Gilbert Ling's Theory Confirmed - ATP Required For Protein Solubility & Aggregation Control

haidut

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As some of you know, the Wikipedia article on Gilbert Ling's AI hypothesis was removed due to being too "alternative" and not accepted as valid by the scientific "consensus". In the mainstream biochemical view, ATP is nothing but an energy currency for cells and has no role in maintaining cellular structure. In fact, mainstream biochemistry claims the cell has little structure, consisting instead of a bag of salty water solution containing electrolytes and proteins.
This new study shows that ATP has a crucial role in allowing proteins to dissolve properly and stay inside the cell in a proper structure. As the study mentions, in aging and neurodegenerative conditions such as Alzheimer's Disease (AD) and Creutzfeldt–Jakob (mad cow) disease, these cellular proteins tend to aggregate in abnormally shaped clumps and ultimately cause cell death. If ATP was simply an energetic currency then the cell would maintain it in micromolar concentrations. But the cells go through great trouble to maintain millimolar concentrations of ATP and the only reasonable explanation is the role of ATP as hydrotrope and protein aggregation watchdog, as ATP function as such only in millimolar concentrations. So, keeping ATP levels high (aka high metabolism) is crucial for maintaining proper structure of the cell and preventing degeneration commonly seen in aging and diseases. As such, once again, "function and structure are interdependent --RP".
Hey @Drareg, @aguilaroja and @Such_Saturation - you guys may want to look at this as I know you were interested in the confirmation of some of Ling's postulates.


Journal Club: ATP could help proteins dissolve in cells, prompting a rethink about its function and evolution | National Academy of Sciences
"...ATP’s protein-solubilizing role may be even more ancient than its energy storage functions, Krishnan says. Large molecules clumping together would have posed an early problem during the evolution of life, so it’s possible that ATP—as one of the basic building blocks of DNA and RNA—may have been deployed to solubilize proteins."

“...This sort of turns ATP on its head, the idea that ATP evolved to solubilize proteins and only later to function as an energy source,” Weiss says. “One of the first examples of chemical energy we learn as kids is ATP, and it’s exciting to think we might have to re-teach that role.”


ATP as a biological hydrotrope | Science

"...We reconstituted FUS compartments in vitro at physiological concentration (7) using low salt (70 mM) buffer conditions (8) and tested the effect of ATP around its physiological concentration range of 2 to 8 mM (9), complexed with Mg2+ ions (ATP-Mg) (10). (For the chemical structures of all compounds used in this paper, see figs. S1A and S2A.) Indeed, 8 mM ATP-Mg prevented liquid-liquid phase separation and dissolved previously formed drops (Fig. 1, A and B). We observed similar effects of ATP with other proteins that form liquid compartments (11) (Fig. 1, A and B). A fluorescent tracer molecule confirmed that ATP was enriched in the liquid drops (Fig. 1C). Importantly, APPNP was as efficient as ATP in preventing the formation of liquid drops (Fig. 1, D and F). Thus, at millimolar concentrations, ATP dissolved drops independently of its role as an energy source."

"...Given the similarities between classical hydrotropes and ATP (Fig. 2A), we sought to explore whether ATP might act like a hydrotrope in a classical hydrotrope assay, in which the solubility of a hydrophobic compound such as fluorescein diacetate (FDA) in water is quantified as a function of hydrotrope concentration (15). For a hydrotrope such as NaXS, as its concentration increases, FDA solubility in water increases and the latter is quantified by ultraviolet absorption at 480 nm of the aqueous medium (Fig. 2B, upper panel). NaXS required concentrations greater than ~1 M to effectively solubilize FDA (Fig. 2B). However, ATP achieved the same effect at concentrations as low as 100 mM (Fig. 2B, lower panel). Water-soluble assemblies comprising amphiphiles (e.g., hydrotropes and surfactants) (fig. S2A) structured around a hydrophobic molecule consist of relatively nonpolar interior microenvironment. An organic dye, ANS (8-anilino-1-naphthalenesulfonic acid) is commonly used to probe the polarity near the head group (hydrophilic) or interfacial region of such amphiphilic assemblies. The fluorescence emission maximum of ANS is blue-shifted in a hydrophobic microenvironment (Fig. 2C, upper panel). Thus, the concentration at which the blue shift of ANS is maximal is a widely used indicator of the effectiveness of a hydrotrope (15, 22). Classical hydrotropes such as NaXS and NaTO induce a blue shift in the emission spectrum of ANS (15). ATP altered the emission spectrum of ANS to the same degree as NaXS and NaTO, albeit at much lower concentrations (Fig. 2C, lower panel). This shows that ATP is much more efficient than classical hydrotropes for creating a solubilizing microenvironment for hydrophobic molecules that are unlike micelles (fig. S2B and supplementary text)."

"...We next investigated whether high concentrations of ATP could also prevent protein aggregation. Using a centrifugation assay, we showed that millimolar concentrations of ATP kept FUS soluble and that higher concentrations of ATP prevent FUS aggregation (Fig. 3, A and B, and fig. S3, A to C). Notably, millimolar concentrations of ATP could also dissolve preformed FUS fibers, albeit at higher concentrations than were required to prevent aggregation (Fig. 3, C and D, and fig. S3, D to F). We also showed, using incorporation of thioflavin T, that ATP prevents the aggregation of two proteins that tend to cause amyloids: (i) synthetic Aß42 peptides, which aggregate to form Amyloid beta, associated with Alzheimer’s disease (25); and (ii) the prion domain of the yeast protein Mot3 (Mot3-PrD), which is thought to form functional aggregates in yeast cells (26) (Fig. 3, E and F)."

"...To investigate the role of ATP in a more physiological mixture of biological molecules at physiological concentrations, we studied protein aggregation in chicken egg white. At high temperatures, egg proteins lose their native conformation, thus exposing hidden hydrophobic patches within the proteins, which drive the aggregation of egg-white proteins. ATP inhibited the aggregation of boiled egg white in a dose-dependent manner (Fig. 4, A to C; fig. S4, A and B; and movie S1). Thus, ATP appears to prevent aggregation of egg white by stabilizing the native globular state (fig. S4C). Taken together, our experiments suggest that ATP has two different chemical properties. At micromolar concentrations, it acts as an energy source to drive chemical reactions, whereas at millimolar concentrations it acts to solubilize proteins."

"...The high concentration of ATP in cells has long been a puzzle, because ATP-dependent enzymes require micromolar concentrations of ATP. Why, then, would a cell invest so much energy into maintaining its cytoplasmic ATP concentration at ~5 mM? One explanation is that the free-energy difference between ATP and ADP is required to drive ATP-dependent reactions and that the 50-fold higher ATP/ADP ratio is necessary to fuel the myriad metabolic reactions taking place simultaneously in a cell. However, cytoplasm can have protein concentrations over 100 mg/mL (31–33), and it is extremely difficult to maintain such high protein concentrations in a test tube without spontaneous aggregation. The hydrotrope activity of ATP may help keep proteins soluble in the cytoplasm (34) and provide another, but not mutually exclusive, explanation for high ATP concentrations in cells. Possibly also, as the levels of ATP decline with age or mitochondrial impairment, this could lead to increased aggregation and consequently neurodegenerative decline during aging. Our work in this paper has focused on the role of ATP in keeping unstructured proteins soluble, because these are the types of proteins that have a propensity to form pathological aggregates (35). It will be interesting to examine the role of high ATP concentrations in stability and function of multimolecular protein machines."

Some excerpts from Ray discussing the role of ATP in the cell.
Age Pigment: Cause And Effect Of Aging And Stress
"...In Ling's view, ATP causes cells to retain water in a tightly organized form, and when ATP is seriously depleted, adsorbed potassium is released to become osmotically active, and sodium and chloride enter along with water, which is then in the "loosely held" state of normal bulk water, lacking the special properties of water that had been dominated by polymer surfaces. This swelling has been called "depolarization swelling," and is partly responsible for the swelling of injured or dying cells. Presumably, less drastic energy changes will cause physiological changes in the amount of organized water , in which water is usefully retained in proportion to the energy level."

"...Estrogen's early effects include activation of dehydrogenases and peroxidase (Jellinck and Lyttle, 1971 ; Talalay and Williams-Ashman, 1958; Temple, et al., 1960), and it participates in the interaction of NADH and NADPH as well as in the oxidation of NADH (Beard and Hollander, 1962, Hollander and Stephens, 1959; Yokota and Yamazaki, 1965; Lucas, et al., 1955; Villee, et al., 1965). The oxidation of NADH is involved in many harmful free radical processes. (McCay, 1971, an early study, but recently others have been published.) The most visible early effect of estrogen is to stimulate water-uptake by the cell. How it causes this immediate swelling isn't known, but it probably involves this consumption of oxygen, since simply cutting off the cell's supply of oxygen also causes water-uptake and edema. (Maybe ATP is needed to "extrude" water from the cell generally, as it is in the mitochondria.) The oxidation of NADH tends to raise the pH of the cell, and by increasing the electrical charge of the proteins this would be likely to cause swelling. I suspect that the normal (respiratory) function of oxygen is to adjust the electrical charge of the cell proteins, in a way that favors ATP synthesis and controls hydration. ATP (which is an acid, and is strongly adsorbed to proteins, influencing their charge) is known to cause swollen mitochondria to extrude water."
 
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Holy crap that made it on Science?
 

Drareg

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Thanks,this is very interesting.

Interesting because this may imply more protein in the diet may require more atp-mg or the opposite more atp-mg and protein is used more efficiently?
Some may get the impression that too much ATP will make your proteins soluble.
 

haidut

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Holy crap that made it on Science?

I know, right? Probably because they can easily claim another "paradigm shift" or "scientific revolution" and explain their past ignorance/fraud away.
 

haidut

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Thanks,this is very interesting.

Interesting because this may imply more protein in the diet may require more atp-mg or the opposite more atp-mg and protein is used more efficiently?
Some may get the impression that too much ATP will make your proteins soluble.

I agree, and incidentally there is plenty of evidence that better metabolism or magnesium supplementation (hence - more ATP) allow one to get by on much less protein probably due to increased efficiency or utilization due to increase solubility. Or if the diet is high protein then it protects the person's kidneys and liver.
 

Travis

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An attack on the "high-energy phosphate bond" concept can be found here: Reassessment of the Role of ATP in Vivo

Here are some quotes:
It has long been supposed that ATP is the “primary energy source” for contraction of skeletal muscle. As such it is often referred to as the “fuel” for muscle function. There is no doubt that this view is largely derivative of Lipmann’s “high energy phosphate bond” concept [from 1941]. However, it was noted that there is rather little ATP in muscle; for example frog sartorius contains about 2 μmol ATP/g compared with 20 μmol phosphorylcreatine/g. More importantly it was found that during normal contraction no change in the ATP concentration could be demonstrated. In writing about this Davies (1964) comments, “Numerous experiments . . . have shown that the concentration of ATP remains constant in living muscle during an extended series of contractions and no direct evidence was available that it was involved in muscle contraction. However, the view that it was so involved in this process became widely held when it was realized that adenosine triphosphate was the major energy supply for a whole series of endergonic processes in living matter . . . .” The implication that although the concentration of ATP does not change it is still the energy source for contraction represents a commonly held but quite erroneous idea since in any energetic (i.e. thermodynamic) accounting only those substances whose chemical potential changes need be considered. It follows that if, during normal contraction, the concentration of ATP does not change then the thermodynamic parameters associated with its formation and breakdown, such as the standard free energy of hydrolysis, are totally irrelevant. The confusion arises because of a failure to distinguish between a thermodynamic and a mechanistic problem.
You might wonder why most people think it's necessary for muscle contraction? Read on:
This was first achieved by Davies and his colleagues (see Davies, 1964) who found, surprisingly enough, that after treatment of frog sartorius or rectus abdominus muscle with a solution of 1-fluoro-2,4-dinitrobenzene a few contractions could still be elicited and that, under these circumstances, the concentration of phosphorylcreatine remained stationary while that of ATP decreased. Further experiments showed that 1 -fluoro-2,4-dinitrobenzene largely prevents the formation of ATP by glycolysis and by oxidative phosphorylation, completely inhibits phosphorylcreatine kinase and partially inhibits myokinase [the four ways in which ATP is regenerated]. Only under these extreme conditions can ATP be said to be the energy source for muscle contraction. Under normal conditions its concentration remains in steady state by the action of an elaborate buffer system the significance of which is obscured by “energetic” interpretations of the role of ATP.
I was questioning the role of ATP in muscle contraction myself after reading about microtubules. It seems silly that a diffusible molecule (ATP) would be the cause of muscle contraction. Why would the body rely on diffusion when there are microtubules carrying electrons through every myosin fiber? Perhaps ATP is involved in some way, but creatine is probably more important.
The nearest to an actual physical model is by analogy; for example, Baum (1968) supposes that the “electrical energy” causes conformational changes in the mitochondrial membrane which are likened to the coiling of a spring. When the spring uncoils ATP or some “high-energy” precursor is automatically synthesized. This cannot be said to constitute a mechanism.
Don't hold back Dr. Banks. I would have said, "Words fail to describe the idiocy of likening ATP synthesase to a vending machine."
He then goes on to attack Mitchell, who would go on to win a Nobel Prize for his chemi-osmotic theory of ATP production which is still taught today in textbooks.
The alternative theory, the so-called chemiosmotic hypothesis of Mitchell, is much more ingenious, even if equally obscure, and deserves credit for the stimulating effect its initial enunciation and subsequent frequent modification has had of research in this field. Mitchell’s model is that of a fuel cell rather than of an electrochemical cell. He supposes that the electron transport chain consists of alternating hydrogen and electron carrying components orientated in the membrane in such a way that protons are discharged on one side only, so generating a proton gradient across the membrane. This generates a “proton motive force” and the inevitable calculation showed that the associated free energy change is greater than the standard free energy of hydrolysis of ATP. This is taken to mean that ATP synthesis can now occur. How it occurs is not very clear. In the original version of the theory, the excess of protons on one side of the membrane and the excess of hydroxide ions, formed by reduction of oxygen by electrons, on the other was imagined to drive the reverse of ATP hydrolysis by abstracting hydroxide ions from ADP on one side of the membrane and hydrogen ions from inorganic phosphate on the other. The net result is to abstract the elements of water but precisely how this process would work is by no means clear. In any case the theory came under heavy attack and resulted in a regrettable modification in which the “proton motive force” generates, by some obscure process, an anhydride precursor of ATP. This anhydride is originally formed as a “low-energy” compound but migration across the membrane mysteriously transforms it into a “high-energy” compound [LOL] the hydrolysis of which reverses the hydrolysis of ATP. The theory is now close to “chemical link” theories and suffers from the disadvantage that the hypothetical anhydride has not been detected.
Mitchell may have been on the right track. You really do need a proton (H⁺) to form ATP from ADP and phosphate.
ADP + HPO₄²⁻ + H⁺ ⟹ ATP + H₂O
In attempting to account for the “high-energy” nature of ATP, discussions centred on the structure of this molecule (e.g. theories of opposing resonance) while the production of a proton in the course of hydrolysis is often ignored. It should be obvious from the above that the production of a proton is the dominant factor in deciding the direction in which equilibrium lies under physiological conditions (George & Rutman, 1960).
I have seen a good experiment which measured ΔG° for ATP at –4.7 kcal/mol (Podolsky & Morales). Dr. Banks (who doesn't even think ΔG° is important) thinks the most reliable estimate is –5.6 kcal/mol. These values are little different than the Gibbs free energies of inorganic pyrophosphate. Gilbert Ling also thinks the concept of the "high-energy phosphate bond" is ridiculous: "In time it became established that while ATP does not carry so-called high-energy phosphate bonds, ATP has powerful affinity for the protein it interacts with, thereby affirming the unique role of this compound as the queen of cardinal adsorbents in maintaining the resting living state and in shifting between alternate states."–Ling
APPENDIX: The Standard Free Energy of Hydrolysis of ATP
Although it has been shown that the value of this quantity has no particular significance, it is of interest to examine the validity of the data upon which phosphate esters are classified into “low” or “high” energy compounds. The reaction primarily involved is represented by equation (A1) [equation (4) written with the ionization states appropriate to pH 7.41 ATP⁴⁻ + H₂O = ADP³⁻ +HPO₄²⁻ +H⁺ (A1) It is worth pointing out that usage of the conventional symbol for standard free energy change, ΔG°, is incorrect in the present context since the standard free energy change refers to conditions in which all components are present at unit activity. It is made clear (Burton & Krebs, 1953) that on this definition, ΔG°, (pH independent) is +1 kcal/mol. [...]The earliest estimates of the standard free energy change were in the range –10 to –14 kcal/mol but were based on imprecise thermochemical measurements (see Oesper, 1951) and are clearly of little value.
 
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yerrag

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So, this is more reason then for arguing for oxidative metabolism right? Over and above it producing energy most efficiently, oxidative metabolism contributes to the integrity of our cells. If the body is further away from using this process, it will lose its structure that maintains the ionic balance. This ionic balance influences the electrical impulses, such as in the beating and pumping of the heart. Whether or not it does its job of distributing oxygen and sugar and nutrition to the cells, and of transporting out of the cell of its waste and by-products, is wholly dependent on enabling the body to run with all four cylinders - with efficiency and with integrity.
 

Travis

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So, this is more reason then for arguing for oxidative metabolism right?
Yeah. There is something wrong the idea that ATP is "a fuel" which transfers energy in its "high-energy phosphate bond".

It's still necessary, but Gilbert Ling and Barbara Banks (⇑) think that its misunderstood.

Some textbooks, and Wikipedia, give the impression that the entire point of the electron transport chain, the citric acid cycle, glycolysis, and β-oxidation is merely to regenerate ATP. The cell purportedly can then take this "stored chemical energy" to other parts of the cell—notably muscle and Na⁺/K⁺ ATPase (another biological unicorn)—and "release it".

But in the process of ATP generation, we already have electron flow within the cell. I think that instead electron flow is the main purpose of the the citric acid cycle, glycolysis, and β-oxidation. I think the production of ATP is to buffer the excess H⁺ created and to lower heat. The formation of ATP from ADP and P cools the cells as energy is taken from the environment (~4.7 kcal/mol) to form ATP. This is made apparent by the fact that uncoupling (from ATP synthesis) mitochondria leads to increased heat production.
 
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Mito

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But in the process of ATP generation, we already have electron flow within the cell. I think that instead electron flow is the main purpose of the the citric acid cycle, glycolysis, and β-oxidation. I think the production of ATP is to buffer the excess H⁺ created and to lower heat. The formation of ATP from ADP and P cools the cells as energy is taken from the environment (~4.7 kcal/mol) to form ATP. This is made apparent by the fact that uncoupling (from ATP synthesis) mitochondria leads to increased heat production.
Interesing thought. If true, supplementing exogenous ATP would not be beneficial.
 

Ledo

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Yeah. There is something wrong the idea that ATP is "a fuel" which transfers energy in its "high-energy phosphate bond".

It's still necessary, but Gilbert Ling and Barbara Banks (⇑) think that its misunderstood.

Some textbooks, and Wikipedia, give the impression that the entire point of the electron transport chain, the citric acid cycle, glycolysis, and β-oxidation is merely to regenerate ATP. The cell purportedly can then take this "stored chemical energy" to other parts of the cell—notably muscle and Na⁺/K⁺ ATPase (another biological unicorn)—and "release it".

But in the process of ATP generation, we already have electron flow within the cell. I think that instead electron flow is the main purpose of the the citric acid cycle, glycolysis, and β-oxidation. I think the production of ATP is to buffer the excess H⁺ created and to lower heat. The formation of ATP from ADP and P cools the cells as energy is taken from the environment (~4.7 kcal/mol) to form ATP. This is made apparent by the fact that uncoupling (from ATP synthesis) mitochondria leads to increased heat production.
Hi @Travis ,

I have never closely studied these cellular energy mechanisms with the intent of really learning much or being able to question much. I have really only cared about what I can eat or do from the big perspective to optimize them as much as possible with the really few inputs we have as organisms.

So no intent to challenge you at all but isn't what you suggest either absurd or alternatively, a sad state of affairs that the science consensus would have things so backwards some guy on the internet could so casually up end it all with a brief refitting of the entire theory of how our orgaanism makes energy?

FWIW I hope you are right. Maybe we can make some progress for a change. LOL
 

Travis

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So no intent to challenge you at all but isn't what you suggest either absurd or alternatively, a sad state of affairs that the science consensus would have things so backwards some guy on the internet could so casually up end it all with a brief refitting of the entire theory of how our orgaanism makes energy?
It's not just me saying this, it's respectable biochemists Barbara Banks, C.A. Vernon, and Gilbert Ling.

If I'm merely "some guy on the internet", then you're merely "that other guy on the internet".

And Ray Peat quotes are always admissible here:
Energy and relaxation, cellular inhibition, a structural state involving the entire cell substance. High energy phosphate bonds explain nothing about the cell’s energy.

You have to realize that the concept of the "high-energy phosphate bond" was formulated in 1941 based on imprecise caloric measurements. Lipmann probably didn't subtract the heat of ionization leading to excessive values. Almost every single measurement since then—in addition to quantum mechanical calculations—has given values little different that inorganic pyrophosphate.

Most of the biochemistry taught in textbooks was elaborated in the 1960s. This was before the discovery of microtubules inside of nerves linked to mitochondria. There is simply no other biological structure capable of long-distance energy transfer.

This isn't a "casual up-ending". The Banks & Vernon article is 26 pages of good information and my Gilbert Ling book is 600+ pages of good insight. Gilbert Ling did his own experiments. I have also read also Mitchell's papers on ATP.

There isn't even a good theory on muscle contraction, and much less on how ATP purportedly "causes" it. The consensus is Andrew Huxley's mind-numbingly stupid Crossbridge Theory, which Harold Hillman says this about:
It is an absolutely beautiful hypothesis, but there are some problems: (a) the filaments are too uniformly distant apart in sections. They should appear in a range of distances apart depending upon the angle of section; (b) it is extremely difficult to find oblique sections of muscle in electron micrographs; one usually sees either perfect transverse or perfect longitudinal sections. This would seem to be rather strange, as it is so difficult to align a muscle before it is stained and sectioned; (c) the muscle should contract with the maximal force when it begins to contract, because the cross bridges should be maximally stretched at the beginning. When the muscle has contracted maximally, the force exerted by the transverse component should have reached its maximum, and, therefore, the muscle fibres should narrow their waists. A contracted muscle should look thinner not fatter. The usual explanation given for this is that muscles are isovolaemic, so that a longitudinal contraction must cause a transverse expansion. Unfortunately, this failure of the muscle to contract in its middle is seen not only in the whole muscle, but also when single muscle fibres are dissected out. It must be concluded that the myoplasm in life is a viscous fluid, which, when dehydrated, forms thick and thin filaments. A new alternative theory to the sliding filament hypothesis requires to be formulated.

As for ATP as an acid base buffer, see here:
ATP formation caused by acid-base transition of spinach chloroplasts

As for ADP⇒ATP as an entropic cooling device, see here:
Table IV
Uncoupled ATPase Activity and Heat Production by the Sarcoplasmic Reticulum Ca²⁺-ATPase
REGULATION BY ADP
 
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haidut

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An attack on the "high-energy phosphate bond" concept can be found here: Reassessment of the Role of ATP in Vivo

Here are some quotes:
You might wonder why most people think it's necessary for muscle contraction? Read on:

I was questioning the role of ATP in muscle contraction myself after reading about microtubules. It seems silly that a diffusible molecule (ATP) would be the cause of muscle contraction. Why would the body rely on diffusion when there are microtubules carrying electrons through every myosin fiber? Perhaps ATP is involved in some way, but creatine is probably more important.
Don't hold back Dr. Banks. I would have said, "Words fail to describe the idiocy of likening ATP synthesase to a vending machine."
He then goes on to attack Mitchell, who would go on to win a Nobel Prize for his chemi-osmotic theory of ATP production which is still taught today in textbooks.
Mitchell may have been on the right track. You really do need a proton (H⁺) to form ATP from ADP and phosphate.
ADP + HPO₄²⁻ + H⁺ ⟹ ATP + H₂O

I have seen a good experiment which measured ΔG° for ATP at –4.7 kcal/mol (Podolsky & Morales). Dr. Banks (who doesn't even think ΔG° is important) thinks the most reliable estimate is –5.6 kcal/mol. These values are little different than the Gibbs free energies of inorganic pyrophosphate. Gilbert Ling also thinks the concept of the "high-energy phosphate bond" is ridiculous: "In time it became established that while ATP does not carry so-called high-energy phosphate bonds, ATP has powerful affinity for the protein it interacts with, thereby affirming the unique role of this compound as the queen of cardinal adsorbents in maintaining the resting living state and in shifting between alternate states."–Ling

I suspect ATP is nothing but a sign/symptom of a well functioning electron flow. It by itself probably has a very minor role in muscle function or the function of any organ for that reason. Peat wrote about Szent-Gyorgyi making "dead" muscle contract like normal by supplying the proper ratios of electron donors and acceptors (quinones).
 

Travis

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I suspect ATP is nothing but a sign/symptom of a well functioning electron flow. It by itself probably has a very minor role in muscle function or the function of any organ for that reason. Peat wrote about Szent-Gyorgyi making "dead" muscle contract like normal by supplying the proper ratios of electron donors and acceptors (quinones).
Yeah, I agree. It seems more like a "side-effect" than the primary agent. I need to read about those Szent-Györgyi experiments someday. Coenzyme Q₁₀ (coenzyme quinone) is way more important to muscle contraction in the heart than ATP seems to be. A deficiency in CoQ₁₀ can actually cause heart failure (this can be caused by statins through inhibiting CoQ₁₀ tail synthesis. The same isoprene units that make-up cholesterol also form the tail of CoQ₁₀.)

If you look at the chemistry of ATP, you see that it buffers free H⁺ and lowers entropy. It does other things as well. It participates in numerous enzymatic kinase reactions.

Everyone intuitively knows that electric potential is what causes muscle contraction, not ATP. But before the discovery of microtubules, chemists were puzzled because most proteins are non-conductive. Szent-Györgyi theorized that this was because chemists usually measure the conductivity of globular proteins (like casein) instead of long structural proteins. He hypothesized that methylglyoxal played a role in unsaturating the peptide backbone of structural proteins, making them electrically conductive.

But the erroneous idea of the "high-energy phosphate bond" has been clouding people's perceptions about ATP and muscle contraction for over 80 years.

Even when Mitchell formulated his chemiosmotic theory in the 60s that describes how H⁺ turns ADP into ATP, he was biased in this manner. He knew that the one of the only ways to do chemical work is to create an electric potential, or a proton gradient (in his words). But if the cell already has an electric gradient which can perform muscle contraction directly, then why do you need to use this gradient form ATP?

I think ATP has a strong role in donating H⁺ to O₂ to form H₂O. In fact, this almost certainly has to be the case. Nicotinamide adenine dinucleotide (NADH) only differs from NAD⁺ by one H⁺ and 2e⁻, or hydride [:H⁻]. To make water from O₂ in cytochrome c oxidase, you need one additional H⁺ for every [:H⁻] donated by NADH which must come from somewhere.

O₂=12e⁻
2H₂O=16e⁻
Δ=4e⁻

O₂+4e⁻(2NADH)+2H⁺(2NADH)+2H⁺(which must come from somewhere)=2H₂O

This is why you cannot permanently form and store ATP. Every H⁺ that is used to form ATP must be donated to O₂ at some point. Transporting ATP much further that it's source will cause a pH inbalance. Adenosine triphosphate must exist in a more-or-less steady-state.

The more people think about the ATP phosphate bond as a source of "energy", the less they think about electrons or biophotons driving energy. Biophotons aren't woo. There are textbooks written on it and we have all seen glowing insects. Some animals even have light that emits from their eyes. This can be seen in the dark.

There are only two main ways (that I'm aware) that you could use ATP to produce energy. Entropy is produced from breaking a bond and can manifest as heat. This comes from the additional kinetic energy of having two smaller molecules instead of one larger one. I haven't heard of anyone try to say that heat or entropy creates muscle contraction, although this function of ATP can be utilized during mitochondrial uncoupling to produce heat.

The second way is to set-up an electric potential: the reverse of the Mitchell ATP-chemiosmotic gradient. This actually seems plausible, but would make molecules such as acetylcholine, creatine, and NADH every bit as energetic as ATP.

The way I generally see energy production is that charges are separated during the citric acid cycle (H⁺, :H⁻) and then recombined in a manner that sets-up an electric potential. "High-energy phosphate bond" proponents can never explain how this imaginary energy is harnessed in a way that makes even the slightest bit of sense.
 
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haidut

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A deficiency in CoQ₁₀ can actually cause heart failure (this can be caused by statins through inhibiting CoQ₁₀ tail synthesis

That was a great explanation, thanks. So, maybe the primary role of ATP is to generate heat/water, even in the non-uncoupled state?? I always wondered why ATP is one of the most potent downregulators of the enzyme PDH. If ATP was indeed an energy storage molecule why wouldn't the body want more, in fact as much as it can get? Instead, if ATP accumulates it downregulates its own synthesis AND activates the uncoupling proteins. But muscle contraction does not deteriorate the slightest bit, showing (as you said) that it is not ATP that drives the process.
In regards to the above quote - by disrupting the CoQ10 synthesis statins can indeed do all kinds of damage to muscle fibers and affect the ability to contract. If statins can cause heart failure through this mechanism, what other muscle disorder do you think they can cause? How about ALS, Huntington, and myasthenia gravis?
Medscape: Medscape Access
http://www.medscape.org/viewarticle/581181
STATINS MAY AGGRAVATE MYASTHENIA GRAVIS
Statin-associated weakness in myasthenia gravis: a case report

Given that statins also inhibit the synthesis of vitamin K2 (the alternative electron carrier then CoQ10 is low), their names should be changed to "quinone antagonists" to reflect the profound metabolic antagonism that occurs with the use of these drugs.
Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. - PubMed - NCBI
"...In contrast to the current belief that cholesterol reduction with statins decreases atherosclerosis, we present a perspective that statins may be causative in coronary artery calcification and can function as mitochondrial toxins that impair muscle function in the heart and blood vessels through the depletion of coenzyme Q10 and 'heme A', and thereby ATP generation. Statins inhibit the synthesis of vitamin K2, the cofactor for matrix Gla-protein activation, which in turn protects arteries from calcification. Statins inhibit the biosynthesis of selenium containing proteins, one of which is glutathione peroxidase serving to suppress peroxidative stress. An impairment of selenoprotein biosynthesis may be a factor in congestive heart failure, reminiscent of the dilated cardiomyopathies seen with selenium deficiency. Thus, the epidemic of heart failure and atherosclerosis that plagues the modern world may paradoxically be aggravated by the pervasive use of statin drugs. We propose that current statin treatment guidelines be critically reevaluated."

Btw, there is a proposal that excessive ATP drive cancer appearance and progression.
Does excessive adenosine 5'-triphosphate formation in cells lead to malignancy? A hypothesis on cancer. - PubMed - NCBI
 
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Travis

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Yeah. I would find it funny—it it wasn't so destructive—that a drug class (statins) mad to prevent cardiovascular events actually contributes to two of them: congestive heat failure from low CoQ₁₀ biosynthesis, and arterial calcification from low vitamin K₂ synthesis.

These "opposing" effects (protection vs causation) might seem to balance eachother, which could then be used to argue that statins could have more a beneficial effect than a deleterious effect. However, I think we all here know that depressing cholesterol synthesis wouldn't be expected to improve cardiovascular disease anyhow. This makes statins one of the most Orwellian (triple-plus bad?) drug therapies ever conceived, although their discoverer (Eno) had good intentions.

He was blinded by the Ancel Keyesian Lipid Hypothesis.
 

yerrag

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Travis

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Repurposing as a cancer treatment:
These people. I still haven't seen anything as safe effective as methylglyoxal or bromopyruvate for cancer. These two drugs (one is natural) reverse tumors in 90% to 100% of cases. I have rat studies that show this. The studies come out of India and China.

This is why I don't get excited about most cancer drugs that only work about 20% of the time. Methylglyoxal is so effective that it captivated Albert Szent-Györgyi.

And besides inhibiting synthesis of CoQ₁₀ and vitamin K₂, statins inhibit the production of heme. I can't see how this can be a good thing for normal cells, since you would expect this to inhibit respiration. Heme needs a "tail" (farnesyl) too, which is constructed from isoprene units.

Statins inhibit every downstream event dependent on isoprene units, not just cholesterol synthesis.
 

chispas

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I know, right? Probably because they can easily claim another "paradigm shift" or "scientific revolution" and explain their past ignorance/fraud away.

That's what the scientific method has always aimed to achieve.
 
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