Final step in B12 biosynthesis revealed

[Guest guest]

Hey All,

I received this news item about B12 synthesis today from my friend and

our listmate Colleen today - http://web.mit.edu/newsoffice/2007/b12.html

.. This is of course not in humans,

but in the microorganisms that synthesize B12. As mammals, we humans can’t

synthesize B12 – that’s why it’s classified as a vitamin –

but we can recycle oxidized forms of cobalamin (B12) as long as we have enough coming

into the body through the diet. The new information about B12

synthesis in microorganisms segues very nicely with what Dr. Yasko wrote

recently about the MTRR enzyme (methionine synthase reductase, the enzyme that recycles

methylcobalamin) requiring NADH and riboflavin (B2) and being oxygen sensitive

- http://www.ch3nutrigenomics.com/phpBB2/viewtopic.php?t=9455 & highlight=.

Sublingual MB12, NADH (and its precursor, niacinamide) and Riboflavin were big

WOWs for Lulu. Lulu is homozygous for the MTRR-11 mutation.

Here is the ediro’s summary and the first paragraph of new article

about B12 synthesis in microorganisms:

http://www.nature.com/nature/journal/v446/n7134/edsumm/e070322-07.html

Nature, Volume 446 Number 7134 pp347-468.

22

March 2007

The long road to vitamin B12

Vitamin B12 (cobalamin) is one

of the largest known non-polymeric natural products, and it is the only vitamin

that is synthesized exclusively by microorganisms. Despite years of study, the

biosynthesis of one part of the vitamin is poorly understood. Now the last

unknown step in its biosynthesis is revealed. The X-ray crystal structure of

BluB, an enzyme that uses molecular oxygen to cleave a flavin mononucleotide

cofactor to form the lower ligand of vitamin B12,

has been determined. This reaction is an example of an unusual process, the

enzymatic destruction of one cofactor to synthesize another.

News

and Views: Biochemistry: Molecular cannibalism

The biosynthesis of vitamin B12 has

fascinated generations of scientists, but part of the pathway was unknown. The

missing enzymatic link has now been found, only to raise more mechanistic

questions.

E. Ealick and Tadhg P. Begley

doi:10.1038/446387a

Full Text | PDF (177K)

Letter: BluB cannibalizes flavin to form the

lower ligand of vitamin B12

Michiko E. Taga, A. Larsen,

leise R. -, T. Walsh and Graham C.

doi:10.1038/nature05611

First paragraph | Full Text | PDF (2,045K)

| Supplementary

information

Letter

Nature 446, 449-453 (22

March 2007) | doi:10.1038/nature05611;

Received 25 October 2006; Accepted 19 January 2007

BluB cannibalizes flavin to form the

lower ligand of vitamin B12

Michiko E. Taga1,3, A. Larsen2,3, leise R.

-2, T. Walsh2 and Graham C. 1

Department of Biology, Massachusetts

Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts

02139, USA

Department of Biological Chemistry and

Molecular Pharmacology, Harvard Medical School,

240 Longwood Avenue, Boston,

Massachusetts 02115,

USA

These authors contributed equally to this

work.

Correspondence to: T.

Walsh2Graham C. 1 Correspondence and

requests for materials should be addressed to G.C.W. (Email: gwalker@...) or C.T.W.

(Email: christopher_walsh@...).

Top of page

Vitamin B12 (cobalamin) is

among the largest known non-polymeric natural products, and the only vitamin

synthesized exclusively by microorganisms1. The biosynthesis of the lower ligand of vitamin B12, 5,6-dimethylbenzimidazole (DMB), is poorly

understood1, 2, 3. Recently, we discovered that a Sinorhizobium meliloti

gene, bluB, is

necessary for DMB biosynthesis4. Here we show that BluB triggers the

unprecedented fragmentation and contraction of the bound flavin mononucleotide

cofactor and cleavage of the ribityl tail to form DMB and d-erythrose 4-phosphate. Our structural

analysis shows that BluB resembles an NAD(P)H-flavin oxidoreductase, except

that its unusually tight binding pocket accommodates flavin mononucleotide but

not NAD(P)H. We characterize crystallographically an early intermediate along

the reaction coordinate, revealing molecular oxygen poised over reduced flavin.

Thus, BluB isolates and directs reduced flavin to activate molecular oxygen for

its own cannibalization. This investigation of the biosynthesis of DMB provides

clarification of an aspect of vitamin B12 that was

otherwise incomplete, and may contribute to a better understanding of vitamin B12-related disease.