Sunday, November 12, 2023

Life (33) Transient hunger

Just a brief repeat that the origin of metabolism is this reaction at
pH 6:

CO₂ + 2e- + E(in) -> CO + O2-

where the electrons and activating energy E(in) come from molecular hydrogen in solution at pH 10.

The next step is:

CO + O2- + 2H+ -> HCOOH + E(out)

where E(out) is greater than E(in) , making the reaction exothermic and not reversible without the input of energy. Because there is no system for resupplying this energy to drive the reaction in reverse, you cannot convert the hydrocarbons back to molecular hydrogen and CO₂. Once the proto-metabolite hydrocarbons are formed they are stable and so able to accumulate as the building blocks of life. It's a one way process.

Biomolecules accumulate. They are energetically stable.

So if we look at these conditions:

there is no need for localised stability, the wiggly line of the interface can move left or right at random. So long as there is an interface, biomolecules will form, be stable and so accumulate.

That's step one.

Next comes the development of another use for the energy provided by hydrogen at an alkaline pH.

A very, very early product of evolution was the development of the ferredoxin (Fd) molecule, an FeS cluster bound to one of the most ancient but tightly conserved very small proteins on earth. It allows the capture of both the electrons and the activation energy from our primordial hydrogen source in to a storable form, rather than it being used immediately to fix CO₂. Again the electrons and energy come from hydrogen at pH 10, as per hydrocarbon formation.

Ferredoxin + 2e- + E(in) -> Ferredoxin2-

If we take out all intermediate steps we can summarise the generation of Fd2- near the origin of life like this

H2 + Fd -> Fd2- + 2H+

Fd2- (reduced ferredoxin) can supply electrons and energy to drive metabolic processes throughout the protocell, well away from the site where pH gradient recapitulation is driving hydrogen oxidation. I think ferredoxin came well before ATP arrived but it did, and still does do, the same job.

This cannot happen in the core primordial situation. High energy ferredoxin in the presence of a catalyst would react with random protons immediately to regenerate molecular hydrogen and heat. Stability of Fd2- requires a cell membrane to protect it from the catalytic primordial FeS and NiFeS surface.

This happens automatically when organics accumulate as a coating to the acidic area of the protocell surface. So now an amino acid derived "tube" is needed to get the pH 6 fluid in to the cell and the NiFeS and FeS clusters need to be embedded in some sort of amino acid derived structure to hold them in the correct pH zones. Like this:

which is the basis of this:

which we can declutter to this:

We are now in a position to speculate about what might happen in a protocell which experiences fluctuations in the supply of hydrogen rich alkaline vent fluid. Loss of vent fluid allows the pH of the protocell to drop towards the acidic pH 6 of the ocean, shown as the red alkaline fluid in the above doodle turning to a more blue acidic fluid, as here below:

Recall that organic molecules are safe from degradation under these circumstances but that ferredoxin is not. So it is very easy to degrade Fd2- to molecular hydrogen, losing some of its stored energy as heat energy. Note the reversal of the arrows in the above diagram as this happens.

If this is a short term fluctuation there is the potential to preserve on-going protocell function in two ways. One is to stop the flow of electrons derived from Fd2- jumping from the embedded FeS cluster to the embedded NiFeS cluster. All that is needed is either a conformational change to the NiFeS structure to move it physically away from the FeS cluster or to change its local environment to make it an unattractive target for electrons. Changing the shape of a protein in response to protonation is a very simple concept and I've illustrated in this next doodle where the acidified NiFeS support structure has moved the NiFeS cluster away from the FeS cluster due to such a shape change.

This stops the wasteful generation of molecular hydrogen from Fd2-.

The second technique is to limit the ingress of protons from the acidic ocean fluid.

We currently have a situation where electrons are still free to travel from Fd2- to the embedded FeS cluster, producing a net negative charge:

All that is now needed is a positively charged area of amino acids in the transmembrane tube structure, like this:

and we now have the potential to alter the shape of the transmembrane tube to stop the ingress of protons from the oceanic fluid. All that is needed is for a positively charged localised area of the transmembrane tube to move towards the now negatively charged FeS cluster and produce a conformational change. This can limit acidic fluid ingress and preserve whatever alkaline conditions are still present within the protocell. Note the reinstatement/preservation of some degree of red alkaline pH-ness in to the intracellular fluid zone and lack of blue acidic pH-ness in the protocell area of the catalytic FeS cluster:

This provides a temporary "pro-survival" state for the protocell using the remaining Fd2- pool while awaiting the prompt (hopefully) return of vent fluid. Return of vent fluid's alkaline conditions removes protonation of the area around the NiFeS cluster, returning it to close proximity of the FeS cluster and establishing electron flow from the now resupplied hydrogen to the now depleted Fd2- pool. This opens the transmembrane channel and allows normal cell function to return:

and we're back where we started from.

These thoughts came from a combination of Nick Lane's comment about the protonation of Ech (also read MBH, complex I or about 6 other membrane pumps from the same family) in the region of a transmembrane channel coupled with some degree of reverse engineering of complex I mechanism in these two papers, which are another post but if anyone wants to read ahead they're here:

Symmetry-related proton transfer pathways in respiratory complex I

especially figures 2A and 6

and here:

It's all about what is reversible and what is not. The above doodles describe a pre-adaptation to a situation where reversal will lead to proton pumping. They're not describing a pump per se but they provide the basis for a pump should that become advantageous.



Passthecream said...

Amazing. Peter do you have an appropriately stinky fishtank in your office to test the possibility of new life arising?

karl said...

I originally bought my first Nick Lane book (about Oxygen), thinking it would be a sleep aid, but found it to be a page turner. Ended up reading everything he wrote. It is rare that I've found such well written bits about biology - not only skilled in biology..

His books provide a starting point for understanding biology. I think those trying to understand biology without the history will be at a disadvantage.

I saw in the news :
Wegovy reduced the risk of non-fatal heart attack by 28%, non-fatal stroke by 7% and death from cardiovascular causes death by 15% compared to a placebo (though the numbers did not quite meet the bar for statistical significance).

(I would use other means of correcting insulin than taking a drug).
This is semaglutide a GLP-1 agonist. That something that messes with insulin would have a large effect on CVD further pushes my take that focusing on lipids as the cause of CVD was misguided.

(It would be interesting to see the actual data - can't find it - wondering about some way to measure clot resorption time vs insulin --

cavenewt said...

Just an uninformed comment…"Wegovy reduced the risk of non-fatal heart attack by 28%, non-fatal stroke by 7% and death from cardiovascular causes death by 15% compared to a placebo (though the numbers did not quite meet the bar for statistical significance)." If those numbers, which look somewhat impressive on their face, aren't statistically significant, they must be referring to relative risk which I've learned to always suspect as playing hanky-panky with the numbers in order to hoodwink people.

These semaglutide "weight loss" drugs are predicted to be more profitable even than statins (will anything *ever* overtake Covid vaccines?) Which is why major media is all agog about them. What's never mentioned, unless your reading material is of the skeptical or low-carb variety, is what happens if you ever stop taking them. As I recall, you end up much worse than you started.

No thank you.

cavenewt said...

I'm plowing through Transformer right now, just approaching the part Peter's writing about here. Interesting to see two writers approaching it in parallel but slightly differently.

I can grok just enough of it to be awestruck at the amazing wonderfulness of the chemistry.

Eric said...

totally off topic:

Assuming these poor people have such a massive CVD problem and the PSK9 treatments on the market so far or the new gene editing treatment do really improve their health, what is the mechanism? The article makes it sound like it is the cholesterol production being switched off. However, in those extreme cases of FH, is is really the cholesterol or rather the coagulation system that is the culprit? So how does a treatment designed to interfere with cholesterol production affect coagulation?

cavenewt said...

@eric—did you look at the original study rather than the NYT article? Because 1. Journalist are terrible at interpreting scientific studies, and, furthermore, tend to latch onto something they can sensationalize rather than the main point.. 2. A lot of people can't get past the NYT paywall. 3. The NYT has its head up its butt and as a result is not a reliable source on pretty much anything.

Peter said...

Hi Eric,

There are a massive number of assumptions in there. I wasn't aware that people with FH had reduced life expectancy, so any purported benefits must be hard to find! So long since I had much interest in "cholesterol" levels but IIRC there is a small non-significant increase in all cause mortality from PSK9 therapy. Many NYT medical articles smell like they have been where it has had its head stuck (as cave suggests) most of the time...


Peter said...

Lots of typos this morning!

Pass, sadly the origin of life is utterly impossible in the presence of 21% O2... A nasty drug!!!

karl, yes Oxygen was a good read. I especially enjoyed the section on the natural origin water moderated uranium oxide nuclear reactor in Africa. That started me chasing papers too.

cave, yes Wegovy et al will be interesting to watch the fall-out from. The drug is notable in that it does *actually* work (!) cf statins and is not acutely actively toxic, as in the mRNA "products". Even the pancreatitis will probably be found to be triggered by the release of LA from adipocytes with the weight loss.


Passthecream said...

The more fossil hydrogen that gets burned for fuel the less of that pesky oxygen there will be to get in the way of re-evolution. But the less hydrogen there will be to power it.

Isn't that a famous song

"We're gonna have a re-evolution ..."


karl said...

One thing is clear - the folks pushing PSK9(IRNA) drugs have proven that they can not be trusted to do studies.

(They stopped early when all-cause-mortality was about to become significant - can't put the investment in jeopardy. Money comes first - public health is near the end .. )

Peter said...



Peter said...

Pass, do we have fossil hydrogen? Outside of the sun of course...

Oh, and the supernovas which gave us the olivine which releases the hydrogen during serpentinisation. You could say all the elements are fossil hydrogen. It's just a question of which combinations are most stable under a given set of circumstances, from the core of a neutron star to a proton in a pint of ale.