CoA metabolism: a Little Cluster Worth a Note

I recently found an interesting little cluster that may (or may not) relate to CoA biosynthesis (Andrei would certainly be able to make a more informed judgement than I could). I noted that genes encoding Phosphopantetheine adenylyltransferase (EC 2.7.7.3), which is called PPAT in Andrei's subsystem .

Here is the cluster I would like to discuss. First, note the green gene numbered 2. It is clearly closely coupled with PPAT. It is often annotated as a methyltransferase. I have just noted that other groups are starting to call it phosphopantetheine adenylyltransferase, which seems better to me.

There is also the blue number 3, which we often call a Lon-like protease with PDZ domain. It is less clearly coupled, but when you look at the Listeria, Strep, Lactobacillus, etc, there it is apparently in a cluster with PPAT and phosphopantetheine adenylyltransferase.

Those are my off-the-cuff comments, which should not be taken too seriously. I am pointing Andrei at this cluster, and I suspect that he will understand what is happening.

Ross

Here are Andrei's comments:


1. To your comment: ”First, note the green gene numbered 2. It is
clearly closely coupled with PPAT. It is often annotated as a
methyltransferase. I have just noted that other groups are starting to call 
it phosphopantetheine adenylyltransferase, which seems better to me”


A. Of course those who are “are starting to call it phosphopantetheine
adenylyltransferase” are 100% wrong. PPAT is one of the most universal
component of CoA synthesis (a step before the last one), It occurs in
two flavors – bacterial CoaD (used to be kdtB before they figured the
function) and eukaryotic/archaeal, which we happened to discover and
publish. They are nonorthologous. Both forms are easily recognizable
and present in nearly all genomes (very few exceptions in
intracellular endosymbionts). The only reason folks may be
misannotating gene 2 is simply because it is often near gene 1 (being
PPAT). It is possible that at least in one species they are fused
(either for real or over sequencing error) and that led to propagation
of nonsense. I have noticed it happening with almost all nearby genes
(look in your previous example that we discussed). People 
don’t like hypothetical proteins and they use every opportunity to
name them something. Rare fusion events give an excellent opportunity
for that. Very disturbing.  

B. Therefore PPAT is entirely out of
question. As far as methyltransferase or in some “Ribosomal RNA small
subunit methyltransferase D (EC 2.1.1.-)”, I am quite convinced that
it is real. First of all SAM dependent methyltransferases are really
easy to recognize by sequence, there are many of tehm and they play
various regulatory roles often via methylation of DNA and RNA. Why
coupling with PPAT (metabolic enzyme)??? This is a very good question
that interests me the most and not only in this context. I can give
you more examples (eg in NAD, where the signal is even
stronger). Although I can not give you a precise answer, but I am
almost certain that this is one of the cases where metabolism links
with global regulation. This is the most fascinating area, which I am
willing to explore. We have single examples when this connection is
understood (eg CibB/Sir2 story of NAD-dependent deacetylation, which
allows eukaryotic cells to sense redox status of the cell via NAD and
translate it to triggering or suppressing big programs such as global
gene expression, apoptosis and so on). Very interesting and I am sure
that examples like yours may lead to understanding of more
mechanisms. I am thinking of how to pursue them, and so far I do not
have a real plan.

C. Of course explanation could be more trivial that gene 2 is somehow
involved in metabolism of CoA. The problem is that there is no gaps in
it in these species and I cannot think of methylation reaction that
would be involved directly in CoA biochemistry. Only via regulatory
chains, something like methylation of NA or proteins leading to
activation or inactivation of some CoA related circuits. Too vague to
even try anything. New approaches are needed to pursue these
things. Needless to say that novel metabolites (some methuylated form

2. To your comment: “There is also the blue number 3, which we often
call a Lon-like protease with PDZ domain. It is less clearly coupled,
but when you look at the Listeria, Strep, Lactobacillus, etc, there it
is apparently in a cluster with PPAT” Likewise, I have absolutely no
reason to dislike the current annotation. It is indeed closely related
to ATP-dependent proteases, such as Lon, which are involved in a
number of cellular processes (degradation of misfolded proteins,
translocation etc). A couple of other calls (as you may find in
PsiBlast) sound different (eg translocase) but in fact point in the
same direction – regulatory cascades. As in the previous case, I can
easily see that these regulatory processes are coupled with metabolic
pathways (sensing them and/or affecting them, switching metabolic
status of the cell in a big way). Understanding the real purpose and
mechanism of this coupling should become a focus of microbial science
in this century (think how little we know beyond two-component systems
and such).  That said, we see that coupling in case of gene 3 is less
global and may not be as significant as with #2? Nevertheless worth
considering.

I am afraid my comments may be a disappointment, however I do not feel
that way. Interestingly when we talk about mainstream organisms or
about global clusters (which is nearly the same), there is less and
less straightforward biochemistry left unattended. It really changed
over the last 10 years in a big way! Many of the genes with unknown
functions in these clusters and species (like e.coli and bacillus), I
feel, will fall in these uncharted regulatory cascades that link
metabolism with other cellular processes. It is certainly not a
low-hanging fruit (at least today) but it is a potentially sweet
one. Once we figure out how to attack them (I have some ideas).