The gymnast in action: This computer-generated image shows how Vitamin B12, a small molecule shown in dark green and dark blue, interacts with much larger molecules during the reaction known as methyltransfer that is vital to humans, animals and bacteria. Photo Credit: MIT/U-M |
You
see it listed on the side of your cereal box and your multivitamin
bottle. It’s vitamin B12, part of a nutritious diet like all those other
vitamins and minerals.
But when it gets inside your body, new research suggests, B12 turns into a gymnast.
In
a paper published recently in the journal Nature, scientists from the
University of Michigan Health System and the Massachusetts Institute of
Technology report they have created the first full 3-D images of B12 and
its partner molecules twisting and contorting as part of a crucial
reaction called methyltransfer.
That
reaction is vital both in the cells of the human body and, in a
slightly different way, in the cells of bacteria that consume carbon
dioxide and carbon monoxide. That includes bacteria that live in the
guts of humans, cows and other animals, and help with digestion. The new
research was done using B12 complexes from another type of carbon
dioxide-munching bacteria found in the murky bottoms of ponds.
The
3-D images produced by the team show for the first time the intricate
molecular juggling needed for B12 to serve its biologically essential
function. They reveal a multi-stage process involving what the
researchers call an elaborate protein framework—a surprisingly
complicated mechanism for such a critical reaction.
U-M Medical School professor and co-author Stephen Ragsdale, Ph.D., notes
that this transfer reaction is important to understand because of its
importance to human health. It also has potential implications for the
development of new fuels that might become alternative renewable energy
sources.
“Without
this transfer of single carbon units involving B12, and its partner B9
(otherwise known as folic acid), heart disease and birth defects might
be far more common,” explains Ragsdale, a professor of biological
chemistry. “Similarly, the bacteria that rely on this reaction would be
unable to consume carbon dioxide or carbon monoxide to stay alive—and to
remove gas from our guts or our atmosphere. So it’s important on many
levels.”
In
such bacteria, called anaerobes, the reaction is part of a larger
process called the Wood-Ljungdahl pathway. It’s what enables the
organisms to live off of carbon monoxide, a gas that is toxic to other
living things, and carbon dioxide, which is a greenhouse gas directly
linked to climate change. Ragsdale notes that industry is currently
looking at harnessing the Wood-Ljungdahl pathway to help generate liquid
fuels and chemicals.
In addition to his medical school post, Ragsdale is a member of the faculty of the U-M Energy Institute.
In
the images created by the team, the scientists show how the complex of
molecules contorts into multiple conformations—first to activate, then
to protect, and then to perform catalysis on the B12 molecule. They had
isolated the complex from Moorella thermoacetica bacteria, which are
used as models for studying this type of reaction.
The
images were produced by aiming intense beams of X-rays at crystallized
forms of the protein complex and painstakingly determining the position
of every atom inside.
“This
paper provides an understanding of the remarkable conformational
movements that occur during one of the key steps in this microbial
process, the step that involves the generation of the first in a series
of organometallic intermediates that lead to the production of the key
metabolic intermediate, acetyl-CoA,” the authors note.
Senior
author Catherine L. Drennan from MIT and the Howard Hughes Medical
Institute, who received her Ph.D. at the U-M Medical School, adds, “We
expected that this methyl-handoff between B vitamins must involve some
type of conformational change, but the dramatic rearrangements that we
have observed surprised even us.”
In
addition to Ragsdale and Drennan, the research team included the first
author, Yan Kung, from MIT, and co-authors include U-M’s Gunes Bender,
MIT’s Nozomi Ando, former MIT researchers Tzanko Doukov and Leah C.
Blasiak, and the University of Nebraska’s Javier Seravalli.
The
research was funded by the National Institutes of Health and the MIT
Energy Initiative. Two U.S. Department of Energy-funded synchrotron
facilities were used to produce the crystallographic images: the
Advanced Photon Source and its Northeastern Collaborative Access Team
beamlines supported by NIH, and the Advanced Light Source. The atomic
coordinates for the structures published by the team are deposited in
the Protein Data Bank under accession codes 4DJD, 4DJE and 4DJF.
Visualizing molecular juggling within a B12-dependent methyltransferase complex l
