Acetylene containing cyclo(L-Tyr-L-Tyr)-analogs as mechanism-based inhibitors of CYP121A1 from Mycobacterium tuberculosis

Ugalde, Sandra Ortega; Wallraven, Kerstin; Speer, Alexander; Bitter, Wilbert; Grossmann, Tom N.; Commandeur, Jan N. M.

doi:10.1016/j.bcp.2020.113938

Cited by 3 publications

(6 citation statements)

References 56 publications

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“…Cytochrome P450 enzymes perform a wide variety of functions in bacteria (51), from secondary metabolite production (20–22) to carbon source metabolism (15–17), to synthesis of lipids critical for cell wall integrity (51, 57). In some cases, these functions are essential to microbial growth (44); therefore, it has been suggested that CYP enzymes may be useful targets for novel antibiotic therapies, particularly for pathogens that are intractable to current treatments (58, 59). P. aeruginosa is a gram-negative opportunistic pathogen that is particularly prevalent in the lungs of patients with cystic fibrosis, chronic obstructive pulmonary disease, and nosocomial pneumonia (60–62).…”

Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosacytochrome P450 CYP168A1 is a fatty acid hydroxylase that metabolizes arachidonic acid to the vasodilator 19-HETE

Tooker

Kandel

Work

et al. 2021

Preprint

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Pseudomonas aeruginosa is a gram-negative opportunistic human pathogen that is highly prevalent in individuals with cystic fibrosis (CF). A major problem in treating CF patients infected with P. aeruginosa is the development of antibiotic resistance. Therefore, the identification of novel P. aeruginosa antibiotic drug targets is of the upmost urgency. The genome of P. aeruginosa contains four putative cytochrome P450 enzymes (CYPs) of unknown function that have never before been characterized. Analogous to some of the CYPs from M. tuberculosis, the P. aeruginosa CYPs may be important for growth and colonization of the CF patient’s lung. In this study, we cloned, expressed, and characterized CYP168A1 from P. aeruginosa and identified it as a sub-terminal fatty acid hydroxylase. Spectral binding data and computational modeling of substrates and inhibitors suggest that CYP168A1 has a large, expansive active site preferring long chain fatty acids and large hydrophobic inhibitors. Furthermore, metabolism experiments confirm that the enzyme is capable of hydroxylating arachidonic acid, an important inflammatory signaling molecule present in abundance in the CF lung, to 19-hydroxyeicosatetraenoic acid (19-HETE; Km = 41.1 µM, Vmax = 222 pmol/min/nmol P450), a potent vasoconstrictor which may play a role in the pathogen’s ability to colonize the mammalian lung. Metabolism of arachidonic acid is subject to substrate inhibition and is also inhibited by the presence of ketoconazole. This study points to the discovery of a new potential drug target that may be of utility in treating drug resistant P. aeruginosa.

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Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosacytochrome P450 CYP168A1 is a fatty acid hydroxylase that metabolizes arachidonic acid to the vasodilator 19-HETE

Tooker

Kandel

Work

et al. 2021

Preprint

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“…These dipeptides were treated with 20 % piperidine in acetonitrile to remove the Fmoc group, and then cyclization was performed by heating in a mixture of toluene and secbutanol to obtain corresponding DKP analogues, 19-27 (Figure 1). [21,22,56] This set of DKP analogues (19)(20)(21)(22)(23)(24)(25)(26)(27) with varying ChemistrySelect number and kinds of halogen atoms might facilitate the structure-activity relationships for biological activities against different cancer cell lines.…”

Section: Synthesis Of Iodinated Tyrosine Dkpsmentioning

confidence: 99%

“…[21][22][23][24][25] It is surmised that the incorporation of single iodine in the substrate of the enzyme CYP121 significantly increased the binding affinity, presumably due to engendering new interactions. [26,27] Cyclic dipeptide containing amino acids with aromatic side chains represents small, conformationally constrained heterocycles termed 2,5-diketopiperazines (DKPs). [28,29] DKP bearing tyrosine side chains is endowed with unique properties, including conformational rigidity, [30,31] foci of intermolecular interactions, [32] rapid structural diversification, [33][34][35][36] bioavailability, [37,38] and biocompatibility.…”

Section: Introductionmentioning

confidence: 99%

“…[28,29] DKP bearing tyrosine side chains is endowed with unique properties, including conformational rigidity, [30,31] foci of intermolecular interactions, [32] rapid structural diversification, [33][34][35][36] bioavailability, [37,38] and biocompatibility. [39,40] These constrained peptides are embedded in larger and more complex natural products, especially those isolated from marine organisms, and found to have biological properties including antitumor, [41][42][43] antimicrobial, [27,44,45] antifungal, [46] anti-inflammatory activities, [47] neuroprotective [34,48] and modulation of biochemical receptors. [49,50] For example, the biological activity of the tyrosine-containing DKPs such as Cyclo (L-Phe-L-Tyr) and Cyclo (L-Tyr-L-Tyr) as in opioid peptides place more importance on the tyrosine hydroxyl group for its biological activities.…”

Section: Introductionmentioning

confidence: 99%

“…CYP121 converts the substrate Cyclo (L‐Tyr‐L‐Tyr) into the formation of Mycocyclosin (Scheme 1C) by the oxidative C−C bond formation [21–25] . It is surmised that the incorporation of single iodine in the substrate of the enzyme CYP121 significantly increased the binding affinity, presumably due to engendering new interactions [26,27] …”

Section: Introductionmentioning

confidence: 99%

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Iodinated Diketopiperazines: Synthesis and Biological Evaluation of Iodinated Analogues of Cyclo(L‐Tyrosine‐L‐Tyrosine) Peptides

Purushotham

Paul

2022

ChemistrySelect

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We developed a simple strategy to diiodinated tyrosine (Tyr) amino acid at the 3‐ and 5‐ positions from the commercially available Fmoc/Boc‐L‐Tyrosine monomer. The iodinated tyrosine monomer have been further adopted to generate a variety of iodinated Fmoc tyrosine dimers. Upon Fmoc elimination, we obtained diketopiperazine (DKP) analogues of Cyclo(L‐Tyr‐L‐Tyr) with varied number of iodine atoms. We also report the biological studies of these iodinated DKP analogues in three different cancer cell lines. We demonstrate that the number of iodine atoms in the Cyclo(L‐Tyr‐L‐Tyr) DKP analogues, and the presence of electron‐rich phenolic group are essential structural parameters to have pronounced cytotoxic activity in three different cancer cell lines.

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Discovery of Mycobacterium tuberculosis CYP121 New Inhibitor via Structure-based Drug Repurposing

Moudaka¹,

Murugan²,

Rahman³

et al. 2023

JST

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Tuberculosis (TB) remains a serious threat to human health with the advent of multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). The urge to find novel drugs to deal with the appearance of drug-resistant TB and its variants is highly needed. This study aims to find new CYP121 inhibitors by screening 8,773 compounds from the drug repositioning database RepoDB. The selection of CYP121 potential inhibitors was based on two criteria: the new inhibitor should bind to CYP121 with higher affinity than its original ligand and interact with catalytically important residues for the function of CYP121. The ligands were docked onto CYP121 using AutoDock Vina, and the molecular dynamics simulation of the selected ligand was conducted using YASARA Structure. We found that antrafenine, an anti-inflammatory and analgesic agent with high CYP inhibitory promiscuity, was bound to CYP121 with a binding affinity of -12.6 kcal/mol and interacted with important residues at the CYP121 binding site. Molecular dynamics analysis of CYP121 bound to the original ligand and antrafenine showed that both ligands affected the dynamics of residues located distantly from the active site. Antrafenine caused more structural changes to CYP121 than the original ligand, as indicated by a significantly higher number of affected residues and rigid body movements caused by the binding of antrafenine to CYP121.

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Acetylene containing cyclo(L-Tyr-L-Tyr)-analogs as mechanism-based inhibitors of CYP121A1 from Mycobacterium tuberculosis

Cited by 3 publications

References 56 publications

Pseudomonas aeruginosacytochrome P450 CYP168A1 is a fatty acid hydroxylase that metabolizes arachidonic acid to the vasodilator 19-HETE

Pseudomonas aeruginosacytochrome P450 CYP168A1 is a fatty acid hydroxylase that metabolizes arachidonic acid to the vasodilator 19-HETE

Iodinated Diketopiperazines: Synthesis and Biological Evaluation of Iodinated Analogues of Cyclo(L‐Tyrosine‐L‐Tyrosine) Peptides

Discovery of Mycobacterium tuberculosis CYP121 New Inhibitor via Structure-based Drug Repurposing

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