17278-73-8Relevant 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)
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
Selective ?-1 oxidation of fatty acids by CYP147G1 from Mycobacterium marinum
Child, Stella A.,Rossi, Vanessa P.,Bell, Stephen G.
, p. 408 - 417 (2018/12/11)
Background: Cyp147G1 is one of 47 cytochrome P450 encoding genes in Mycobacterium marinum M, a pathogenic bacterium with a high degree of sequence similarity to Mycobacterium tuberculosis and Mycobacterium ulcerans. Cyp147G1 is one of only two of these cyp genes which are closely associated with a complete electron transfer system. Methods: The substrate range of the enzyme was tested in vitro and the activity of CYP147G1 was reconstituted in vivo by co-producing the P450 with the ferredoxin and ferredoxin reductase. Results: Substrates of CYP147G1 include fatty acids ranging from octanoic to hexadecanoic acid. CYP147G1 catalysed the selective hydroxylation of linear and ω-2 methyl branched fatty acids at the ω-1 position (≥ 98%). Oxidation of ω-1 methyl branched fatty acids generated the ω and ω-1 hydroxylation products in almost equal proportions, indicating altered position of hydrogen abstraction. Conclusions: This selectivity of fatty acid hydroxylation inferred that linear species must bind in the active site of the enzyme with the terminal methyl group sequestered so that abstraction at the C–H bonds of the ω-1 position is favoured. With branched substrates, one of the methyl groups must be close to the compound I oxygen atom and enable hydroxylation at the terminal methyl group to compete with the reaction at the ω-1C–H bond. General significance: Hydroxy fatty acids are widely used for industrial, food and medical purposes. CYP147G1 demonstrates high regioselectivity for hydroxylation at a sub-terminal position on a broad range of linear fatty acids, not seen in other CYP enzymes.
H-Bonding-promoted radical addition of simple alcohols to unactivated alkenes
Tian, Yunfei,Liu, Zhong-Quan
supporting information, p. 5230 - 5235 (2017/11/09)
H-Bonding-induced radical addition of simple alcohols to unactivated olefins was achieved. It effectively solved the long-standing problems of reactivity and selectivity in this type of reaction. The hydroxyalkylation occurred via site-specific cleavage of the α-hydroxyl-C-H bond in alcohols. This method allows a highly atom-economical, operationally simple and environmentally benign access to diverse primary, secondary and tertiary alcohols, diols, and even polyfluorinated alcohols. These useful chemicals are traditionally synthesized by using commercially unavailable organometallics via complex operations. In contrast, they can be facilely obtained through this protocol utilizing widely available starting materials.
