B12, the most chemically complex of all vitamins, is essential for human health. Four Nobel Prizes have been awarded for research related to B12, but one fragment of the molecule remained an enigma-until now.
The researchers report that a single enzyme synthesizes the fragment, and they outline a novel reaction mechanism that requires cannibalization of another vitamin.
The work, which has roots in an MIT undergraduate teaching laboratory, "completes a piece of our understanding of a process very fundamental to life," said Graham Walker, MIT professor of biology and senior author of a paper on the work that will appear in the March 22 online edition of Nature.
Vitamin B12 is produced by soil microbes that live in symbiotic relationships with plant roots. During the 1980s, an undergraduate research course taught by Walker resulted in a novel method for identifying mutant strains of a soil microbe that could not form a symbiotic relationship with a plant.
Walker's team has now found that one such mutant has a defective form of an enzyme known as BluB that leaves it unable to synthesize B12.
BluB catalyzes the formation of the B12 fragment known as DMB, which joins with another fragment, produced by a separate pathway, to form the vitamin. One of several possible reasons why it took so long to identify BluB is that some bacteria lacking the enzyme can form DMB through an alternate pathway, Walker said.
One of the most unusual aspects of BluB-catalyzed synthesis is its cannibalization of a cofactor derived from another vitamin, B2. During the reaction, the B2 cofactor is split into more than two fragments, one of which becomes DMB.
Normally, the B2-derived cofactor would assist in a reaction by temporarily holding electrons and then giving them away. Such cofactors are not consumed in the reaction.
Cannibalization of a cofactor has very rarely been observed before in vitamin synthesis or any type of biosynthetic pathway, says Michiko Taga, an MIT postdoctoral fellow in Walker's lab and lead co-author of the Nature paper.
"There are almost no other examples where the cofactor is used as a substrate," she said.
One early clue to BluB's function was that a gene related to it is located near several other genes involved in B12 synthesis in a different bacterium. Still, the researchers were not convinced that one enzyme could perform all of the complicated chemistry needed to produce DMB.
"It looked like a number of things had to happen in order to make the DMB," said Walker. "We originally thought that BluB might be just one of several enzymes involved in DMB synthesis."
Therefore, it came as a surprise when Taga isolated the BluB protein and showed that it could make DMB all by itself.
Nicholas Larsen, lead co-author and a former college classmate of Taga's now at Harvard Medical School, did a crystallographic analysis of the protein after Taga told him about her research over coffee one day. The protein structure he developed clearly shows the "pocket" of BluB where the DMB synthesis reaction takes place.
Still to be explored is the question of why soil bacteria synthesize B12 at all, Walker said. Soil microorganisms don't require B12 to survive, and the plants they attach themselves to don't need it either, so he speculates that synthesizing B12 may enable the bacteria to withstand "challenges" made by the plants during the formation of the symbiotic relationship.
More than 30 genes are involved in vitamin B12 synthesis, and "that's a lot to carry around if you don't need to make it," Walker said.
The full implications of the new research will probably not be known for some years, which is often the case with basic research, Walker said. "I've been in many other situations in research where we did something very basic and did not immediately realize the importance of it, and subsequently the implications were found to be much more broad-reaching," he said.
Other authors on the paper are Annaleise Howard-Jones, a postdoctoral fellow at Harvard Medical School, and Christopher Walsh, professor of biological chemistry and molecular pharmacology at Harvard Medical School.
The research was funded by the National Institutes of Health and the Jane Coffin Childs Memorial Fund for Medical Research.
Elizabeth A. Thomson | MIT News Office
Flow of cerebrospinal fluid regulates neural stem cell division
22.05.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Chemists at FAU successfully demonstrate imine hydrogenation with inexpensive main group metal
22.05.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...
A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.
The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...
Cardiovascular tissue engineering aims to treat heart disease with prostheses that grow and regenerate. Now, researchers from the University of Zurich, the Technical University Eindhoven and the Charité Berlin have successfully implanted regenerative heart valves, designed with the aid of computer simulations, into sheep for the first time.
Producing living tissue or organs based on human cells is one of the main research fields in regenerative medicine. Tissue engineering, which involves growing...
A team of scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg investigated optically-induced superconductivity in the alkali-doped fulleride K3C60under high external pressures. This study allowed, on one hand, to uniquely assess the nature of the transient state as a superconducting phase. In addition, it unveiled the possibility to induce superconductivity in K3C60 at temperatures far above the -170 degrees Celsius hypothesized previously, and rather all the way to room temperature. The paper by Cantaluppi et al has been published in Nature Physics.
Unlike ordinary metals, superconductors have the unique capability of transporting electrical currents without any loss. Nowadays, their technological...
02.05.2018 | Event News
13.04.2018 | Event News
12.04.2018 | Event News
18.05.2018 | Power and Electrical Engineering
18.05.2018 | Information Technology
18.05.2018 | Information Technology