Leukotriene A4Hydrolase/Aminopeptidase

Rudberg, Peter; Tholander, Fredrik; Thunnissen, Marjolein M.G.M.; Haeggström, Jesper Z.

doi:10.1074/jbc.m106577200

Cited by 73 publications

(53 citation statements)

References 36 publications

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“…This interaction between Glu-386 and the water molecule was previously described by Vazeux et al (17), who suggested that this residue is the catalytic effector of APA. In addition, the interaction between Glu-352 and the water molecule shown by the model may account for the large decrease in the catalytic constant following the mutation of this residue or equivalent residues in other enzymes (21,22). The water molecule is not present in the active site of LTA 4 H complexed with bestatin.…”

Section: Discussionmentioning

confidence: 99%

“…These studies resulted in the identification of several residues involved in zinc coordination (16,17), catalysis (17,18), and substrate binding (19). Some of these conserved residues were also recently identified in other related aminopeptidases such as thyrotropin-releasing hormone-degrading enzyme (EC 3.4.19.6) (20), aminopeptidase N (EC 3.4.11.2) (21), leukotriene A 4 hydrolase (LTA 4 H; EC 3.3.2.6) (22,23), and insulin-regulated membrane aminopeptidase (EC 3.4.11.3) (24). On the basis of our data, we proposed a model for the organization of the active site of APA and a putative catalytic mechanism for this enzyme (25) similar to that proposed for thermolysin on the basis of x-ray diffraction studies (26).…”

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confidence: 99%

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Contribution of Molecular Modeling and Site-directed Mutagenesis to the Identification of Two Structural Residues, Arg-220 and Asp-227, in Aminopeptidase A

Rozenfeld¹,

Iturrioz²,

Maigret³

et al. 2002

Journal of Biological Chemistry

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Aminopeptidase A is a zinc metalloenzyme involved in the formation of brain angiotensin III, which exerts a tonic stimulatory action on the central control of blood pressure. Thus, central inhibitors of aminopeptidase A constitute putative central antihypertensive agents. Mutagenic studies have been performed to investigate organization of the aminopeptidase A active site, with a view to designing such inhibitors. The structure of one monozinc aminopeptidase (leukotriene A 4 hydrolase) was recently resolved and used to construct a threedimensional model of the aminopeptidase A ectodomain. This new model, highly consistent with the results of mutagenic studies, showed a critical structural interaction between two conserved residues, Arg-220 and Asp-227. Mutagenic replacement of either of these two residues disrupted maturation and subcellular localization and abolished the enzymatic activity of aminopeptidase A, confirming the critical structural role of these residues. In this study, we generated the first threedimensional model of a strict aminopeptidase, aminopeptidase A. This model constitutes a new tool to probe further the active site of aminopeptidase A and to design new inhibitors of this enzyme.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Contribution of Molecular Modeling and Site-directed Mutagenesis to the Identification of Two Structural Residues, Arg-220 and Asp-227, in Aminopeptidase A

Rozenfeld¹,

Iturrioz²,

Maigret³

et al. 2002

Journal of Biological Chemistry

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“…Adaptation of catalase to a biosynthetic enzyme is accomplished primarily with surprisingly modest changes in the immediate heme environment in the context of only 11% sequence identity. Another eicosanoid biosynthetic enzyme has been described that represents similarly an adapted enzyme: leukotriene A4 hydrolase is a modified zinc peptidase with structural homology to thermolysin (38). Leukotriene A4 hydrolase retains the catalytic activity of the progenitor enzyme and is a peptidase as well as a hydrolase, whereas AOS represents a complete switch from a H 2 O 2 -metabolizing catalase to a biosynthetic fatty acid hydroperoxidase.…”

Section: The Chemical Nature Of the U-shaped Cavity Is Complementary mentioning

confidence: 99%

The structure of coral allene oxide synthase reveals a catalase adapted for metabolism of a fatty acid hydroperoxide

Oldham

Brash

Newcomer

2004

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

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8R-Lipoxygenase and allene oxide synthase (AOS) are parts of a naturally occurring fusion protein from the coral Plexaura homomalla. AOS catalyses the production of an unstable epoxide (an allene oxide) from the fatty acid hydroperoxide generated by the lipoxygenase activity. Here, we report the structure of the AOS domain and its striking structural homology to catalase. Whereas nominal sequence identity between the enzymes had been previously described, the extent of structural homology observed was not anticipated, given that this enzyme activity had been exclusively associated with the P450 superfamily, and conservation of a catalase fold without catalase activity is unprecedented. Whereas the heme environment is largely conserved, the AOS heme is planar and the distal histidine is flanked by two hydrogen-bonding residues. These critical differences likely facilitate the switch from a catalatic activity to that of a fatty acid hydroperoxidase.eicosanoids ͉ heme

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“…In contrast, the C-terminal domains are partially conserved and differ considerably in their relative positions (32). The remarkable structural similarity between the LTA4H and F3 catalytic domains, the high sequence conservation around the M1 catalytic domains, and site-directed mutagenesis studies (20,(33)(34)(35)(36) suggest that they use a common catalytic mechanism and that different N-terminal residue preferences (neutral (APN), acidic (APA), arginyl (L-RAP), or PPII) are supported by discrete changes near the active site. In the M1 aminopeptidases, specific recognition of the free N-terminal group of substrates and inhibitors involves hydrogen bonding with two conserved residues.…”

mentioning

confidence: 99%

“…The structure of LTA4H in complex with the competitive inhibitor bestatin shows that Glu-271, located within the exopeptidase motif, and Gln-136 are positioned in the active site; both make hydrogen bonds to the free amine of the inhibitor, which chemically resembles a peptide substrate, suggesting their participation in the binding of the N-terminal group of substrates. Experimental analysis as well as examination of the x-ray structure of LTA4H-E271Q inactive mutant, indicates that Glu-271 carboxylate is not only involved in the N-terminal recognition but also has a critical role in the aminopeptidase activity (33). It is proposed that the counterparts of LTA4H-Glu-271, APA-Glu-352, and APN-Glu-355 interact with the free amino group of substrates and inhibitors via a hydrogen bond, with their negative charge stabilizing the transition state (34,35).…”

mentioning

confidence: 99%