Getting the Adrenaline Going

Martin, Jennifer L.; Begun, Jakob; McLeish, Michael J.; Caine, Joanne M.; Grunewald, Gary L.

doi:10.1016/s0969-2126(01)00662-1

Cited by 63 publications

(83 citation statements)

References 32 publications

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“…PNMT is also a potential target in diseases like Alzheimer's and Parkinson's. 25,26 Tetrahydroisoquinoline derivatives are one class of inhibitors found for PNMT for which several crystal structures have been reported in literature. [25][26][27][28] A set of ten different tetrahydroisoquinoline derivatives was investigated in this study (Fig.…”

Section: Phenylethanolamine N-methyltransferasementioning

confidence: 99%

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Comparison of enveloping distribution sampling and thermodynamic integration to calculate binding free energies of phenylethanolamine N-methyltransferase inhibitors

Riniker

Christ

Hansen

et al. 2011

The Journal of Chemical Physics

128

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Articles you may be interested inCombine umbrella sampling with integrated tempering method for efficient and accurate calculation of free energy changes of complex energy surface J. Chem. Phys. 141, 044108 (2014) The relative binding free energy between two ligands to a specific protein can be obtained using various computational methods. The more accurate and also computationally more demanding techniques are the so-called free energy methods which use conformational sampling from molecular dynamics or Monte Carlo simulations to generate thermodynamic averages. Two such widely applied methods are the thermodynamic integration (TI) and the recently introduced enveloping distribution sampling (EDS) methods. In both cases relative binding free energies are obtained through the alchemical perturbations of one ligand into another in water and inside the binding pocket of the protein. TI requires many separate simulations and the specification of a pathway along which the system is perturbed from one ligand to another. Using the EDS approach, only a single automatically derived reference state enveloping both end states needs to be sampled. In addition, the choice of an optimal pathway in TI calculations is not trivial and a poor choice may lead to poor convergence along the pathway. Given this, EDS is expected to be a valuable and computationally efficient alternative to TI. In this study, the performances of these two methods are compared using the binding of ten tetrahydroisoquinoline derivatives to phenylethanolamine N-transferase as an example. The ligands involve a diverse set of functional groups leading to a wide range of free energy differences. In addition, two different schemes to determine automatically the EDS reference state parameters and two different topology approaches are compared.

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Section: Phenylethanolamine N-methyltransferasementioning

confidence: 99%

“…For the ten ligands, binding constants have been measured experimentally. 25,[27][28][29][30][31] For ligands 3 and 9, the binding constants for each enantiomer were determined, 30 whereas for ligands 2, 4, 6, 8, and 10 only data for the racemate or single enantiomers is available.…”

Section: Phenylethanolamine N-methyltransferasementioning

confidence: 99%

Comparison of enveloping distribution sampling and thermodynamic integration to calculate binding free energies of phenylethanolamine N-methyltransferase inhibitors

Riniker

Christ

Hansen

et al. 2011

The Journal of Chemical Physics

128

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“…A DALI search for structures similar to that of DnrK returned several hits with Z-scores of Ͼ18, namely RdmB, isoflavone O-methyltransferase (IOMT) (35), chalcone O-methyl- transferase (ChOMT) (35), yeco methyltransferase (36), and phenylethanolamine N-methyltransferase (PNMT) (37). All of these except RdmB are small molecule methyltransferases, and the structural homology of DnrK to these enzymes identifies it as a member of this subfamily of methyltransferases.…”

Section: Dnrk Is a Member Of A Sequence Family Of Methyltransferases mentioning

confidence: 99%

Crystal Structure of a Ternary Complex of DnrK, a Methyltransferase in Daunorubicin Biosynthesis, with Bound Products

Jansson

Koskiniemi

Mäntsälä

et al. 2004

Journal of Biological Chemistry

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One of the final steps in the biosynthesis of the widely used anti-tumor drug daunorubicin in Streptomyces peucetius is the methylation of the 4-hydroxyl group of the tetracyclic ring system. This reaction is catalyzed by the S-adenosyl-L-methionine-dependent carminomycin 4-Omethyltransferase DnrK. The crystal structure of the ternary complex of this enzyme with the bound products S-adenosyl-L-homocysteine and 4-methoxy-⑀-rhodomycin T has been determined to a 2.35-Å resolution. DnrK is a homodimer, and the subunit displays the typical fold of small molecule O-methyltransferases. The structure provides insights into the recognition of the anthracycline substrate and also suggests conformational changes as part of the catalytic cycle of the enzyme. The position and orientation of the bound ligands are consistent with an S N 2 mechanism of methyl transfer. Mutagenesis experiments on a putative catalytic base confirm that DnrK most likely acts as an entropic enzyme in that rate enhancement is mainly due to orientational and proximity effects. This contrasts the mechanism of DnrK with that of other O-methyltransferases where acid/base catalysis has been demonstrated to be an essential contribution to rate enhancement.Daunorubicin and doxorubicin are aromatic polyketide antibiotics that exhibit high cytotoxicity and are widely applied in the chemotherapy of a variety of cancers (1, 2). These and related anthracyclines consist of a cyclic polyketide backbone, 7,8,9,10-tetrahydrotetracene-5,12-quinone, glycosylated at position C7 or C10 (Fig. 1). Diversity is generated by variations in the modification of the aglycone moiety and the composition of the attached carbohydrate. Biosynthesis of daunorubicin/doxorubicin starts with the formation of the polyketide backbone catalyzed by a class II polyketide synthase with subsequent cyclization of the polyketide chain (3). These steps lead to the formation of aklavinone, a common intermediate in the synthesis of most anthracyclines. This aglycone is then further modified through a series of steps, i.e. hydroxylation, glycosylation, methylester hydrolysis, decarboxylation, methylation, and, in

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“…2 Adrenaline is synthesized in vivo from noradrenaline in a reaction catalyzed by phenylethanolamine N-methyltransferase (PNMT), a 30 kDa enzyme that utilizes the cofactor SAM to methylate the amine of noradrenaline. 3 PNMT is employed as a catecholamine biosynthetic marker, and the presence of PNMT-containing neurons in the brain suggests that CNS adrenaline is involved in the central control of blood pressure, respiration, and pituitary hormone secretion. 3 It has been implicated in the effects of ethanol intoxication and neural degeneration observed in Alzheimer's disease.…”

Section: Introductionmentioning

confidence: 99%

“…3 PNMT is employed as a catecholamine biosynthetic marker, and the presence of PNMT-containing neurons in the brain suggests that CNS adrenaline is involved in the central control of blood pressure, respiration, and pituitary hormone secretion. 3 It has been implicated in the effects of ethanol intoxication and neural degeneration observed in Alzheimer's disease. 4,5 There have been efforts to develop potent PNMT inhibitors as angina pectoris, myocardial infarction and anxiety neuroses agents.…”

Section: Introductionmentioning

confidence: 99%

Flavonoids can be Potent Inhibitors of Human Phenylethanolamine N-Methyltransferase (hPNMT)

Lee¹,

Jeong²,

Kim

2009

Bulletin of the Korean Chemical Society

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Inhibition of human phenylethanolamine N-methyltransferase (hPNMT) has been proposed as a method for the treatment of several mental processes which related on adrenaline metabolism. We performed in silico screening to identify flavonoid inhibitors of hPNMT using automated docking method and selected 9 inhibitor candidates based on ligand score (LigScore) and binding free energy (∆Gbind) estimation. Among 9 flavonoid candidates, 7 flavonoids belong to flavones while the rest of them belong to flavanone. All candidates have common chemical features; two hydrogen bond interactions with side chain of Lys75 and backbone carbonyl oxygen of Asn39, and two hydrophobic interactions. One hydrophobic site is formed by Val53, Leu262, and Met258 and the other is made up of Phe182, Ala186, Tyr222, and Val269. This study can be helpful to understand the structural features for inhibition of PNMT and showed flavonoids as promising inhibitor candidates for hPNMT.

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Getting the Adrenaline Going

Cited by 63 publications

References 32 publications

Comparison of enveloping distribution sampling and thermodynamic integration to calculate binding free energies of phenylethanolamine N-methyltransferase inhibitors

Comparison of enveloping distribution sampling and thermodynamic integration to calculate binding free energies of phenylethanolamine N-methyltransferase inhibitors

Crystal Structure of a Ternary Complex of DnrK, a Methyltransferase in Daunorubicin Biosynthesis, with Bound Products

Flavonoids can be Potent Inhibitors of Human Phenylethanolamine N-Methyltransferase (hPNMT)

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