Close to 1.8 billion people worldwide are infected with Mycobacterium tuberculosis (Mtb), the common and occasionally deadly bacterium that causes millions of cases of tuberculosis each year. The bacteria, having coevolved with humans over millennia, have devised ways of hijacking nutrients from its human host for its own benefit. Humans have equally complex ways of fighting back.
In a new study appearing in the journal Science, a team of researchers have discovered a specific mechanism by which a "weapon" used by the immune system, called itaconate, targets Mtb.
Researchers only recently discovered that itaconate is produced in large amounts by the immune system when under attack. So far, just how itaconate disarms disease-causing bacteria has been somewhat of a mystery.
Mtb hides inside human immune cells, using cholesterol for the energy needed to grow and proliferate. During this process, the bacteria produce a toxic intermediate called propionate, which it must get rid of.
One strategy for propionate disposal relies on vitamin B12 derived from the human host. "B12 is a very interesting vitamin in that it is required in very low concentrations by our cells, perhaps the lowest of any vitamin, yet it's essential for life," says the senior author of the new paper.
A biologically active form of the vitamin, called coenzyme B12, was discovered more than 60 years ago and is involved in cellular metabolism. Coenzyme B12 allows very complex chemistry to occur in bacteria and human cells because it releases radicals, or unpaired electrons, that enable otherwise very challenging chemical reactions.
Typically, radicals are highly unstable and therefore short-lived. "In the body, free radicals cause cellular and DNA damage because they are very reactive," says the senior author. The pair of radicals (called a biradical) generated by coenzyme B12 is so reactive, that it raises the question as to how the enzyme is able to contain and use it.
The team was able to show that an activated form of itaconate, called itaconyl-CoA, blocks the B12-dependent pathway in the tuberculosis bacterium, preventing it from using propionate to grow. It does so by acting as a decoy, "tricking the B12-dependent enzyme into using itaconyl-CoA as a substrate, which then leads one of the radicals to commit suicide," says the author.
What's more, the itaconyl-CoA/coenzyme B12 reaction produced a stable biradical that lingered for more than an hour instead of disappearing rapidly. This enabled lead author to grow crystals of the enzyme containing the biradical and obtain its 3D structure.
"This is the first time anyone has seen this biradical," says the author. "Understanding how an enzyme can harness such reactivity can perhaps allow us to repurpose the method and could be invaluable in terms of chemistry," added another author.
This new observation could also begin to explain why 3% to 5% of the human population carries a mutated gene. "People with a mutation in the CLYBL gene have no obvious ill effects except their B12 levels are slightly lower," says the senior author, who speculates that this could confer an advantage against infection.
https://science.sciencemag.org/content/366/6465/589
Immune system targets vitamin B12 pathway to neutralize bacteria
- 1,266 views
- Added
Edited
Latest News
Abusive drugs hijack natura…
By newseditor
Posted 23 Apr
Mechanism of action of the…
By newseditor
Posted 23 Apr
Role of fat in rare neurolo…
By newseditor
Posted 23 Apr
How protein synthesis in de…
By newseditor
Posted 22 Apr
Atlas of mRNA variants in d…
By newseditor
Posted 22 Apr
Other Top Stories
High-Throughput Assay for Malaria Transmission
Read more
microRNA Function During Virus Infection
Read more
A New Trick for Artificial Photosynthesis
Read more
Mechanism of fungal killing!
Read more
Tissue-specific protein profiles in sepsis
Read more
Protocols
A programmable targeted pro…
By newseditor
Posted 23 Apr
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Publications
Exploiting pancreatic cance…
By newseditor
Posted 23 Apr
Structure of antiviral drug…
By newseditor
Posted 23 Apr
Type-I-interferon-responsiv…
By newseditor
Posted 23 Apr
Selenium, diabetes, and the…
By newseditor
Posted 23 Apr
Long-term neuropsychologica…
By newseditor
Posted 23 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar