Schematic model for lipoprotein-mediated B12 acquisition by B. theta. Starting from the closed state in which EL8 occupies the B12 binding site on BtuG, the BtuBG complex opens, which might happen spontaneously or perhaps is promoted by accessory proteins such as BtuH.
(ii) After opening, EL8 moves away from the B12 binding site, allowing acquisition of the vitamin by BtuG from the external environment or from BtuH.
(iii) Upon lid closing, EL8 act as a spring-loaded hinge to destabilize the bound B12, causing its release and transfer to BtuB. Binding of B12 by BtuB generates allosteric changes in the plug that leads to TonB box exposure in the periplasmic space.
During the final stage (iv), the C-terminal domain (CTD) of TonB binds to the TonB box and causes unfolding of the plug due to mechanical force generated by the TonB-ExbB-ExbD complex in the IM. The channel that is formed allows diffusion of the substrate into the periplasmic space.
Credit: Nature Communications (2023). DOI: 10.1038/s41467-023-40427-2
A team of scientists led by Dr. Ulrich Kleinekathöfer, professor of Theoretical Physics at Constructor University in Bremen, has now discovered how B12 is absorbed by certain intestinal bacteria. Published in the journal Nature Communications at the beginning of August, the findings will serve as a basis for research on how to better fight diseases and develop better antibiotics.
Kleinekathöfer and his team's breakthrough finding, what they call "pedal-bin mechanisms," offers critical understanding for how bacteria in the intestine known as bacteroides can absorb vitamin B12. This is important for human health since B12 cannot be produced or absorbed by humans themselves.
The scientists' name for the finding derives from its similarity to the pedal mechanism of a bucket; the proteins have a lid that opens when vitamin B12 is nearby, takes it in and closes again. Other bacteria do not have this mechanism.
"In this project we aimed at understanding the mode of action of the vitamin B12 uptake system," Kleinekathöfer said. "Although the human gut microbiome has been implicated in many aspects of human health, the uptake of small molecules by gut bacteria is poorly characterized."
Kleinekathöfer and his team's breakthrough finding, what they call "pedal-bin mechanisms," offers critical understanding for how bacteria in the intestine known as bacteroides can absorb vitamin B12. This is important for human health since B12 cannot be produced or absorbed by humans themselves.
The scientists' name for the finding derives from its similarity to the pedal mechanism of a bucket; the proteins have a lid that opens when vitamin B12 is nearby, takes it in and closes again. Other bacteria do not have this mechanism.
"In this project we aimed at understanding the mode of action of the vitamin B12 uptake system," Kleinekathöfer said. "Although the human gut microbiome has been implicated in many aspects of human health, the uptake of small molecules by gut bacteria is poorly characterized."
Kleinekathöfer and his team believe the results can help to design antibiotics which are not being taken up by gut bacteria. Since intestinal bacteria are "good" bacteria, research is interested in ensuring that they are not killed by absorbing antibiotics. However, further research will need to first explain through which proteins the gut bacteria do actually take up antibiotics. In the future, this finding could be the basis for placing specific substances in the bacteria in order to fight diseases.
"Our simulations at the molecular level helped interpreting the results obtained by our experimental colleagues," Kleinekathöfer said. "A detailed understanding of these processes is potentially a first step in curing problems in the gut microbiome."
The research team focused on specific proteins of the bacterium, of which three variants exist. The starting point was static crystal structures of the proteins provided by scientists from Newcastle University, a cooperation partner in this project. The Constructor University team then used simulation to determine the capture process of B12 by the proteins. The simulations allowed the researchers to simulate several hundred thousand atoms simultaneously.
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Inflammation and Vitamin B12: Unraveling the Hidden Connection
By SOCIETY OF CHEMICAL INDUSTRY NOVEMBER 1, 2023
A new study identified a compelling link between vitamin B12 deficiency and chronic inflammation, which is linked to several health problems including cardiovascular disease, diabetes, and neurodegenerative disorders. The research, which was published in the Journal of the Science of Food and Agriculture, explored how varying levels of B12 in the bloodstream affect key inflammatory markers in humans and mice.
Essential Nutrient and Health Implications
Vitamin B12, an essential nutrient with roles in various physiological processes, is known to be critical for overall health. Its deficiency can be the result of dietary insufficiency, particularly in vegetarian and vegan populations, or inefficient absorption in the body. This can lead to a range of complications, including neurological disorders. While previous research has hinted at the potential anti-inflammatory properties of vitamin B12, the precise relationship is not fully understood.
Now, a team of researchers in Spain have investigated the effects of vitamin B12 on the levels of two molecules in the body which promote inflammation, specifically interleukin (IL)-6 and C-reactive protein (CRP).
Now, a team of researchers in Spain have investigated the effects of vitamin B12 on the levels of two molecules in the body which promote inflammation, specifically interleukin (IL)-6 and C-reactive protein (CRP).
Rosa M. Lamuela-Raventós, co-corresponding author of the study and Professor of Nutrition, Food Sciences, and Gastronomy at INSA-University of Barcelona and Inés Domínguez López, a predoctoral researcher at the University of Barcelona and co-first author of the study explained the motivations behind the study.
Study Motivation and Clinical Relevance
‘Since chronic inflammation is associated with a wide range of diseases, understanding how vitamin B12 status influences inflammation could have significant implications for disease prevention and management. IL-6 and CRP are widely recognized as key markers of inflammation in clinical practice, as elevated levels of these markers are associated with various inflammatory conditions and chronic diseases. Establishing the relationship between inflammatory markers like IL-6 and CRP [and vitamin B12 levels] could have direct clinical relevance and open doors to novel therapeutic strategies.’
The study utilized samples from a randomized subsection of participants in PREDIMED, a large clinical trial based in Spain, designed to assess the effect of the Mediterranean diet on the primary prevention of cardiovascular disease. An assessment of the serum levels of vitamin B12 and the concentrations of the inflammatory markers revealed a correlation between the two.
‘Our study found that in general, the more vitamin B12 an individual has, the lower their inflammatory markers are — we call this an inverse relationship’, explained Marta Kovatcheva, a postdoctoral researcher at the Institute for Research in Biomedicine (IRB Barcelona) and co-first author of the study. ‘With regards to vitamin B12 deficiency, we must point out that we did not specifically look at deficient individuals in this study. Nevertheless, our results raise some important questions. We already know that vitamin B12 deficiency can be harmful in many ways, but what we have reported here is a novel relationship. This might help us better understand why some unexplained symptoms of human B12 deficiency, like neurologic defects, occur.’
To validate the findings of the research within the general population, Domínguez López noted, ‘It will be important to expand the cohorts, to look at sex-specific differences (as males and females often have different biology) and also to investigate the specific situations such as B12 deficiency, infection, or aging in humans.’
Observations in Mice Models and Future Research Directions
The study also observed the same relationship between vitamin B12 and inflammatory markers in naturally aged mice, offering a valuable avenue of using mouse models to delve deeper into the underlying mechanisms of the inverse correlation. Lamuela-Raventós explained, ‘This will help us understand the biology of this relationship we’ve observed, and will help us to ascertain any dietary and/or clinical recommendations that could be made in the future’.
Surprisingly, the researchers noted that, unlike humans, mice do not become B12 deficient with age. ‘We didn’t know this before, and it poses the possibility that studying mice could potentially help us understand how we could prevent B12 deficiency in older humans,’ said Kovatcheva.
The team now hopes to explore the link between vitamin B12 and inflammation, within the context of specific high-inflammation conditions, such as infection, obesity, and irritable bowel syndrome. ‘We already know that vitamin B12 deficiency is not good for an individual and that dietary measures should be taken to correct it. It will be interesting to understand if vitamin B12 supplementation can play a role in disease management,’ noted Lamuela-Raventós
Study Motivation and Clinical Relevance
‘Since chronic inflammation is associated with a wide range of diseases, understanding how vitamin B12 status influences inflammation could have significant implications for disease prevention and management. IL-6 and CRP are widely recognized as key markers of inflammation in clinical practice, as elevated levels of these markers are associated with various inflammatory conditions and chronic diseases. Establishing the relationship between inflammatory markers like IL-6 and CRP [and vitamin B12 levels] could have direct clinical relevance and open doors to novel therapeutic strategies.’
The study utilized samples from a randomized subsection of participants in PREDIMED, a large clinical trial based in Spain, designed to assess the effect of the Mediterranean diet on the primary prevention of cardiovascular disease. An assessment of the serum levels of vitamin B12 and the concentrations of the inflammatory markers revealed a correlation between the two.
‘Our study found that in general, the more vitamin B12 an individual has, the lower their inflammatory markers are — we call this an inverse relationship’, explained Marta Kovatcheva, a postdoctoral researcher at the Institute for Research in Biomedicine (IRB Barcelona) and co-first author of the study. ‘With regards to vitamin B12 deficiency, we must point out that we did not specifically look at deficient individuals in this study. Nevertheless, our results raise some important questions. We already know that vitamin B12 deficiency can be harmful in many ways, but what we have reported here is a novel relationship. This might help us better understand why some unexplained symptoms of human B12 deficiency, like neurologic defects, occur.’
To validate the findings of the research within the general population, Domínguez López noted, ‘It will be important to expand the cohorts, to look at sex-specific differences (as males and females often have different biology) and also to investigate the specific situations such as B12 deficiency, infection, or aging in humans.’
Observations in Mice Models and Future Research Directions
The study also observed the same relationship between vitamin B12 and inflammatory markers in naturally aged mice, offering a valuable avenue of using mouse models to delve deeper into the underlying mechanisms of the inverse correlation. Lamuela-Raventós explained, ‘This will help us understand the biology of this relationship we’ve observed, and will help us to ascertain any dietary and/or clinical recommendations that could be made in the future’.
Surprisingly, the researchers noted that, unlike humans, mice do not become B12 deficient with age. ‘We didn’t know this before, and it poses the possibility that studying mice could potentially help us understand how we could prevent B12 deficiency in older humans,’ said Kovatcheva.
The team now hopes to explore the link between vitamin B12 and inflammation, within the context of specific high-inflammation conditions, such as infection, obesity, and irritable bowel syndrome. ‘We already know that vitamin B12 deficiency is not good for an individual and that dietary measures should be taken to correct it. It will be interesting to understand if vitamin B12 supplementation can play a role in disease management,’ noted Lamuela-Raventós
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