Vitamin B12 Puzzle Solved By MIT Biologists

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Vitamin Puzzle Solved By MIT Biologists

http://www.medicalnewstoday.com/medicalnews.php?newsid=65927

Solving a mystery that has puzzled scientists for decades, MIT and

Harvard researchers have discovered the final piece of the synthesis

pathway of vitamin B12-the only vitamin synthesized exclusively by

microorganisms.

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 , MIT professor of

biology and senior author of a paper on the work that appears in the

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 resulted in a novel method for

identifying mutant strains of a soil microbe that could not form a

symbiotic relationship with a plant.

'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, 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 '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 . " 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.

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, 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, "

said.

The full implications of the new research will probably not be known

for some years, which is often the case with basic research,

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.