Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota

Zhu, Yingying; Jameson, Eleanor; Crosatti, Marialuisa; Schäfer, Hendrik; Rajakumar, Kumar; Bugg, Timothy D. H.; Chen, Yin

doi:10.1073/pnas.1316569111

Cited by 275 publications

(322 citation statements)

References 60 publications

(96 reference statements)

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“…The microbial enzyme was found within a "choline utilization" (cut) gene cluster that contains several tightly clustered genes, including a catalytic unit (cutC) and a regulatory polypeptide (cutD), both of which were required for anaerobic TMA production from choline (75,76). In other studies that used a similar bioinformatics approach with Acinetobacter baumannii as the model, an alternative microbial enzyme cluster (catalytic and regulatory protein CntA and CntB) specific for carnitine TMA lyase activity was also recently reported (77). Characterization of recombinant isolated CntA/B showed they formed a 2-component Rieske-type oxygenase/reductase complex (77).…”

Section: R E V I E W S E R I E S : G U T M I C R O B I O M Ementioning

confidence: 93%

“…examples of microbial enzymes that generate tmA, using choline or carnitine as substrates. Thus far, 2 distinct microbial enzyme systems have been identified in vitro that can produce TMA from either choline or carnitine as substrate (75,77). The choline-utilizing enzyme cutC (catalytic polypeptide) and its partner cutD (regulatory polypeptide) make a complex that selectively uses choline as substrate and releases TMA (choline TMA lyase activity).…”

Section: A Diet/meta-organismal Pathway Is Involved In Tmao Formationmentioning

confidence: 99%

“…Thus far, 2 distinct classes of enzymes have been reported that differ in their overall catalytic strategy for cleaving the C-N bond in choline and carnitine ( Figure 3 and refs. [75][76][77]. TMA produced by these enzymes can actually be considered a bacterial waste product released by the microbial enzyme systems, with the remaining carbon fuel source liberated from the parent substrate (choline/PC or carnitine) being used.…”

Section: R E V I E W S E R I E S : G U T M I C R O B I O M Ementioning

confidence: 99%

“…In other studies that used a similar bioinformatics approach with Acinetobacter baumannii as the model, an alternative microbial enzyme cluster (catalytic and regulatory protein CntA and CntB) specific for carnitine TMA lyase activity was also recently reported (77). Characterization of recombinant isolated CntA/B showed they formed a 2-component Rieske-type oxygenase/reductase complex (77).…”

Section: R E V I E W S E R I E S : G U T M I C R O B I O M Ementioning

confidence: 99%

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The contributory role of gut microbiota in cardiovascular disease

2014

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R e v i e w s e R i e s : g u t m i c R o b i o m eSeries Editor: Martin J. Blaser IntroductionCardiovascular disease (CVD) remains the leading cause of death in both the United States and industrialized societies, with growing incidence in developing countries (1). Factors contributing to CVD arise from genetic sources, environmental sources, or a combination of genetic and environmental sources (2). Despite extensive investigations in search of causal genetic variants, such as large-scale GWAS, less than one-fifth of attributable cardiovascular risk has been accounted for from genetic determinants (3, 4). At the same time, major advances in the treatment of atherosclerosis beyond high-potency lipid-lowering agents has not yet materialized (5). Indeed, even with high-potency statin therapy, at least a 50% residual risk remains (6), with the majority of events unchecked. Therefore, there is still ample room for improving our understanding of the processes contributing to CVD pathogenesis, and for improved prevention and treatment of CVD. While the recognizable contribution of genetics to CVD will no doubt significantly increase with time, a reassessment of environmental contributions to CVD pathogenesis and risks for adverse events is certainly worthwhile.Our largest environmental exposure is what we eat. Technically speaking, food is a foreign object that we take into our bodies in kilogram quantities every day. From the latest National Health and Nutrition Examination Survey (NHANES, 2009(NHANES, -2010, the majority of individuals sampled achieved an intermediate or poor Healthy Eating Index (1). However, dietary composition is often difficult to assess, and even precise quantification of dietary intake may not necessarily reveal the many known and unknown factors that may influence the contributions of specific dietary nutrients to disease susceptibility (7). There has also been an overwhelming lack of appreciation at the bedside regarding the intricate and complicated processes that transform ingested food into the myriad metabolites that enter the circulation and fulfill or adversely affect various functional and metabolic processes in the body.Over the past decade we have increasingly begun to appreciate the ecological diversity of microbes living symbiotically within us, a large proportion of which reside within our intestines. We now know that the human gut harbors more than 100 trillion microbial cells, far outnumbering the human host cells of the body (8). Indeed, a sobering fact is that Homo sapiens DNA is estimated to represent less than 10% of the total DNA within our bodies, due to the staggeringly large numbers of microbes that reside in and on us, primarily within our gut (9). Our microbial symbiont guests have coevolved with us and affect a wide range of physiologic and metabolic processes of the body. The major taxa present in gut microbiota consist primarily of 2 major bacterial phyla, Firmicutes and Bacteroidetes, whose proportions appear to remain remarkably stable over time within individu...

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Section: R E V I E W S E R I E S : G U T M I C R O B I O M Ementioning

confidence: 93%

Section: A Diet/meta-organismal Pathway Is Involved In Tmao Formationmentioning

confidence: 99%

Section: R E V I E W S E R I E S : G U T M I C R O B I O M Ementioning

confidence: 99%

Section: R E V I E W S E R I E S : G U T M I C R O B I O M Ementioning

confidence: 99%

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The contributory role of gut microbiota in cardiovascular disease

2014

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“…In the marine environment, TMAO is a compatible osmolyte for a variety of marine biota (Yancey et al, 1982;Treberg et al, 2006) and TMA is produced from the reduction of compatible osmolytes, such as glycine betaine, TMAO and choline (King, 1984;Arata et al, 1992). TMA production can also occur under aerobic conditions through oxidation of carnitine (Zhu et al, 2014), which may help explain the presence of TMA in oxygenated marine surface waters (Carpenter et al, 2012). Standing concentrations of TMA range from low nanomolar (nM) in coastal and open ocean surface waters to low micromolar (mM) in the pore water of marine sediments (Gibb et al, 1999;Fitzsimons et al, 2001;Gibb and Hatton, 2004).…”

Section: Introductionmentioning

confidence: 99%

Trimethylamine and trimethylamine N-oxide are supplementary energy sources for a marine heterotrophic bacterium: implications for marine carbon and nitrogen cycling

2014

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Bacteria of the marine Roseobacter clade are characterised by their ability to utilise a wide range of organic and inorganic compounds to support growth. Trimethylamine (TMA) and trimethylamine N-oxide (TMAO) are methylated amines (MA) and form part of the dissolved organic nitrogen pool, the second largest source of nitrogen after N 2 gas, in the oceans. We investigated if the marine heterotrophic bacterium, Ruegeria pomeroyi DSS-3, could utilise TMA and TMAO as a supplementary energy source and whether this trait had any beneficial effect on growth. In R. pomeroyi, catabolism of TMA and TMAO resulted in the production of intracellular ATP which in turn helped to enhance growth rate and growth yield as well as enhancing cell survival during prolonged energy starvation. Furthermore, the simultaneous use of two different exogenous energy sources led to a greater enhancement of chemoorganoheterotrophic growth. The use of TMA and TMAO primarily as an energy source resulted in the remineralisation of nitrogen in the form of ammonium, which could cross feed into another bacterium. This study provides greater insight into the microbial metabolism of MAs in the marine environment and how it may affect both nutrient flow within marine surface waters and the flux of these climatically important compounds into the atmosphere.

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Light‐Activated Electron Transfer and Catalytic Mechanism of Carnitine Oxidation by Rieske‐Type Oxygenase from Human Microbiota

et al. 2020

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Oxidation of quaternary ammonium substrate, carnitine by non‐heme iron containing Acinetobacter baumannii (Ab) oxygenase CntA/reductase CntB is implicated in the onset of human cardiovascular disease. Herein, we develop a blue‐light (365 nm) activation of NADH coupled to electron paramagnetic resonance (EPR) measurements to study electron transfer from the excited state of NADH to the oxidized, Rieske‐type, [2Fe‐2S]2+ cluster in the AbCntA oxygenase domain with and without the substrate, carnitine. Further electron transfer from one‐electron reduced, Rieske‐type [2Fe‐2S]1+ center in AbCntA‐WT to the mono‐nuclear, non‐heme iron center through the bridging glutamate E205 and subsequent catalysis occurs only in the presence of carnitine. The electron transfer process in the AbCntA‐E205A mutant is severely affected, which likely accounts for the significant loss of catalytic activity in the AbCntA‐E205A mutant. The NADH photo‐activation coupled with EPR is broadly applicable to trap reactive intermediates at low temperature and creates a new method to characterize elusive intermediates in multiple redox‐centre containing proteins.

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Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota

Cited by 275 publications

References 60 publications

The contributory role of gut microbiota in cardiovascular disease

The contributory role of gut microbiota in cardiovascular disease

Trimethylamine and trimethylamine N-oxide are supplementary energy sources for a marine heterotrophic bacterium: implications for marine carbon and nitrogen cycling

Light‐Activated Electron Transfer and Catalytic Mechanism of Carnitine Oxidation by Rieske‐Type Oxygenase from Human Microbiota

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