BackgroundTo investigate the association between metabolic syndrome, including its factors, and gallstone disease (GSD) in a Taiwanese population.MethodsWe conducted a cross-sectional study during 2011 ~ 2012. A total of 12050 subjects who completed a questionnaire and underwent physical examination, laboratory tests and abdominal ultrasonography formed the study population.ResultsThe prevalences of metabolic syndrome and gallstone disease were 24.09% and 6.16%. In an age- and sex-adjusted logistic regression model, metabolic syndrome was associated with gallstone disease (OR = 1.61; P < 0.0001). Age, abdominal obesity, and lower high-density lipoprotein cholesterol were associated with gallstone disease after adjusting for other factors. Females had a higher odds ratio than males in waist circumference for GSD, whereas males had a lower odds ratio than females in HDL-C for GSD.ConclusionsThe present study suggests that metabolic syndrome is related to gallstone disease. Waist circumference and high-density lipoprotein cholesterol are all associated with GSD. Men and women may possibly have different priorities and strategies to reduce the burden of GSD.

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 (kcat ) 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.

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We recently showed that, upon the addition of fluorine substituents on n‐octane, van der Waals interactions including dispersion between a ‐CF2‐ and an aromatic π system account for changes in the alkane hydroxylation mediated by variants of recombinant cytochrome P450 BM3. Here, for the first time, we demonstrate that P450 BM3 also recognizes fluorinated C12–C15 chain‐length fatty acids. Despite the fact that residues, Arg47 and Tyr52, exert significant controls for the sub‐terminal hydroxylation via hydrogen bonding interactions at carboxylate ends of these fatty acids, in any case, the fluorine substituent(s) at omega position plays an essential role in the regio‐selective hydroxylation occurred at omega‐3 position through unique van der Waals interactions. For instance, the catalytic turnover of fluorinated lauric acid substrates by recombinant cytochrome P450 BM3 exhibit higher activities than that of their parent substrate. In conclusion, our data suggest that hydrophobic residues in the heme pocket of P450 enzymes are involved in tuning the orientation of substrates and this further leads to the controlled oxidation of aliphatics mediated by high valent iron‐oxo species.This work was supported by Academia Sinica and grants from the National Science Council, R.O.C. (NSC 97–2113‐M‐001–006‐MY3 and 101–2113‐M‐001–007‐MY3).