593-11-3Relevant articles and documents
Regioselective hydroxylation of C12-C15 fatty acids with fluorinated substituents by cytochrome P450 BM3
Chiang, Chih-Hsiang,Ramu, Ravirala,Tu, Yi-Jung,Yang, Chung-Ling,Ng, Kok Yaoh,Luo, Wen-I,Chen, Charles H.,Lu, Yu-Ying,Liu, Chen-Lun,Yu, Steve S.-F.
, p. 13680 - 13691 (2013/10/22)
We demonstrate herein that wild-type cytochrome P450 BM3 can recognize non-natural substrates, such as fluorinated C12-C15 chain-length fatty acids, and show better catalysis for their efficient conversion. Although the binding affinities for fluorinated substrates in the P450 BM3 pocket are marginally lower than those for non-fluorinated substrates, spin-shift measurements suggest that fluoro substituents at the ω-position can facilitate rearrangement of the dynamic structure of the bulk-water network within the hydrophobic pocket through a micro desolvation process to expel the water ligand of the heme iron that is present in the resting state. A lowering of the Michaelis-Menten constant (Km), however, indicates that fluorinated fatty acids are indeed better substrates compared with their non-fluorinated counterparts. An enhancement of the turnover frequencies (k cat) for electron transfer from NADPH to the heme iron and for C-H bond oxidation by compound I (Cpd I) to yield the product suggests that the activation energies associated with going from the enzyme-substrate (ES state) to the corresponding transition state (ES≠ state) are significantly lowered for both steps in the case of the fluorinated substrates. Delicate control of the regioselectivity by the fluorinated terminal methyl groups of the C12-C15 fatty acids has been noted. Despite the fact that residues Arg47/Tyr51/Ser72 exert significant control over the hydroxylation of the subterminal carbon atoms toward the hydrocarbon tail, the fluorine substituent(s) at the ω-position affects the regioselective hydroxylation. For substrate hydroxylation, we have found that fluorinated lauric acids probably give a better structural fit for the heme pocket than fluorinated pentadecanoic acid, even though pentadecanoic acid is by far the best substrate among the reported fatty acids. Interestingly, 12-fluorododecanoic acid, with only one fluorine atom at the terminal methyl group, exhibits a comparable turnover frequency to that of pentadecanoic acid. Thus, fluorination of the terminal methyl group introduces additional interactions of the substrate within the hydrophobic pocket, which influence the electron transfers for both dioxygen activation and the controlled oxidation of aliphatics mediated by high-valent oxoferryl species. Regiospecific enzyme catalysis: The unique van der Waals interactions between a fluorine substituent(s) and neighboring residues in the heme pocket of recombinant cytochrome P450 BM3 give rise to excellent regioselective oxidation of substrates such as fluorinated lauric acids and pentadecanoic acid at the ω-3 position (67-100 %; see figure). Copyright
Synthesis and antifungal activities of myristic acid analogs
Parang, Keykavous,Knaus, Edward E.,Wiebe, Leonard I.,Sardari, Soroush,Daneshtalab, Mohsen,Csizmadia, Ferenc
, p. 475 - 482 (2007/10/03)
Myristic acid analogs that are putative inhibitors of N-myristoyl transferase were tested in vitro for activity against yeasts (Saccharomyces cerevisiae, Candida albicans, Cryptococcus neoformans) and filamentous fungi (Aspergillus niger). Several (±)-2-halotetradecanoic acids including (±)-2-bromotetradecanoic acid (14c) exhibited potent activity against C. albicans (MIC = 39 μM), C. neoformans (MIC = 20 μM), S. cerevisiae (MIC = 10 μM), and A. niger (MIC 42 μM) in RPMI 1640 media. Improved synthetic methods have been developed for the synthesis of 12-fluorododecanoic acid (12a) and 12-chlorododecanoic acid (12c). Three novel fatty acids, 12-chloro-4-oxadodecanoic acid (8a), 12-phenoxydodecanoic acid (12i), and 11-(4-iodophenoxy)-undecanoic acid (13d) were also synthesized and tested.
