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In through the out door for the TCA and urea cycle is not simple

Discussion in 'Mitochondrial Rx' started by Jack Kruse, May 21, 2018.

  1. Jack Kruse

    Jack Kruse Administrator

    The terms anaplerosis and cataplerosis describe reciprocal and correlative reactions involved in the function of the TCA cycle. The enzymatic steps in these processes have long been known, but the overall concept of a linkage between anaplerosis and cataplerosis should be underscored because the balance between these two processes controls the entry and exit of TCA cycle anions. Anaplerotic and cataplerotic reactions are involved in the ultimate disposal of all metabolic intermediates. The metabolic role of anaplerosis and cataplerosis in amino acid metabolism varies with specific organs and is dependent on the nutritional/metabolic status of the individual. During feeding, the intestine is an important site of catabolism of enterally derived amino acids, whereas in the starved state amino acid catabolism occurs primarily in the kidney, liver, and muscle.

    Every tissue differs in how it uses anaplerosis and cataplerosis.

    The catabolism of amino acids produces gluconeogenic or ketogenic precursors (Table I).

    Table I

    Metabolic fates of amino acids in the TCA cycle

      1.  Amino acids converted to pyruvate    Alanine, serine, glycine, threonine, cysteine, tryptophan
      2.  Amino acids converted to oxaloacetate    Aspartate, asparagine
      3.  Amino acids converted to α-ketoglutarate    Glutamate, glutamine, proline, histidine, arginine
      4.  Amino acids converted to fumarate    Phenylalanine, tyrosine
      5.  Amino acids converted to succinyl-CoA    Methionine, isoleucine, valine
      6.  Amino acids converted to acetyl-CoA    Leucine, isoleucine, lysine, phenylalanine, tyrosine, tryptophan, threonine

    The disposal of gluconeogenic anions in the TCA cycle employs anaplerotic and cataplerotic pathways for their terminal oxidation. The only known pathway for the terminal oxidation of leucine is through acetoacetate to acetyl-CoA and subsequent oxidation in the TCA cycle. However, other amino acids also have for their disposal alternate ketogenic pathways for terminal oxidation. Thus, the ketogenic amino acids from proteolysis can be terminally oxidized in muscle, whereas the gluconeogenic amino acids are dependent upon anaplerosis and cataplerosis for conversion to glucose in the liver and kidney before oxidation to CO2 and H2O.

    The first reaction of the TCA cycle, citrate synthase, catalyzes the condensation of oxalacetate with acetyl-CoA; the oxalacetate is subsequently regenerated by the reactions of the cycle and condenses with another molecule of acetyl-CoA. However, the TCA cycle also functions in biosynthetic processes in which intermediates are removed from the cycle; this necessitates anaplerotic reactions to replenish TCA cycle intermediates to ensure its continued function. Pyruvate carboxylase, which synthesizes oxalacetate from pyruvate in the mitochondrial matrix, is the archetypical anaplerotic enzyme.

    Anaplerosis is obligatory during both gluconeogenesis and lipogenesis when malate (gluconeogenesis) or citrate (lipogenesis) leaves the mitochondria and is further metabolized to form glucose or fatty acids, respectively.
    Lahelada likes this.
  2. Jack Kruse

    Jack Kruse Administrator

    If intermediates can be added to the TCA cycle, it is equally important to remove them to avoid the accumulation of anions in the mitochondrial matrix. Cataplerosis describes reactions involved in the disposal of TCA cycle intermediates. There are several cataplerotic enzymes; these include PEPCK, aspartate aminotransferase, and glutamate dehydrogenase. Each of these reactions has as a substrate a TCA cycle anion that is converted to a product that effectively removes intermediates from the cycle.

    The regulation of anaplerosis and cataplerosis depends upon the metabolic and physiologic state and the specific tissue/organ involved. For example, during starvation, cataplerosis via phosphoenolpyruvate to support gluconeogenesis may be regulatory in the liver, whereas in the kidney anaplerosis via uptake of glutamine may be regulatory.
    Lahelada likes this.
  3. Jack Kruse

    Jack Kruse Administrator

    This implies the regulation of anaplerosis and cataplerosis is very dependant on deuterium kinetics in the matrix from normal or abnormal metabolic and physiologic states.

    Methionine: Propionyl-CoA forms as a catabolite of methionine, threonine, and the branched-chain amino acids. β-Oxidation of fatty acids with an odd number of carbon atoms yields propionyl-CoA.
    The oxidation of the side chain of cholesterol also yields propionyl-CoA. Thus, propionyl-CoA is derived from the catabolism of lipids and proteins.

    Propionyl-CoA is converted to succinyl-CoA, which is oxidized or converted to glucose by way of oxaloacetate and pyruvate. Succinyl-CoA may also form δ-aminolevulinate, a precursor of porphyrin biosynthesis. This is critical in oncogenesis because cancer cells need brisk ECT which means that cancer cells can use methionine to usurp oxygen using methionine to increases both angiogenesis and hemoglobin production to make sure that oxygen delivery is brisk and apoptosis stays inhibited PROVIDED VDR/D3 and/or UVA are absent to slow ECT flow. (May 2018 and QT#8)
    Josh Rosenthal, drezy and Lahelada like this.
  4. Jack Kruse

    Jack Kruse Administrator

    cholesterol levels are usually low in cancers.......so this means methionine becomes key to the creating an oxygen demand pathway for a transformed cell.
    drezy and Lahelada like this.
  5. Jack Kruse

    Jack Kruse Administrator

    Formation of succinyl-CoA from propionyl-CoA requires three mitochondrial enzymes and two vitamins, biotin, and cobalamin.

    Methionine is converted to homocysteine in the activated methyl cycle. Cystathionine synthase converts homocysteine to cystathionine, which is then converted to propionyl-CoA. The propionyl-CoA is then converted to succinyl-CoA via methylmalonyl-CoA.

    S-adenosyl methionine (SAM) is formed in the activated methyl cycle by transfer of the adenosyl group from ATP to the sulfur of methionine. The methyl group attached to the methionine sulfur transfers readily to a nitrogen, oxygen, or carbon of an acceptor.

    In cancers, methionine rises and cannot be metabolized as quickly as normal because of the defective mitochondria. Cancers manifest because UVA and UVB light is used to make melatonin during daylight but methionine is an adjunct to melatonin creation especially in epithelial cells. This is why melatonin is so low in cancer patients and the high ROS in the matrix of broken mitochondria are not repaired by the action of melatonin. Carnitine limits the TCA ability to use fats and creatine limits the speed of the PPP. This points out why cancer must use glucose and glutamine for biosynthesis.

    S-adenosyl homocysteine is the major donor of methyl groups in the synthesis of phospholipids, nucleotides, epinephrine, carnitine, melatonin, and creatine.
    Lahelada likes this.
  6. Jack Kruse

    Jack Kruse Administrator

    The essential amino acids include valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, threonine, lysine and histidine.

    The amino acids arginine, methionine and phenylalanine are considered essential because their rate of synthesis is insufficient to meet the growth needs of the body. Most of synthesized arginine is cleaved to form urea. Methionine is required in large amounts to produce cysteine, the other sulfated amino acid if the latter amino acid is not adequately supplied in the diet. Cysteine is needed for glutathione and detoxification pathways in the body. When the TCA and urea cycle kinetics are altered the sulfated amino acids cycles are altered and endogenous detox drops and things begin to show up in tissues that normally would not be there if the redox state of the mitochondria was more optimal. This also affects sulfation pathways in the blood and skin as a collateral effect.

    Similarly, phenylalanine is needed in large amounts to form tyrosine if the latter is not adequately supplied in the diet.
  7. Jack Kruse

    Jack Kruse Administrator

    The initial two steps of the urea cycle occur in the mitochondria. The first by carbamyl phosphate synthetase mediates the formation of carbamoyl phosphate from NH3−, HCO3−, and ATP. The second step is the condensation of ornithine with carbamyl phosphate by the enzyme ornithine transcarbamylase to form citrulline. The activity of this enzyme is directly related to dietary protein. This is why mTOR and cancer are linked.......it is only true when the urea cycle kinetics are SLOWED for some reason.


    You might want to remember this post when I get to the Patreon post on bicarb.
    Sajid Mahmood, drezy and Lahelada like this.
  8. Jack Kruse

    Jack Kruse Administrator

    Methionine catabolism involves nine steps. When the TCA urea cycle has altered the kinetics of these 9 steps is dramatically slowed and this lowers glutathione and taurine production. Methionine can be metabolized to cysteine, the RAREST amino acid when the mitochondria have a poor redox state, but this is not true in a heteroplastic state. This means cysteine is chronically low when the TCA and urea cycle kinetics are slowed.
    Cysteine makes up 66% of glutathione (GSH) by and taurine is a bile salt modifying compound that is the KEY source of the sulfur for coenzyme-A synthesis. When this is lowered no beta oxidation can occur and this also forces the cell toward glycolysis. Cancer cells do not favor glucose.......it is the only choice they have with a faulty TCA and urea cycle because of altered kinetic flux. What causes this most? The May 2018 webinar has that answer.

    The first step is catalyzed by methionine adenosyl transferase which tranfers the adenosyl group of ATP to the sulfur of methionine to form S-adenosylmethionine (SAM). SAM methylase transfers the activated methyl group to an acceptor to form S-adenosylhomocysteine which is hydrolyzed by adenosylhomocysteinase to form homocysteine. Cystathionine β-synthase catalyzes the condensation of a serine residue with homocysteine to form cystathionine. Cystathioniine γ-lyase cleaves cystathionine into cysteine and α-ketobutyrate, the latter being converted into propionyl CoA by an α-ketobutyrate dehydrogenase.
    Sajid Mahmood and Lahelada like this.
  9. drezy

    drezy New Member

    You told us to get facile with red box #5.

    My biology is still baby-like, but I'm always ready even for a swing and a miss.

    1. Are we talking nudging the system toward the Pentose cycle?
    2. Are we talking about slyly using some ROS to our advantage?
  10. Jack Kruse

    Jack Kruse Administrator

    Oxygen levels are the carburetor for mitochondria. When oxygen is high we use urea and TCA.......when it is blocked for some reason, in fact, ANY reason we default to glycolysis and the PPP.......now think about what this means for deuterium and Kreb's bicycle and what Wallace has found at the IMJ's.
  11. Jude

    Jude Gold

    And that is the bottom line......BOOM, I get it, finally and wow!!
    drezy likes this.
  12. b.pezzia

    b.pezzia Bruno Pezzia

    Trying to absorb these amazingly detailed info. When urea in a blood test is elevated what that means for the cycle ? Can we say that Kreb's bicycle is like an intelligent traction system of mito which deciphers in real time the terrain the organism is in and adapts accordingly ?
  13. shiran

    shiran Curious

    I feel like Neo in the Matrix...
    Cant wait to find out where the amazing ELF UV ligh comes from ..
    Jack, you're just a wonderful teacher
  14. Jack Kruse

    Jack Kruse Administrator

    New blog out this AM in the Quantum Thermodynamic series. It is Krebs bicycle part two and blog #9 in the series. What is the question this blog raises and answers fully? Why would our eyes and cancer cells share a metabolism is that metabolism is viewed as a problem by all of biology? Should you pay attention to skeptics of your theory as you lay out your thesis? Y'all will like this one especially if you liked my talk at Vermont last year. https://www.patreon.com/posts/18987318

  15. Jack Kruse

    Jack Kruse Administrator

    QT #10 went live this AM as a warm up for Vermont 2018.

    Saturday, June 2

    Doors Open: 8AM

    8:00 AM - Registration and Visit Exhibits & Marketplace

    8:45 - Welcome - David Hollenbeck, Founder of Nourish Vermont

    9:00-10:30AM - Zach Bush, MD

    10:45AM-12:15PM- Dr. Boros

    12:30-2:00PM - Lunch

    2:00-5:00PM - Dr. Jack Kruse
    Jude likes this.
  16. Penny

    Penny New Member

    Well, now I sort of get why Gerolsteiner is such a hit with my body... the bicarbonate raises oxygen plus the bicarbonate delivers the magnesium to the mitochondria...

    And why VO2 max would be an indicator of low oxygen... I still need to delve deeper into this - OXPHOS, my nemesis... I guess I'll attempt to fathom it one more time... nice post:)
    EStein and Lahelada like this.
  17. EStein

    EStein New Member

    the water with the highest levels of Bicarb is in a natural spring in California - amazing DDW results from the lab as well. Highest levels Mg per Liter as well. I found the spring to be extremely helpful. An entire book was written on the health benefits of the spring.

    Adobe Springs

    Penny likes this.
  18. Petrad

    Petrad New Member

    Dr. Kruse, have you heard of the mitochondrial function test MITOSWAB? It measures citrate synthase and activity of complexes 1 and 4 from an oral swab. Does that have any value? It is my understanding that mitochondria function at different rates in different tissues much like the microbiome of the skin is very different than that of the other tissues. And energy and epigentics 12 also goes deep into the mitochondrial capacity and how loss of charge across membranes is the key. Is it safe to say this test is not conclusive?


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