Efficient Catalytic Promiscuity in an Enzyme Superfamily: An Arylsulfatase Shows a Rate Acceleration of 10<sup>13</sup> for Phosphate Monoester Hydrolysis

Olguín, Luis F.; Askew, Sarah E.; O’Donoghue, AnnMarie C.; Hollfelder, Florian

doi:10.1021/ja8047943

Cited by 81 publications

(143 citation statements)

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“…The x-ray structure of BcPMH confirms that it is structurally and mechanistically closely related to arylsulfatases and also, albeit more distantly, to AP and nucleotide phosphodiesterase (11,13). These three enzymes catalyze at least two reactions besides their native activity that are the native reactions of another family member (14)(15)(16)(17)(18)(19). BcPMH promotes all native reactions of these three enzymes, making catalytic promiscuity a widespread feature of this superfamily.…”

Section: Discussionmentioning

confidence: 63%

“…PMH is a member of the alkaline phosphatase (AP) superfamily that encompasses structurally related enzymes known to hydrolyze phosphate monoesters and diesters and sulfate monoesters (13). Several members of the AP superfamily show catalytic promiscuity, and in some cases the promiscuous reactions are the native activities of other superfamily members (14)(15)(16)(17)(18)(19).BcPMH catalyzes the hydrolysis of a total of six different substrate classes, four of which correspond to activities seen in the AP superfamily. The collection of substrate classes, for which rate accelerations between 10 7 and 10 19 are observed, encompasses large variations in charge, the reaction center, size, hydrophobicity, reactivity, and nature of the TS of the uncatalyzed reaction.…”

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confidence: 99%

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An efficient, multiply promiscuous hydrolase in the alkaline phosphatase superfamily

Loo

Jonas

Babtie

et al. 2010

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

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164

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We report a catalytically promiscuous enzyme able to efficiently promote the hydrolysis of six different substrate classes. Originally assigned as a phosphonate monoester hydrolase (PMH) this enzyme exhibits substantial second-order rate accelerations (ðk cat ∕K M Þ∕ k w ), ranging from 10 7 to as high as 10 19 , for the hydrolyses of phosphate mono-, di-, and triesters, phosphonate monoesters, sulfate monoesters, and sulfonate monoesters. This substrate collection encompasses a range of substrate charges between 0 and −2, transition states of a different nature, and involves attack at two different reaction centers (P and S). Intrinsic reactivities (half-lives) range from 200 days to 10 5 years under near neutrality. The substantial rate accelerations for a set of relatively difficult reactions suggest that efficient catalysis is not necessarily limited to efficient stabilization of just one transition state. The crystal structure of PMH identifies it as a member of the alkaline phosphatase superfamily. PMH encompasses four of the native activities previously observed in this superfamily and extends its repertoire by two further activities, one of which, sulfonate monoesterase, has not been observed previously for a natural enzyme. PMH is thus one of the most promiscuous hydrolases described to date. The functional links between superfamily activities can be presumed to have played a role in functional evolution by gene duplication.catalytic promiscuity | evolution | mechanism | sulfatase | superfamily E nzymes are usually seen as highly specific catalysts following the classical rule "one enzyme, one activity." This view is challenged by an increasing number of enzymes with broad substrate specificities or side activities indicating that enzymes are catalytically more flexible than originally assumed. Some of these promiscuous enzymes can turn over substrates with different structures while catalyzing the same chemical reaction involving the same transition state (substrate promiscuity). Catalytic promiscuity, by contrast, is the ability of an enzyme to catalyze chemically distinct reactions by stabilization of different transition states (TSs) (1). Catalytic efficiencies (k cat ∕K M ) for the promiscuous substrates are often substantially lower (2 to 9 orders of magnitude) than for the native conversions (1-3). The growing number of examples of this phenomenon (1-4) has engendered excitement on a number of fronts. Catalytic promiscuity provides a functional basis for enzyme evolution by gene duplication. The initial head-start activity of the duplicated gene copy could support an immediate selective advantage (1, 2, 5, 6), to be followed by improvement of the initially weak activity (7). Even low k cat ∕K M values for a promiscuous function can support a significant selective advantage (8). Mimicking this evolutionary shortcut could also provide a more efficient route to changing the function of proteins by directed evolution (5).We describe multiple and efficient catalytic promiscuity in an enzyme from Burkh...

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Section: Discussionmentioning

confidence: 63%

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confidence: 99%

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confidence: 99%

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An efficient, multiply promiscuous hydrolase in the alkaline phosphatase superfamily

Loo

Jonas

Babtie

et al. 2010

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

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164

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“…It constitutes a very important property of many enzymes, having a natural role in evolution and, occasionally, in the biosynthesis of secondary metabolites. [1][2][3][4][5][6][7] For example, it has been demonstrated that vanadium-dependent chloroperoxidase shows phosphatase activity when vanadate is not present, indicating that its active site is very similar to that of the acid phosphatases. 8 On the other hand, it was found that an acid phosphatase from plants (in contrast to the kidney bean purple acid phosphatase (PAP)) uniquely exhibits chloroperoxidase activity with loss of phosphatase activity when orthovanadate is added to the apo form of the enzyme.…”

Section: Introductionmentioning

confidence: 99%

“…11,12 Nevertheless, no catecholase activity for any of the well characterized PAPs has as yet been described. While several enzymes displaying catalytic promiscuity have been the subject of recent related investigations, [1][2][3][4][5][6][7] there are few examples of synthetic analogues which exhibit such multifunctional activities. [13][14][15][16][17][18] In recent years, considerable attention has been devoted to the synthesis, X-ray structural analysis and physicochemical characterization of structural and functional dinuclear Fe III M II mimetics for the active site of metallohydrolases such as purple acid phosphatase.…”

Section: Introductionmentioning

confidence: 99%

Catalytic promiscuity: catecholase-like activity and hydrolytic DNA cleavage promoted by a mixed-valence FeIII FeII complex

Neves¹,

Bortoluzzi²,

Jovito³

et al. 2010

J. Braz. Chem. Soc.

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Os estudos sobre enzimas têm mostrado que existe uma relação clara entre a evolução enzimática e a propriedade de promiscuidade catalítica que elas podem apresentar. Com isto, o desenvolvimento de sistemas biomiméticos capazes de atuar de modo promíscuo, de forma similar a algumas enzimas, mostrou-se um novo desafio para os químicos bioinorgânicos. Neste trabalho, reportamos a estrutura de raios X e os estudos em solução e de promiscuidade catalítica do complexo [(bpbpmp)Fe . Assim, o complexo 1 apresenta atividades de hidrolase e oxidoredutase, sendo um interessante modelo sintético para estudos de promiscuidade catalítica.Catalytic promiscuity has emerged as an important property of many enzymes since the relationship of this property to enzymatic evolution became clear. Simultaneously, the development of suitable biomimetic catalytic systems capable of mimicking the promiscuous catalytic properties of such enzymes represents a new challenge for bioinorganic chemists. In this paper we report on the X-ray structure, the solution studies and the promiscuous catalytic activity of the mixed-valence complex [(bpbpmp)Fe III (m-OAc) 2 Fe II ](ClO 4 ), (1), containing the unsymmetrical dinucleating ligand 2-{[(2-hydroxybenzyl)(2-pyridylmethyl)aminomethyl]-4-methyl-6-[bis(2-pyridylmethyl) aminomethyl]}phenol (H 2 bpbpmp). Potentiometric and spectrophotometric titrations and kinetics studies showed that this coordination compound generates active species that promote hydrolytic cleavage of double strand DNA (dsDNA), with a rate enhancement of 1.9×10 8 over the non-catalyzed reaction, as well as promote oxidation of 3,5-di-tert-butylcatechol (3,5-dtbc), with k cat = 1.16 × 10 -2 s -1and K M = 7.1×10 -4 mol L -1. Thus, complex 1 shows both hydrolase and oxidoreductase activities and can be regarded as a man-made model for studying catalytic promiscuity.

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Phosphatases

Hengge

Chu

2010

Encyclopedia of Catalysis

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Phosphatases are enzymes that catalyze the hydrolysis of a phosphate monoester, or, in other words, the phosphoryl transfer from an ester substrate to water. Some phosphatases, utilizing a binuclear metal center, accomplish this reaction in a single step. Others, some of which also utilize two‐metal ion catalysis and some of which do not, first form a phosphoenzyme intermediate, which is hydrolyzed by attack of water in a second step. Protein‐tyrosine phosphatases utilize a conserved cysteine residue and form a phosphocysteine intermediate. Alkaline phosphatases utilize two zinc ions and form a phosphoserine intermediate. The protein serine/threonine phosphatases and the purple acid phosphatases have a dinuclear metal center and catalyze the direct transfer of the phosphoryl group to a metal‐coordinated hydroxide. A number of phosphatases have been found capable of catalyzing other hydrolysis reactions, such as those of sulfate esters, or of phosphate and phosphonate diesters. Such so‐called promiscuous activities arise from the ability of the enzymes to stabilize a trigonal bipyramidal transition state, which is common to the reaction of its native substrate as well as the alternate substrates.

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Efficient Catalytic Promiscuity in an Enzyme Superfamily: An Arylsulfatase Shows a Rate Acceleration of 10¹³ for Phosphate Monoester Hydrolysis

Cited by 81 publications

References 94 publications

An efficient, multiply promiscuous hydrolase in the alkaline phosphatase superfamily

An efficient, multiply promiscuous hydrolase in the alkaline phosphatase superfamily

Catalytic promiscuity: catecholase-like activity and hydrolytic DNA cleavage promoted by a mixed-valence FeIII FeII complex

Phosphatases

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Efficient Catalytic Promiscuity in an Enzyme Superfamily: An Arylsulfatase Shows a Rate Acceleration of 1013 for Phosphate Monoester Hydrolysis

Cited by 81 publications

References 94 publications

An efficient, multiply promiscuous hydrolase in the alkaline phosphatase superfamily

An efficient, multiply promiscuous hydrolase in the alkaline phosphatase superfamily

Catalytic promiscuity: catecholase-like activity and hydrolytic DNA cleavage promoted by a mixed-valence FeIII FeII complex

Phosphatases

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Efficient Catalytic Promiscuity in an Enzyme Superfamily: An Arylsulfatase Shows a Rate Acceleration of 10¹³ for Phosphate Monoester Hydrolysis