A 1010 Rate Enhancement of Phosphodiester Hydrolysis by a Dinuclear Aminopeptidase—Transition-State Analogues as Substrates?

Park, Hyun Ik; Ming, Li‐June

doi:10.1002/(sici)1521-3773(19991004)38:19<2914::aid-anie2914>3.0.co;2-p

Cited by 23 publications

(20 citation statements)

References 7 publications

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“…However, some phosphoesters and fluorophosphates can be hydrolyzed by serine proteases and esterases via nucleophilic attack by the active-site Ser [7], which nevertheless produces an indefinitely stable dead-end complex with the phospho-center covalently attached to the Ser. Moreover, the phosphoester bis(p-nitrophenyl)phosphate (BNPP) and the phosphonate ester p-nitrophenyl phenylphosphonate can be effectively hydrolyzed by the dinuclear aminopeptidase (AP) from Streptomyces griseus (SgAP) with activities comparable to some native phosphoesterases [8][9][10]. Since phospho-and phosphono-esters are TS à -like molecules and can inhibit peptide hydrolysis [11][12][13], their hydrolysis by SgAP is novel and must take place according to a unique catalytic pathway of the enzyme.…”

Section: Introductionsupporting

confidence: 75%

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Mechanistic role of each metal ion in Streptomyces dinuclear aminopeptidase: Peptide hydrolysis and 7×1010-fold rate enhancement of phosphodiester hydrolysis

Ercan

Tay

Grossman

et al. 2010

Journal of Inorganic Biochemistry

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Section: Introductionsupporting

confidence: 75%

“…However, ApAP [19] along with mammalian AP-P and Escherichia coli Met AP [20][21][22] require only one metal to activate, and a second metal to modulate, its activity. Conversely, SgAP requires two metal ions for catalysis on the basis of crystallographic, NMR, and kinetic studies [8][9][10]19,[23][24][25].…”

Section: Introductionmentioning

confidence: 95%

Mechanistic role of each metal ion in Streptomyces dinuclear aminopeptidase: Peptide hydrolysis and 7×1010-fold rate enhancement of phosphodiester hydrolysis

Ercan

Tay

Grossman

et al. 2010

Journal of Inorganic Biochemistry

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“…Recent findings that other two metal ion catalysts have promiscuous phosphodiesterase activity provide additional evidence for the inherent catalytic potential of binuclear clusters for catalyzing phosphate diester hydrolysis. The bacterial phosphotriesterase (68), an aminopeptidase from Streptomyces (69), and now alkaline phosphatase have each been shown to provide substantial rate enhancements for cleavage of a phosphate diester bond [(k cat /K m )/k w ) 10 10 - 10 15 ]. As each of these enzymes catalyzes different chemical transformations in their physiological roles and has independent evolutionary histories, this suggests that two metal ions positioned ∼4 Å apart are especially conducive to catalysis of phosphate diester hydrolysis.…”

Section: Discussionmentioning

confidence: 99%

Functional Interrelationships in the Alkaline Phosphatase Superfamily: Phosphodiesterase Activity of Escherichia coli Alkaline Phosphatase

2001

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Escherichia coli alkaline phosphatase (AP) is a proficient phosphomonoesterase with two Zn 2+ ions in its active site. Sequence homology suggests a distant evolutionary relationship between AP and alkaline phosphodiesterase/nucleotide pyrophosphatase, with conservation of the catalytic metal ions. Furthermore, many other phosphodiesterases, although not evolutionarily related, have a similar active site configuration of divalent metal ions in their active sites. These observations led us to test whether AP could also catalyze the hydrolysis of phosphate diesters. The results described herein demonstrate that AP does have phosphodiesterase activity: the phosphatase and phosphodiesterase activities copurify over several steps; inorganic phosphate, a strong competitive inhibitor of AP, inhibits the phosphodiesterase and phosphatase activities with the same inhibition constant; a point mutation that weakens phosphate binding to AP correspondingly weakens phosphate inhibition of the phosphodiesterase activity; and mutation of active site residues substantially reduces both the mono-and diesterase activities. AP accelerates the rate of phosphate diester hydrolysis by 10 11 -fold relative to the rate of the uncatalyzed reaction [(k cat / K m )/k w ]. Although this rate enhancement is substantial, it is at least 10 6 -fold less than the rate enhancement for AP-catalyzed phosphate monoester hydrolysis. Mutational analysis suggests that common active site features contribute to hydrolysis of both phosphate monoesters and phosphate diesters. However, mutation of the active site arginine to serine, R166S, decreases the monoesterase activity but not the diesterase activity, suggesting that the interaction of this arginine with the nonbridging oxygen(s) of the phosphate monoester substrate provides a substantial amount of the preferential hydrolysis of phosphate monoesters. The observation of phosphodiesterase activity extends the previous observation that AP has a low level of sulfatase activity, further establishing the functional interrelationships among the sulfatases, phosphatases, and phosphodiesterases within the evolutionarily related AP superfamily. The catalytic promiscuity of AP could have facilitated divergent evolution via gene duplication by providing a selective advantage upon which natural selection could have acted.Two divalent metal ions are a common active site feature found in a number of evolutionarily distinct classes of enzymes, including enzymes that catalyze the hydrolysis of phosphate monoesters, diesters, and triesters (for reviews, see refs 1 and 2). The structural similarity shared by these active sites raises the possibility that a single active site with two divalent metal ions might be able to catalyze these different classes of reactions. However, the partial negative charge on a phosphoryl oxygen atom of the phosphate monoester dianion is lost upon conversion to a diester monoanion, and the steric bulk of the added esterifying group of the diester could result in steric clashes with...

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“…Park and Ming found that the dizinc aminopeptidase from Streptomyces griseus (sAP) with native amidase activity showed phosphatase activity towards phosphodiesters and phosphonates with enormous catalytic proficiencies comparable to some phosphatases and phosphodiesterases (Scheme 47). 87 The authors proved that the transformation took place at the active site of the enzyme since no activity was observed with covalently inhibited enzyme.…”

Section: Phosphatase Activity Of Aryl Aminopeptidasesmentioning

confidence: 99%

Hydrolases: catalytically promiscuous enzymes for non-conventional reactions in organic synthesis

2010

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During the last three decades the use of hydrolases for the catalysis of environmentally friendly organic processes under mild reaction conditions has been well documented. Hydrolases have shown themselves to be ideal tools for the acceleration of synthetic transformations because of their high stability, catalytic efficiency, commercial availability and broad substrate specificity in a wide spectrum of biocatalyzed processes. In recent years, novel examples have appeared related to non-conventional reactions catalyzed by hydrolytic enzymes. Amongst these, lipases and acylases have gained much attention as promiscuous biocatalysts showing good levels of reactivity in C-C bond formation, C-heteroatom bond formation, oxidative processes, and novel hydrolytic reactions. This critical review covers recent investigation in the field of catalytic promiscuity, and highlights the most surprising and uncommon activities that this class of enzymes shows in organic synthetic transformations (111 references).

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A 1010 Rate Enhancement of Phosphodiester Hydrolysis by a Dinuclear Aminopeptidase—Transition-State Analogues as Substrates?

Cited by 23 publications

References 7 publications

Mechanistic role of each metal ion in Streptomyces dinuclear aminopeptidase: Peptide hydrolysis and 7×1010-fold rate enhancement of phosphodiester hydrolysis

Mechanistic role of each metal ion in Streptomyces dinuclear aminopeptidase: Peptide hydrolysis and 7×1010-fold rate enhancement of phosphodiester hydrolysis

Functional Interrelationships in the Alkaline Phosphatase Superfamily: Phosphodiesterase Activity of Escherichia coli Alkaline Phosphatase

Hydrolases: catalytically promiscuous enzymes for non-conventional reactions in organic synthesis

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