Since getting diagnosed with Chagas(kissing bugs love me in the Amazon), I have been intrigued by Limonene, as well as several other terpenoid compounds that apparently are pretty good for Chagas. Serendipitously I found there is some research to suggest Limonene is a good candidate agent for PCa, perhaps similar in action to Artemisinin(wormwood). So now I burp essence of orange everyday. But this recent Doctoral thesis on orange peel extract has really got me thinking:
As best I understand it, the Citrus extracts they were studying fell into two camps. fat soluble compounds that had strong apoptosis effects on PCa and interestingly, water soluble citrus extract compounds that kept PCa cells in the quiescent G0/G1 phase(non dividing). The compound they identified as most significant to this end was the lowly citrate molecule, abundant of course in citrus foods. It turns out hi levels of citrate modify the krebs cycle, inhibiting at a minimum the phosphofructokinase enzyme. Apparently there is also down stream gene up/downregulation with attendant signal protein manipulation which is apparently tumor suppressive. There are several citations to other studies whereby citrate has shown broad promise in the Cancer arena. The connection that's interesting to me is that it turns out PCa cells have low levels of citrate. Not so with the healthy prostate!. Remember the studies that revealed that Zinc was also low in PCa tissue? Yes high levels of Zn inhibit the conversion of citrate to isocitrate, creating a high concentration of citrate in and around(seminal fluid) the healthy prostate. So apparently high levels of citrate keep the prostate tissue in a good happy place.hmmm,
Also this has me thinking with my tin foil hat on about Provenge..., one of the big side effects I learned about Provenge was the immediate side effects of Citrate (toxicity), apparently very high levels of citrate are used for the procedure to make absolutely sure there is no blood clotting...I wonder if those super high doses of citrate might be an as yet un-considered positive effect of the therapy?
fruit for thought
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sammamish
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"acetyl CoA required for fatty acid synthesis is derived via metabolism of citrate by the enzyme ACLY. Not only is expression of the mRNA that encodes this enzyme increased in prostate cancer, but downregulation of its expression in prostate cancer cells either by pharmacologic reagents or siRNA treatment results in inhibition of proliferation "
when it comes to enzymes, everything is in a feedback loop. products and reactants, can be driven in either direction, depending on the relative concentration matrix and presence or absence of relevant cofactors. Also of note, many metabolites actually tie into a feedback loops with rna upregulation or down regulation, therefore IMHO it is entirely possible citrate could be such a metabolite.
Enzymes are catalysts to make a reaction go in one direction. Pepsin, for example, works with stomach acid to digest proteins into polypeptides. It does not create proteins out of polypeptides. Amylase converts starch into sugars; it does not convert sugars into starches. Enzymes have very specific functions. Biology isn't subject to your opinion, it's just a matter of fact.
Enzymes Are biological catalysts that facilitate a quicker reaction to the equilibrium state, determined by K eq. of the reaction.
They lower the activation energy, allowing BOTH forward and reverse reactions to occur more quickly, they do not change the equilibrium constant for the reaction.
In fact, the definition of an equilibrium constant means there will always be reactions going in forward and reverse directions, hence equilibrium . There are really cool demos of this with the chemical clock tied to an indicator dye you tube etc.. Manipulation of the concentration of either reactants or constants can drive the reaction to reestablish equilbrium. See my favorite college textbook, Lehninger Biochem for details.
You're talking to someone who has a degree in biochemistry. What you missed in your textbook is that enzymes shift the equilibrium strongly to the right. That's why they're there. Without them the reaction doesn't move to the right hardly at all. When was the last time you saw a steak (without heat, fungus or bacteria) spontaneously break down into polypeptides? And do you imagine that peptides will ever spontaneously come together to form a steak? It takes enzymes to break down a steak, and afterwards the same enzyme does not catalyze the recombination of amino acids to become muscle tissue.
All chemical reactions have an equilibrium constant. Enzymes do not change the equilibrium constant of a reaction, all they do is lower the ACTIVATION energy, causing the race to equilibrium to happen more quickly. This is basic chemistry.
When the equilibrium constant is very large or very small( as determined by the Gibbs free energy of the reaction) then the products or reactants appear to go to completion, but not completely. There are numerous reactions in the human body that have equilibrium constant between .01 and 10..these will be reactions that do not ostensibly go to "completion". what drives the reaction further is the presence of another nearby reaction (at low activation energies)that quickly removes reactants while obeying the direction of Gibbs free energy. This is accomplished by LOWERING the Activation energy of a specific reaction via an enzyme..this essentially removes products quickly causing a manipulation of the reaction( LECHATELIER'S principle) favoring a specific reaction versus another and is essentially a recapitulation of the equilibrium constant). That is why I suggest that manipulating certain reactants or products, as with Citrate cited in the aforementioned doctoral thesis of the investigator, might be a viable approach to changing metabolomic outcomes.
To reiterate, take the reaction C6h1206 +6O2=6CO2+6H20. This reaction at room temperature is slow , but favors products due to Gibbs free energy of the reaction, however once equilibrium is reached, co2 molecules actually combine with water molecules to go the other direction. The reaction can be speeded up in both directions tremendously with enzymes, for example in glycolisis and the krebs cycle, but the reaction still has a reverse direction, because enzymes ONLY lower the activation energy for forward and reverse reactions, making each happen ,more easily. The Gibbs free energy determines the net concentration of the products and reactants, Not the enzyme. I might point out that by exhaling co2 and excreting byproducts of metabolism, the system is not closed, so would also help to drive reactions of, for example, glucose metabolism, towards completion (LeChatleirs principle)
Thank you, I do know what enzymes do. When the reaction products have a much lower potential energy than the reagents, they lower the energy "hump" to get the reaction going. But once the products are created, the potential energy for driving the reaction in the other direction is insurmountable. You cannot use the same enzyme to shift the reaction backwards. Your body cannot use pepsin to make peptides into proteins. Instead, proteins are assembled by adding amino acids based on RNA - a completely different process. Your proposal for taking citrate is pure fiction.
Manipulating substrate concentrations is already done in medicine, so I would submit that citrate manipulation "may" be an avenue,or maybe not. that's all. Amylase has an equilibrium constant, like ALL enzymes, thus is able to run in reverse, albeit in biological system it would be VERY small due to Gibbs free energy of the reaction, and subsequent enzymes pulling the reaction to further hydrolysis. However a reactor could be made to siphon off starch, and load up glucose in the presence of Amylase, using LeChatlier's principle, and you could get discacharides. Enzymes, only lower the activation energy increasing the rate both forward and backward. I bring this up because you stated previously that " enzymes shift the equilibrium strongly to the right", ...they do not shift the equilibrium, they merely accelerate reactions, in either direction by lowering activation energy.
Lowering activation energy DOES shift the equilibrium to the right. Good luck taking citrates. Let us know if you are able to create a new biochemistry.
Tall, please provide any peer reviewed chem or biochem journal reference to enzymes changing the equilibrium constant of a reaction, and I will eagerly consume this new biochemistry to which you refer, and self flagellate as well as scorn all of my Biochem and PChem professors of yore.
This is called a "straw man." You make up things I didn't say, and then you refute things that you yourself made up and attributed to me. This biochemistry is NOT new. I think you may have slept through those classes. This is pointless, if you just make things up. Good luck with your imaginary science.
Your words "Enzymes are catalysts to make a reaction go in one direction" and "Lowering activation energy DOES shift the equilibrium to the right" ...not some strawmans' words. Looking for the journal citation backing this . As stated happy and humble enough to self flagellate if this is so,otherwise I'll stay with my imaginary science.
You dont seem to understand the difference between "shifting equilibrium to the right", and an 'equilibrium constant." They are completely different concepts. I nnever even mentioned an "equilibrium constant," a concept that you apparently don't seem to understand. An equilibrium constant only applies at equilibrium. Driving the reaction to the right is a dynamic process, not an equilibrium process. Go self flagellate.
Then you should be more precise with your words "shifting equilibrium to the right" is not correct description. Enzymes don't shift equilibriums, they make reactions happen more quickly , No soup for you... no self flagellation, unless you provide the citation
Enzymes certainly shift equilibrium to the right by lowering the activation energy. Take, for example: starches -> sugars. You can let a sample of cornstarch sit on your counter until the sun explodes, and it won't turn to sugar, unless you heat it up. But spit in it and the amylase in your saliva will drive the reaction to the right, at room temperature. Also, the reaction does not go in the other direction (other than microscopically, when it reaches equilibrium), no matter how much you spit.
Enzymes shift the rate of the reaction (in both directions) not the equilibrium. Yes, and that is by lowering the activation energy. If you put glucose and fructose into water at room temperature, after a while you will find molecules of sucrose. When equilibrium is reached, (long before the sun explodes perhaps hours or days ) there will be about 1 molecule of sucrose, for every 300 molecules of glucose. If you repeat the experiment with an enzyme you end up at the same end point, perhaps a minute or 2. Basic textbook stuff.
You are still trying to put words in my mouth.. I didn't mention disaccharides. I talked about amylase breaking down starches -- get it? Amylase will not make the reaction go in the other direction (from sugars to starches). Now, go back to your original question , where you imagined that- "when it comes to enzymes, everything is in a feedback loop. products and reactants, can be driven in either direction, depending on the relative concentration matrix and presence or absence of relevant cofactors." This is pure fiction. Enzymes catalyze reactions in ONE direction only - driving it to the right. citrate --(ACLY)-->acetylCoA (which is needed for fatty acid synthesis). ACLY does NOT drive the reaction in the other direction, just as amylase does not help change sugars into starches. In fact, I hope you are at least beginning to understand that increasing citrate may, if anything, drive more fatty acid synthesis.
Can you provide references to the papers that your co-conspirators wrote? I'm always interested in terpenoid chemistry, particularly as it MAY relate to PCa.
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