Structure of the angiogenesis inhibitor ovalicin bound to its noncognate target, human Type 1 methionine aminopeptidase

Addlagatta, A.; Matthews, Brian W.

doi:10.1110/ps.062278006

Cited by 23 publications

(17 citation statements)

References 23 publications

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“…27 The highly oxidized cyclohexane portion of 2 , which is also present in the metabolite ovalicin from Pseudeurotium ovalis , 28 has been the subject of intensive synthetic efforts (see review in Yamagushi et al. and references therein).…”

Section: Discussionmentioning

confidence: 99%

Generation of Complexity in Fungal Terpene Biosynthesis: Discovery of a Multifunctional Cytochrome P450 in the Fumagillin Pathway

Lin¹,

Tsunematsu

Dhingra

et al. 2014

J. Am. Chem. Soc.

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Fumagillin (1), a meroterpenoid from Aspergillus fumigatus, is known for its antiangiogenic activity due to binding to human methionine aminopeptidase 2. 1 has a highly oxygenated structure containing a penta-substituted cyclohexane that is generated by oxidative cleavage of the bicyclic sesquiterpene β-trans-bergamotene. The chemical nature, order, and biochemical mechanism of all the oxygenative tailoring reactions has remained enigmatic despite the identification of the biosynthetic gene cluster and the use of targeted-gene deletion experiments. Here, we report the identification and characterization of three oxygenases from the fumagillin biosynthetic pathway, including a multifunctional cytochrome P450 monooxygenase, a hydroxylating nonheme-iron-dependent dioxygenase, and an ABM family monooxygenase for oxidative cleavage of the polyketide moiety. Most significantly, the P450 monooxygenase is shown to catalyze successive hydroxylation, bicyclic ring-opening, and two epoxidations that generate the sesquiterpenoid core skeleton of 1. We also characterized a truncated polyketide synthase with a ketoreductase function that controls the configuration at C-5 of hydroxylated intermediates.

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Section: Discussionmentioning

confidence: 99%

Generation of Complexity in Fungal Terpene Biosynthesis: Discovery of a Multifunctional Cytochrome P450 in the Fumagillin Pathway

Lin¹,

Tsunematsu

Dhingra

et al. 2014

J. Am. Chem. Soc.

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“…As illustrated in Figure 7, ovalicin is an inhibitor of methionine amino peptidases, and the structures of human type 1 and type 2 methionine aminopeptidases (MetAP1 and MetAP2) in complex with ovalicin were reported as PDB 2GZ5 19 and PDB 1B59 20 , respectively. It is known that ovalicin binds with lower affinity to MetAP1 than to MetAP2.…”

Section: Resultsmentioning

confidence: 99%

Residue Preference Mapping of Ligand Fragments in the Protein Data Bank

Wang

Xie

Wipf

et al. 2011

J. Chem. Inf. Model.

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Background The interaction between small molecules and proteins is one of the major concerns for structure-based drug design since the principles of protein-ligand interactions and molecular recognition are not thoroughly understood. Fortunately, the analysis of protein-ligand complexes in the Protein Data Bank (PDB) enables unprecedented possibilities for new insights. Herein, we applied molecule-fragmentation algorithms to split the ligands extracted from PDB crystal structures into small fragments. Subsequently, we have developed a ligand fragment and residue preference mapping (LigFrag-RPM) algorithm to map the profiles of the interactions between these fragments and the 20 proteinogenic amino acid residues. Results A total of 4,032 fragments were generated from 71,798 PDB ligands by a ring cleavage (RC) algorithm. Among these ligand fragments, 315 unique fragments were characterized with the corresponding fragment-residues interaction profiles by counting residues close to these fragments. The interaction profiles revealed that these fragments have specific preferences for certain types of residues. The applications of these interaction profiles were also explored and evaluated in case studies, showing great potential for the study of protein-ligand interactions and drug design. Conclusions Our studies demonstrated that the fragment-residues interaction profiles generated from the PDB ligand fragments can be used to detect whether these fragments are in their favorable or unfavorable environments. The algorithm for a ligand fragment and residue preference mapping (LigFrag-RPM) developed here also has the potential to guide lead chemistry modifications as well as binding residues predictions.

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“…However, electron density for both the unsaturated decanoic acid side chain on fumagillin and the O-(Chloroacetylcarbamoyl) group on TNP-470 was visible up to carbon-43. Methionine aminopeptidases, specifically type 2, have been shown to be irreversibly inhibited by fumagillin and its derivatives through covalent modification of an active site histidine residue with the carbon atom of the spirocyclic epoxide at position C3 on the cyclohexane ring of fumagillin [27,28,46,61,65]. In the X-ray structures of Ec MetAP2c-fumagillin and Ec MetAP2c-TNP-470 electron density is clearly visible for a covalent bond between the Nε2 imidazole nitrogen atom of, the absolutely conserved residue, H109 and carbon 2 of the cleaved spirocyclic epoxide.…”

Section: Resultsmentioning

confidence: 99%

Structure of a microsporidian methionine aminopeptidase type 2 complexed with fumagillin and TNP-470

Alvarado

Nemkal

Sauder³

et al. 2009

Molecular and Biochemical Parasitology

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Microsporidia are protists that have been reported to cause infections in both vertebrates and invertebrates. They have emerged as human pathogens particularly in patients that are immunnosuppressed and cases of gastrointestinal infection, encephalitis, keratitis, sinusitis, myositis and disseminated infection are well described in the literature. While benzimidazoles are active against many species of Microsporidia, these drugs do not have significant activity against Enterocytozoon bieneusi. Fumagillin and its analogues have been demonstrated to have activity in vitro and in animal models of microsporidiosis and human infections due to E. bieneusi. Fumagillin and its analogues inhibit methionine aminopeptidase type 2. Encephalitozoon cuniculi MetAP2 (EcMetAP2) was cloned and expressed as an active enzyme using a baculovirus system. The crystal structure of EcMetAP2 was determined with and without the bound inhibitors fumagillin and TNP470. This structure classifies EcMetAP2 as a member of the MetAP2c family. The EcMetAP2 structure was used to generate a homology model of the E. bieneusi MetAP2. Comparison of microsporidian MetAP2 structures with human MetAP2 provide insights into the design of inhibitors that might exhibit specificity for microsporidian MetAP2.

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Structure of the angiogenesis inhibitor ovalicin bound to its noncognate target, human Type 1 methionine aminopeptidase

Cited by 23 publications

References 23 publications

Generation of Complexity in Fungal Terpene Biosynthesis: Discovery of a Multifunctional Cytochrome P450 in the Fumagillin Pathway

Generation of Complexity in Fungal Terpene Biosynthesis: Discovery of a Multifunctional Cytochrome P450 in the Fumagillin Pathway

Residue Preference Mapping of Ligand Fragments in the Protein Data Bank

Structure of a microsporidian methionine aminopeptidase type 2 complexed with fumagillin and TNP-470

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