The enzymes of microbial nicotine metabolism.
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ABSTRACT:
SUBMITTER: Fitzpatrick PF
PROVIDER: S-EPMC6122326 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
The enzymes of microbial nicotine metabolism.
Beilstein journal of organic chemistry 20180831
Because of nicotine's toxicity and the high levels found in tobacco and in the waste from tobacco processing, there is a great deal of interest in identifying bacteria capable of degrading it. A number of microbial pathways have been identified for nicotine degradation. The first and best-understood is the pyridine pathway, best characterized for <i>Arthrobacter nicotinovorans</i>, in which the first reaction is hydroxylation of the pyridine ring. The pyrrolidine pathway, which begins with oxida ...[more]
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Project description:BACKGROUND:The major mode of metabolism of nicotine is by hydroxylation via cytochrome P450 (CYP) 2A6, but it can also undergo glucuronidation by UDP-glucuronosyltransferases and oxidation by flavin monooxygenases (FMO). The goal of this study was to examine the potential importance of FMOs in nicotine metabolism and assess the potential impact of missense polymorphisms in active FMOs on nicotine-N'-oxide (NOX) formation. METHODS:Urine samples from 106 current Chinese smokers were analyzed for nicotine metabolites by mass spectrometry. Wild-type FMOs 1-5 and their most prevalent nonsynonymous variants were cloned and overexpressed in HEK293 cells, and were tested in oxidation reactions against nicotine. RESULTS:A strong inverse correlation was observed between the ratio of urinary 3'-hydroxycotinine/cotinine, a measure of CYP2A6 activity, and the urinary levels of NOX alone (r = -0.383; P < 0.001) or NOX measured as a ratio of total nicotine metabolites (r = -0.414; P < 0.001) in smokers. In addition to FMO1 and FMO3, the functional FMO2427Q isoform was active against nicotine, whereas FMO4 and FMO5 exhibited low activity against nicotine (K m > 5.0 mmol/L). Significant (P < 0.05) decreases in N'-oxidation activity (V max/K m) were observed for the FMO1I303V, FMO3N61S, FMO3D132H, FMO3V257M, and FMO3E308G variants in vitro when compared with their respective wild-type isoforms; the truncated FMO2Q472stop isoform exhibited no enzyme activity. CONCLUSIONS:These data indicate that increases in nicotine-N'-oxidation occur in subjects with deficient CYP2A6 activity, and that several FMO enzymes are active in nicotine-N'-oxidation. IMPACT:Several common missense FMO variants are associated with altered enzyme activity against nicotine and may play an important role in nicotine metabolism in low-CYP2A6 activity subjects.
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Project description:BackgroundThere is a need to match characteristics of tobacco users with cessation treatments and risks of tobacco attributable diseases such as lung cancer. The rate in which the body metabolizes nicotine has proven an important predictor of these outcomes. Nicotine metabolism is primarily catalyzed by the enzyme cytochrone P450 (CYP2A6) and CYP2A6 activity can be measured as the ratio of two nicotine metabolites: trans-3'-hydroxycotinine to cotinine (NMR). Measurements of these metabolites are only possible in current tobacco users and vary by biofluid source, timing of collection, and protocols; unfortunately, this has limited their use in clinical practice. The NMR depends highly on genetic variation near CYP2A6 on chromosome 19 as well as ancestry, environmental, and other genetic factors. Thus, we aimed to develop prediction models of nicotine metabolism using genotypes and basic individual characteristics (age, gender, height, and weight).ResultsWe identified four multiethnic studies with nicotine metabolites and DNA samples. We constructed a 263 marker panel from filtering genome-wide association scans of the NMR in each study. We then applied seven machine learning techniques to train models of nicotine metabolism on the largest and most ancestrally diverse dataset (N=2239). The models were then validated using the other three studies (total N=1415). Using cross-validation, we found the correlations between the observed and predicted NMR ranged from 0.69 to 0.97 depending on the model. When predictions were averaged in an ensemble model, the correlation was 0.81. The ensemble model generalizes well in the validation studies across ancestries, despite differences in the measurements of NMR between studies, with correlations of: 0.52 for African ancestry, 0.61 for Asian ancestry, and 0.46 for European ancestry. The most influential predictors of NMR identified in more than two models were rs56113850, rs11878604, and 21 other genetic variants near CYP2A6 as well as age and ancestry.ConclusionsWe have developed an ensemble of seven models for predicting the NMR across ancestries from genotypes and age, gender and BMI. These models were validated using three datasets and associate with nicotine dosages. The knowledge of how an individual metabolizes nicotine could be used to help select the optimal path to reducing or quitting tobacco use, as well as, evaluating risks of tobacco use.
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Project description:The biological importance of proteins and nucleic acids in the natural world is undeniable, and research efforts on these macromolecules have often overshadowed those directed at carbohydrates. It is now known, however, that carbohydrates not only play roles in energy storage and plant cell wall structure, but are also intimately involved in such processes as fertilization, the immune response, and cell adhesion. Indeed, recent years have seen an explosion in research efforts directed at uncovering and understanding new sugar moieties. The dideoxysugars and trideoxysugars, which are synthesized by a variety of bacteria, fungi, and plants, represent an especially intriguing class of carbohydrates. They are found, for example, on the lipopolysaccharides of some Gram-negative bacteria or on antibacterial agents such as erythromycin. Many of them are formed from simple monosaccharides such as glucose-6-phosphate or fructose-6-phosphate via a myriad of enzymatic reactions including acetylations, aminations, dehydrations, epimerizations, reductions, and methylations. In this review we focus on the recent structural investigations of the bacterial N-acetyltransferases and the PLP-dependent aminotransferases that function on nucleotide-linked sugar substrates.
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Project description:INTRODUCTION:Metabolism of nicotine has implications for addiction and may be altered in people with type 2 diabetes. Thus, our objective was to analyze nicotine metabolism in adults with and without type 2 diabetes who smoke. METHODS:From an existing cross-sectional study, we analyzed nicotine metabolism in urine of 148 smokers, 36 type 2 diabetics (insulin or antidiabetic medication use and/or fasting glucose >126 mg/dL) and 112 non-diabetics. Nicotine metabolism was quantified as the nicotine metabolite ratio (NMR) = trans-3'-hydroxycotinine (3HC) divided by cotinine (COT). COT and 3HC were measured in the participant urine by ultra-performance liquid chromatography-tandem mass spectrometry. Generalized linear models were used to assess whether NMR was associated with diabetic status (yes/no). RESULTS:Participants categorized as high NMR smoked more cigarettes per day (p = .002) and were more likely to be diabetic (p = .022) compared to low NMR. We found no significant difference in total nicotine equivalents defined as the sum of the nicotine, COT, and 3HC (p > .05). In unadjusted models, NMR was 42.5% higher in diabetics versus non-diabetics (95% confidence interval [CI]: 12.9, 79.8; p = .003). In models adjusted for factors significantly different between low versus high NMR participants, mean NMR was 36.5% higher in the diabetics versus non-diabetics (95% CI: 7.8, 72.8; p = .010). Additionally, in models adjusted for known confounders of NMR, NMR was 40.6% higher in diabetics versus non-diabetics (95% CI: 9.9, 80.0; p = .007). CONCLUSIONS:From these data, we infer that type 2 diabetics metabolize nicotine faster, which may increase the potential for nicotine addiction. IMPLICATIONS:Smoking is addictive and this addiction may be related to tobacco metabolism. Individuals with faster metabolism of nicotine tend to smoke more cigarettes for longer periods of time. People with type 2 diabetes may metabolize nicotine faster, which could lead to higher lifetime tobacco burden, increasing the adverse health outcomes associated with increased exposure to tobacco.
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Project description:BackgroundNicotine metabolism is a major factor in nicotine dependence, with approximately 70% to 80% of nicotine metabolized to cotinine in Caucasians. Cotinine formation is catalyzed primarily by CYP2A6, which also converts cotinine to trans-3'-hydroxycotinine (3HC). The goal of the present study was to examine the effects of CYP2A6 deficiency on nicotine metabolism profiles in vivo and the importance of genetic variants in nicotine-metabolizing enzyme genes on urinary nicotine metabolites levels.MethodsUrine samples from 722 smokers who participated in the Singapore Chinese Health Study were analyzed using UPLC-MS/MS to detect nicotine and eight of its urinary metabolites, and a total of 58 variants in 12 genes involved in nicotine metabolism were investigated in 475 of these subjects with informative genotyping data.ResultsUrine samples stratified by the ratio of 3HC/cotinine exhibited a 7-fold increase in nicotine-N'-oxide, a 6-fold increase in nicotine-Glucuronide (Gluc), and a 5-fold decrease in 3HC-Gluc when comparing the lower versus upper 3HC/cotinine ventiles. Significant (P < 0.0001) associations were observed between functional metabolizing enzyme genotypes and levels of various urinary nicotine metabolites, including CYP2A6 genotype and levels of nicotine, nicotine-Gluc, nicotine-N'-oxide and 3HC, UGT2B10 genotype and levels of cotinine, nicotine-Gluc and cotinine-Gluc, UGT2B17 genotype and levels of 3HC-Gluc, FMO3 genotype and levels of nicotine-N'-oxide, and CYP2B6 genotype and levels of nicotine-N'-oxide and 4-hydroxy-4-(3-pyridyl)-butanoic acid.ConclusionsThese data suggest that several pathways are important in nicotine metabolism.ImpactGenotype differences in several nicotine-metabolizing enzyme pathways may potentially lead to differences in nicotine dependence and smoking behavior and cessation.
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