Multiple Isotope Effects on the Acyl Group Transfer Reactions of Amides and Esters

Marlier, John F.

doi:10.1021/ar000054d

Cited by 106 publications

(90 citation statements)

References 40 publications

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“…5). For acyl substitution reactions involving very good leaving groups, as is the case here, concerted mechanisms are believed to occur through a tetrahedral transition state (20,21), or even by a dissociative mechanism and formation of an acylium ion (22,23). For nitrogen nucleophiles, however, the development of positive charge on nitrogen as bond formation to the carbonyl carbon proceeds (Fig.…”

Section: Discussionmentioning

confidence: 80%

“…For nitrogen nucleophiles, however, the development of positive charge on nitrogen as bond formation to the carbonyl carbon proceeds (Fig. 5) gives a more ambiguous situation where existing data do not distinguish between formation of a tetrahedral transition state or intermediate (20,23). Notwithstanding, the crystal structures show that ␤-LS has evolved to provide functional groups in the active site that both optimize reaction geometries, and stabilize intermediates and transition states during the course of the ␤-LS reaction sequence.…”

Section: Discussionmentioning

confidence: 99%

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The catalytic cycle of β-lactam synthetase observed by x-ray crystallographic snapshots

Miller

Bachmann

Townsend

et al. 2002

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

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The catalytic cycle of the ATP͞Mg 2؉ -dependent enzyme ␤-lactam synthetase (␤-LS) from Streptomyces clavuligerus has been observed through a series of x-ray crystallographic snapshots. Chemistry is initiated by the ordered binding of ATP͞Mg 2؉ and N 2 -(carboxyethyl)-L-arginine (CEA) to the apoenzyme. The apo and ATP͞Mg 2؉ structures described here, along with the previously described CEA⅐␣,␤-methyleneadenosine 5 -triphosphate (CEA⅐AMP-CPP)͞Mg 2؉ structure, illuminate changes in active site geometry that favor adenylation. In addition, an acyladenylate intermediate has been trapped. The substrate analog N 2 -(carboxymethyl)-L-arginine (CMA) was adenylated by ATP in the crystal and represents a close structural analog of the previously proposed CEA-adenylate intermediate. Finally, the structure of the ternary product complex deoxyguanidinoproclavaminic acid (DGPC)⅐AMP͞PP i͞Mg 2؉ has been determined. The CMA-AMP͞PP i͞Mg 2؉ and DGPC⅐AMP͞PPi͞Mg 2؉ structures reveal interactions in the active site that facilitate ␤-lactam formation. All of the ATP-bound structures differ from the previously described CEA⅐AMP-CPP͞Mg 2؉ structure in that two Mg 2؉ ions are found in the active sites. These Mg 2؉ ions play critical roles in both the adenylation and ␤-lactamization reactions.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

The catalytic cycle of β-lactam synthetase observed by x-ray crystallographic snapshots

Miller

Bachmann

Townsend

et al. 2002

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

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“…Secondary kinetic isotope effects are normal if the labeled atom becomes more loosely bonded in the transition state or inverse if bonding becomes tighter. A fuller description of the contributions to isotope effects in general, and to those on sulfuryl transfer reactions in particular, can be found in recent reviews (19,20).…”

Section: Resultsmentioning

confidence: 99%

Transition State of the Sulfuryl Transfer Reaction of Estrogen Sulfotransferase

Hoff

Czyryca

Sun

et al. 2006

Journal of Biological Chemistry

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In 1876, Baumann (1) demonstrated that phenol administered to a patient was excreted as phenyl sulfate. It was not until some 80 years later that the most common biological sulfate donor, 3Ј-phosphoadenosine-5Ј-phosphosulfate (PAPS), 3 was identified (2). Sulfotransferases catalyze the transfer of the sulfuryl group from a donor, which is most often PAPS, to hydroxyl or amine nucleophiles (Fig. 1). The reverse reaction, the hydrolysis of sulfate esters, is catalyzed by sulfatases. Thus, these enzymes have a complementary relationship analogous to that of kinases and phosphatases. However, enzymatic sulfuryl transfer has remained less thoroughly studied than phosphoryl transfer. Among sulfotransferases that utilize PAPS, several structural and mechanistic investigations have been reported. Structures have been solved for catecholamine sulfotransferase (3), dopamine sulfotransferase (4), and hydroxysteroid sulfotransferase (5). The x-ray structures have been solved for estrogen sulfotransferase (EST) with 3Ј-phosphoadenosine 5Ј-phosphate (PAP) and estradiol bound (6) and also for the EST-PAP-vanadate complex (7).EST catalyzes sulfuryl transfer between PAPS and the phenolic oxygen atom of ␤-estradiol. The sulfation prevents ␤-estradiol from binding to and activating the estrogen receptor. EST catalyzes both the forward and the reverse reactions, as shown in Fig. 1; p-nitrophenol is an alternate sulfuryl acceptor in the forward direction, and p-nitrophenyl sulfate ( pNPS) can function as a sulfuryl donor to PAP in the reverse direction (8).X-ray structures and site-directed mutagenesis have identified two crucial active site residues, His-108 and Lys-106, which are each ϳ3 Å from the oxygen atom of estradiol. Mutation of Lys-106 to arginine, serine, and alanine had little impact on the K m for PAPS but decreased the k cat value by a factor of 200 -3000, and mutation of His-108 to serine, leucine, lysine, or arginine resulted in a protein with no detectable catalytic activity (7). This effect and the position of His-108 relative to the phenol group on the substrate suggest a role for this residue as a catalytic base. Lys-106, the only residue in a position to interact with the nonbridging oxygens of the transferring SO 3 moiety, probably functions in substrate positioning and transition state stabilization. The x-ray structures led to the proposal of a concerted, in-line mechanism for transfer of the sulfuryl group (7).Kinetic isotope effects (9) and linear free energy relationships (10 -14) have revealed that uncatalyzed sulfuryl transfer reactions have transition states characterized by extensive leaving group bond fission and little nucleophilic participation. This is described as a loose transition state in which the sulfuryl group resembles SO 3 . In this study, kinetic isotope effects were used to examine the transition state of the EST-catalyzed sulfuryl transfer from the alternate sulfuryl donor pNPS to PAP. The KIEs have previously been reported for the uncatalyzed hydrolysis of pNPS (9) and for the reaction...

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“…[21][22][23][24][25][26][27] In contrast, the DKIEs can only be secondary inverse (k H /k D < 1.0) in a stepwise process (or a normal S N 2 reaction) because the N-H(D) vibrational frequencies invariably increase upon going to the TS because of an increase in the steric congestion. [28][29][30] In this respect, DKIEs have provided a useful means to determine the TS structures in the nucleophilic substitution reactions, as well as how the reactants alter the TS structures, particularly through changes in the substituents.…”

Section: -7mentioning

confidence: 99%

Kinetics and Mechanism of the Anilinolysis of Aryl Ethyl Isothiocyanophosphates in Acetonitrile

Barai¹,

Adhikary²,

Lee³

2013

Bulletin of the Korean Chemical Society

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The nucleophilic substitution reactions of Y-aryl ethyl isothiocyanophosphates with substituted X-anilines and deuterated X-anilines were investigated kinetically in acetonitrile at 75.0 o C. The free energy relationships with X in the nucleophiles exhibited biphasic concave downwards with a break point at X = H. A stepwise mechanism with rate-limiting bond formation for strongly basic anilines and with rate-limiting bond breaking for weakly basic anilines is proposed based on the negative and positive ρ XY values, respectively. The deuterium kinetic isotope effects (DKIEs; k H /k D ) changed gradually from primary normal with strongly basic anilines, via primary normal and secondary inverse with aniline, to secondary inverse with weakly basic anilines. The primary normal and secondary inverse DKIEs were rationalized by frontside attack involving hydrogen bonded, four-center-type TSf and backside attack involving in-line-type TSb, respectively.

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Multiple Isotope Effects on the Acyl Group Transfer Reactions of Amides and Esters

Cited by 106 publications

References 40 publications

The catalytic cycle of β-lactam synthetase observed by x-ray crystallographic snapshots

The catalytic cycle of β-lactam synthetase observed by x-ray crystallographic snapshots

Transition State of the Sulfuryl Transfer Reaction of Estrogen Sulfotransferase

Kinetics and Mechanism of the Anilinolysis of Aryl Ethyl Isothiocyanophosphates in Acetonitrile

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