Role of MoCo in FAD synthesis is not confirmed

Highlights

• If FADS indeed uses Molybdopterin, it appears for FAD to FMN reaction only.

• FAD to FMN reaction requires also Cobalt and Potassium ions and runs at much lower rate (ref 1).

Review of two papers

I’m digging deeper into FAD synthase (FADS) - the enzyme that converts FMN to FAD (and back).

It’s a mystery enzyme. GRJ states that it requires Molybdopterin (MoCo), but it seems it’s not exactly whole truth and actually has the opposite effect. See below.

The other piece I found is intriguing:

The enzyme binds 1 mole of the FAD product very tightly, although noncovalently. Complete release of FAD from the ‘as isolated’ protein requires extensive denaturation. (R1)

We used to think that reactions are as easy as take FMN, apply enzyme, get FAD readily available.

But this doesn’t seem to be the case with FADS - it looks like it’s an enzyme that not only makes FAD, but also delivers it to recipient and when it’s a right moment, FAD is released.

This is interesting.

The role of “molybdopterin-binding resembling domain” is actually the opposite of what we here believed - whatever binds to FADS to that terminal (presumably MoCo) facilitates the reverse reaction - hydrolysis of FAD to FMN, so yay, so much fuzz about molybdenum to make FAD. Turns out exactly the opposite is true.

But that’s not all, another eye-opening finding - FADS reverse reaction depends on Cobalt! (R2):

FADS, consists of two domains: a PAPS reductase C-terminus domain (here named FADSy) responsible for FAD synthesis, and an N-terminus molybdopterin-binding resembling domain (MPTb - here named FADHy), whose FAD hydrolytic activity is hidden unless both Co2+ and chemical mercurial reagents are added to the enzyme."

Open questions

Could it be so, that if FAD is stuck in FADS, the enzyme is basically locked unless there is a target to unload FAD onto, or sufficient presence of MoCo+Cobalt to convert it back to FMN? Would that create a kind of enzymatic deficiency when all enzymes are taken by FAD when there is not enough MoCo and Cobalt to add some “freedom”?

Perhaps MoCo is the regulator of how greedy FADS should be (e.g. brakes)? And when MoCo is low, there could be a tendency for deficiency of FMN?

How exactly cobalt is delivered to FADS? By GSH or using a chaperone protein?

How FADS deliver FAD to other proteins? Where it’s colocated?

How expression of FADS is regulated?