxidation reactions in the same active sites. The mechanisms underlying oxidative decarboxylation by these enzymes and how they control their two activities are not clearly known. This article reviews the current state of knowledge of four enzymes from the l‐amino acid oxidase and l‐hydroxy acid oxidase families, including l‐tryptophan 2‐monooxygenase, l‐phenylalanine 2‐oxidase and l‐lysine oxidase/monooxygenase and lactate monooxygenase which catalyze substrate oxidation and oxidative decarboxylation. Apart from specific interactions to allow substrate oxidation by the flavin cofactor, specific binding of oxidized product in the active sites appears to be important for enabling subsequent decarboxylation by these enzymes. Based on recent findings of l‐lysine oxidase/monooxygenase, we propose that nucleophilic attack of H2O2 on the imino acid product is the mechanism enabling oxidative decarboxylation.

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ChiralN-salicylidene vanadyl carboxylate-catalyzed enantioselective aerobic oxidation of α-hydroxy esters and amides

Weng

Shen²,

Kao³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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A series of chiral vanadyl carboxylates derived from N-salicylidene-L-␣-amino acids and vanadyl sulfate has been developed. These configurationally well defined complexes were examined for the kinetic resolution of double-and mono-activated 2°alcohols. The best chiral templates involve the combination of L-tert-leucine and 3,5-di-t-butyl-, 3,5-diphenyl-, or 3,4-dibromo-salicylaldehyde. The resulting vanadyl(V)-methoxide complexes after recrystallization from air-saturated methanol serve as highly enantioselective catalysts for asymmetric aerobic oxidation of ␣-hydroxyl-esters and amides with a diverse array of ␣-, O-, and N-substituents at ambient temperature in toluene. The asymmetric inductions of the oxidation process are in the range of 10 to >100 in terms of selectivity factors (k rel) in most instances. The previously undescribed aerobic oxidation protocol is also applicable to the kinetic resolution of C-13 taxol side chain with high selectivity factor (k rel ‫؍‬ 35). X-ray crystallographic analysis of an adduct between a given vanadyl complex and N-benzyl-mandelamide allows for probing the stereochemical origin of the nearly exclusive asymmetric control in the oxidation process.alcohol oxidation ͉ ␣-hydroxy acids ͉ asymmetric catalysis ͉ vanadyl(V) methoxides T he oxidation of alcohols normally requires stoichiometric use of DMSO-based reagents or metal oxides of high oxidation state (1). Advances on their aerobic oxidations with catalytic metal oxides [e.g., RuO 2 -H 2 O (2), V 2 O 5 -K 2 CO 3 (3), and OsO 4 -Cu(O 2 CR) 2 (4)], homogeneous metal complexes [e.g., Co(OAc) 2 -N-hydroxyphthalimide (5), Ru(III)NOCl(salen) (6), RuCl 2 (PPh 3 ) 3 -hydroquinone-K 2 CO 3 (7), CuCl-Phen-DBADH 2 (8), RuCl 2 (PPh 3 ) 2 -TEMPO (9)͞CuCl-TEMPO (10), Pd(OAc) 2 -pyridine (11, 12), and Pd 4 Phen 2 (CO)(OAc) 4 (13)], bimetallic complexes [e.g., RuCl 3 -Co(OAc) 2 -aldehyde (14) and MoO 2 (acac) 2 -CuNO 3 ] (14, 15), or heterogeneous metal complexes [e.g., Ru(III) hydroxyapatite (16), polyaniline-supported MoO 2 (acac) 2 (17), and Pd(OAc) 2 -hydrotalcite-pyridine (18)] have been documented. Notably, additives and͞or bases are often needed to increase the catalyst reactivity and͞or to facilitate the turnover process. In addition, the targeted substrates are somewhat limited to primary, benzylic, allylic, and propargylic alcohols. Recently, the asymmetric variants of the aerobic catalytic process have attracted a lot of attention (19,20). So far, Pd(II)-sparteine (21, 22), photoly activated RuNOCl(salen) (23), and Mn(III)(salen)PF 6 (24) have been developed with fair to high enantioselectivity toward kinetic resolutions of 2°benzylic alcohols. In marked contrast, the asymmetric aerobic catalytic process with ␣-hydroxycarboxylic acid derivatives is relatively unexplored (25-31).Optically pure ␣-hydroxycarboxylic acid and mandelic acid derivatives are important precursors toward enantioselective synthesis scopes. Based on our experiences of using vanadyl and oxometallic species in catalyzing C-C and C-X bond forming (47-51), ae...

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Hydroxamates as Substrates and Inhibitors for FMN-Dependent 2-Hydroxy Acid Dehydrogenases

Cited by 3 publications

References 67 publications

Esters of Mandelic Acid as Substrates for (S)-Mandelate Dehydrogenase from Pseudomonas putida: Implications for the Reaction Mechanism

Esters of Mandelic Acid as Substrates for (S)-Mandelate Dehydrogenase from Pseudomonas putida: Implications for the Reaction Mechanism

Dual Activities of Oxidation and Oxidative Decarboxylation by Flavoenzymes

ChiralN-salicylidene vanadyl carboxylate-catalyzed enantioselective aerobic oxidation of α-hydroxy esters and amides

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