Naturally occurring cobalamin (B12) analogs can function as cofactors for human methylmalonyl-CoA mutase

[helvella]

A potentially interesting paper.

I do not feel that I understand anything beyond what the highlights say.

I can see that fuller understanding is desirable. Though I am finding it difficult see any advantages to analogs in this era of readily available "real" B12. However, if these analogs could be absorbed even by those who have impaired absorption of B12, they might have some role.

As so often, the full paper is behind a paywall.

Naturally occurring cobalamin (B12) analogs can function as cofactors for human methylmalonyl-CoA mutase

Olga M.Sokolovskaya, Tanja Plessl, Henry Bailey, Sabrina Mackinnon, Matthias R.Baumgartnerc, Wyatt W.Yued, D. Sean Froesec, Michiko E.Taga

doi.org/10.1016/j.biochi.20...

Highlights

• Human MMUT can use naturally occurring vitamin B12 analogs (cobamides) as cofactors.

• Cobamide affinity for MMUT and binding kinetics vary based on cobamide structure.

• Cobamides that bind MMUT support catalysis, with differences in apparent KM.

• Some cobamides also support the activity of disease-associated MMUT variants.

• Unexplored implications of cobamide diversity in human health are considered.

Abstract

Cobalamin, commonly known as vitamin B12, is an essential micronutrient for humans because of its role as an enzyme cofactor. Cobalamin is one of over a dozen structurally related compounds – cobamides – that are found in certain foods and are produced by microorganisms in the human gut. Very little is known about how different cobamides affect B12-dependent metabolism in human cells. Here, we test in vitro how diverse cobamide cofactors affect the function of methylmalonyl-CoA mutase (MMUT), one of two cobalamin-dependent enzymes in humans. We find that, although cobalamin is the most effective cofactor for MMUT, multiple cobamides support MMUT function with differences in binding affinity (Kd), binding kinetics (kon), and concentration dependence during catalysis (KM, app). Additionally, we find that six disease-associated MMUT variants that cause cobalamin-responsive impairments in enzymatic activity also respond to other cobamides, with the extent of catalytic rescue dependent on the identity of the cobamide. Our studies challenge the exclusive focus on cobalamin in the context of human physiology, indicate that diverse cobamides can support the function of a human enzyme, and suggest future directions that will improve our understanding of the roles of different cobamides in human biology.

sciencedirect.com/science/a...

[fbirder]

It means that some things that look like real B12 can, to some extent, replace real B12 in one reaction but that they are not as efficient as real B12. They don't say, in the abstract just what the difference in efficiency is.

But this is all done in vitro (in glass) which means it's totally irrelevant to real life. In real life they would need to get into the cell. Which means they would need to bind to transcobalamin. And I'm sure I've read somewhere that non-B12 corrinoids bind to haptocorrin, but not transcobalamin. Indeed, some suggest that is the purpose of haptocorrin - to mop up useless corrinoids.

That would evolve because you wouldn't want non-B12 corrinoids getting into the cell and binding to the MMUT enzyme. That is what is known as competitive inhibition. Indeed it is possible that the corrinoid would bind to the enzyme and not be released - an irreversible inhibitor.

Why this is interesting is that seeing what structural factors affect how well the corrinoid works as a MMUT cofactor will give some insight as to exactly how adenosylcobalamin works as a cofactor.

[helvella in reply to fbirder]

Do these B12 analogs have similar properties to real B12 in terms of binding cyanide?

[fbirder in reply to helvella]

I would imagine that some might do.

You would need a lower ligand that leaves the cobalt binding site for the upper ligand open to attack by the CN- group. And you would need an upper ligand that had a weaker affinity for the Co that does the CN- But that's all metallo inorganic chemistry - something I was never, ever, any good at.

[HowCome]

Thanks, Helvella.

Interesting abstract.

Is it saying posh “nature identical” cobalamin may not matter that much?

(Or is that bit if a leap?)

Definitely learnt something.... had to go and read more, as I never knew before that cobalamins “are produced by microorganisms in the human gut.”

[helvella in reply to HowCome]

No - the form of B12 matters because, at least in some reactions in our bodies, the precise form really does matter.

This just suggests that in at least one reaction, some of these analogs work to some extent.

The problem with human gut microorganisms creating B12 is that this takes place after the terminal ileum - which is where B12, as escorted by Intrinsic Factor, gets absorbed.

I do not know what happens to any Intrinsic Factor from there on.