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Isolated PEMT2, CDP-choline, newly produced Phosphatidylethanolamine, and biosynthesis = Disease

PEMT downregulation promotes P53 downregulation of biosynthesis pathways, while promoting DBC1 and Sirt as regulators of cellular survival or cellular deterioration. PEMT causes de facto upregulation of P53 along with upregulation choline kinase alpha. Choline kinase alpha integrates or intercepts both ATP availability and choline availability from choline symporters, sodium coupled choline symporters and phospholipase/phosphodiesterase catabolism of cellular membranes.

Choline exhibits 3 methyl groups and thus at least 3 molecules of hydride or 3 loci of hydridic character, although hydridic character is canonically considered to be distributed within a molecule. Hydride can be freed, distributed or applied incompletely from a hydric context to another molecule or center. Carbocation rearrangements can occur within a molecule, between a compound molecule or between disconnect molecules.

Choline can be imported, produced de novo by PEMT catalysis, freed from membrane phospholipids by phospholipases and phosphodiesterases, and synthesize and oxidized by the bidirectional choline oxidation pathway. Intricate review of the literature in this compendium of resource found multiple contexts of potential noncanonical freeing or synthesis of choline. This includes potential derivation of choline from Super Hydride which require only substitution of nitrogen for the central atom. Numerous other molecules such as caffeine are structural homologues of choline, but these seem to be regarded as noncanonical potentialities. Super hydride is involved with eluting of hydride from the universes level hydride zero-point field or universes level aether of hydridic fields which vary in density, location and status.

The cdp-ethanolamine pathway involves integration of new CH2 or methylene brides into metabolism and physiology by converting ethanolamine to ethanolamine to citidylylethanolamine to phosphatidylethanolamine, followed by phosphatidylethanolamine and Fatty Acid Synthesis integrating at the function of PEMT which moves CH3 from s-adenosyl methionine int three sequential transferase catalytic actions to the nitrogen of phosphatidylethanolamine, resulting in de novo synthesis of enriched, resolution phase dense, hydride dense phosphatidylethanolamine. This pathway, the cdp-ethanolamine pathway, PEMT intermediate substrates PMME, PDME and phosphatidylcholine, along with THMT product methylthioglycolic acid, are toxic, caustic and in the instance of choline are caustic quaternary ammonium factors, performing as extreme antihistamines, separators of biotic phase from abiotic phase, and are sequestering of useful factors from the abiotic phase for movement into the biotic phases. Essentially, these factors melt plastics that have integrated into tissues, deteriorate the structural bases of diverse toxins, xenobiotics, and oncology potentiating molecules. These behemoths, titans, at the center of physiology that sequester space in the biome for biology and Life to emerge, persist and become sustained. These factors are consistently commandeering the biome and the Universes to the benefit of biology, Life and vital being.

Choline is a cation, or negatively polarized alkalinity promoting factor, and in its multiple isoforms are water-soluble quaternary ammonium. Choline hydroxide is an isoform that is a choline base, presenting its function in redox and ph system function. This presents another mechanism through which choline functions to promote an alkaline background ph within 7.2. to 7.6, particularly ph within 7.35 to 7.45 and specifically ph of 7.4.

Choline attracts water molecules which cause a typical exhibition of choline as a clear hydrated, viscous fluid that has an odor similar to trimethylamine because aqueous solution of choline gradually move from stability to dissociation into glycol, trimethylamine and polyethylene glycol. These explain why choline dense foods promote trimethylamine in digestive pathways which can be translated into trimethylaminenoxide by microflora or can transit digestive pathways in leaky gut syndrome to become reduced by Flavin monooxygenases into trimethylaminenoxide. Odorous trimethylamine from upregulating trimethylamine is known as trimethylaminuria and is an ICD classified condition. Preventing trimethylaminenoxide is performed by TMA lyase inhibitors, 33DMB, fasting, avoiding meat/chicken/eggs/fish unless accompanied by or in context of supplemented olive oil, grapeseed oil, balsamic vinegar, regular laxative instrumentation, postbiotics, prebiotics, probiotics or steady obtainment of macrobiotic foods.

The choline observed in supplementation can typically be produced by exposing choline to 2-chloroethanol derivable from ethylene oxides, while hydrolysis of lecithin can be a way of deriving choline from natural substrates, and while lecithin is group of mixed emulsified molecules which occur in biological material and comprise vast aspects of physiological structure in a way the involves phase transitions in lipid chemistry to produce microstructure and superstructure. Lecithin is important to biology and can be transformational as a nutritional, supplemental and therapeutic vectors because it supplies the factors that comprise the substrates for and constitutes molecules pervasively exhibited in biology and biological structures.

Phospholipids are important because the attract water, attract fatty substances, and be inverted to produce polar and nonpolar extremities resulting liposomes, cellular enclosures and the bilipid membranes essential to eukaryotes.

Importantly, lecithin’s constitutive factors exhibit different polarity, which enable these to participate not only circulating systems management of pH but when aggregated in dense cellular membranes, exude polarity into the environment. These promote the background polarity characteristics that result in biology enabling disequilibrium and gradients. Shuttling of phospholipids through the lands cycle involves shuffling fatty acids, freeing phosphatides including production of lysophosphatidylcholine, application freed enriched fatty acids to deteriorate nonresolution phases, promote resolutions phases and stability, followed by integration of lysophospholipid with shuffled fatty acids to produce the diverse microstructure and superstructure exhibited in organisms of different species and organisms of the same species.

Lecithin includes Phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, and choline, while lecithin can occur in different viscosity, density, and characteristic emulsifications, while balances between phospholipids can also exhibit variation. Lecithin in aqueous solution exhibit diversity characteristics of biology including phospholipid configurations of bilayer sheets, micelles, lamellar structure, liposomes, surfactant characteristics and amphipathic characteristics.

Lecithin was discovered most incipiently in about the middle 1700s or earlier.

Choline in the canonical unidirectional pathway includes choline and ATP becoming phosphocholine and ADP, requiring free choline or metabolite of choline, phosphocholine and CTP becoming cdp-choline and pyrophosphate, cdp-choline and DAG becoming phosphatidylcholine and CMP. Choline oxidation occurs in the mitochondria and thus when mitochondria become impaired or deteriorated, this nonPEMT pathway for phosphatidylcholine synthesis becomes deteriorated, resulting in this foundational use of recycled choline and methylene bridge conversion to phosphatidylcholine become diminished. This explains in more intricate detail why PEMT2, mitochondrial PEMT2 is abrogated in pervasive advanced phase of disease, including a massive deterioration of not only enhanced plasticity PEMT2 synthesized phosphatidylcholine at the conclusion of the cdp-ethanolamine pathway but also including deterioration of phosphatidylcholine synthesis through the cdp-choline pathway.

Importantly, there are at least two pathways for supply of phosphatidylethanolamine, including cdp-ethanolamine pathway and through phosphatidylserine decarboxylation/carboxylation cycling that occurs from exhibition of phosphatidylcholine and processing of phosphatidylcholine toward multiple outcomes, including phosphatidylcholine and ceramide becoming sphingomyelin and sn-1,2 diacylglycerols integration competent for sn-1/sn-2 positions in phospholipids.

Phosphatidylserine may be synthesized from phosphatidylethanolamine and serine bp PSS2 resulting in ethanolamine and phosphatidylserine. Phosphatidylserine may be synthesized from phosphatidylcholine and serine, resulting in choline and phosphatidylserine. These present another pathway for recycled choline exhibition, recycled ethanolamine exhibition, and synthesis of de novo phosphatidylserine.

The cdp-choline pathway and the cdp-ethanolamine pathway can potentiate phosphatidylserine, but the cdp-choline pathway produces choline which can enter the choline oxidation/cdp-choline pathway.

Although PEMT2 deterioration is correlated with mitochondrial deterioration, a more pertinent observation is that PEMT2 deteriorated function is linked to dissociation of the mitochondrial associated membrane from connecting the endoplasmic reticulum to hundreds, potentially, of mitochondria, such that Ca2+, Phosphatidylserine, phosphatidylethanolamine and phosphatidylinositol or other substrates cannot be supplied from the endoplasmic reticulum to mitochondria.

Phosphatidylserine can be recycled by phosphatidylserine decarboxylase to produce CO2 and phosphatidylethanolamine, presenting another mechanism through which ph is affected by phospholipid cycling.

Phosphatidylethanolamine from phosphatidylserine and phosphatidylethanolamine from the cdp-ethanolamine pathway exhibit different distribution of fatty acyl species among the sn-1 and sn-2 positions. Experimental small nonhuman mammalian contexts exhibit phosphatidylserine potentiation of primarily polyunsaturated fatty acyl species at sn-2, while the cdp-ethanolamine pathway exhibits preferred exhibition of monounsaturated fatty acids or 2-unsaturated fatty acid species at the SN-2 position.

Newly synthesized phosphatidylserine species were observed in this small nonhuman mammalian experimental context to emerge in the mitochondria followed by dispersion into equilibria between mitochondria and endoplasmic reticulum. This suggests that mitochondrial deterioration which promotes dissociation of the mitochondrial associated membrane prevents newly synthesized phosphatidylethanolamine from being adequately or directly distributed to the endoplasmic reticulum. Downregulation of PEMT, then, may potentiate impaired exchange of phosphatidylethanolamine bidirectionally between the endoplasmic reticulum and mitochondria, while also potentiated in such conditions is impaired supply of products from cdp-ethanolamine pathway from mitochondria to endoplasmic reticulum.

Phosphatidylserine decarboxylase function may be essential for mitochondria because it enables synthesis of newly produced phosphatidylethanolamine. A review of serine metabolism suggests that serine can contribute new methylene bridge to products produced from it as substrate. The Phosphatidylserine synthase pathway, then, along with phosphatidylserine decarboxylase, may contribute new methylene to phosphatidylethanolamine pathway, performing as another modality of integrating new, unrecycled, undeteriorated methylene bridge into phospholipid cycling.

The literature places the antihistamine correlated cdp-ethanolamine pathway and its production of newly synthesized phosphatidylethanolamine in the endoplasmic reticulum, such that during impaired mitochondrial conditions, the newly produced ethanolamine cannot reach PEMT in the mitochondria. PEMT2 emerges near birth as a regulator of growth, while PEMT1 is a growth and development enabler exhibited since conception when PEMT function and the cdp-ethanolamine are assisted by downregulation of numerous competing pathways. The impairment of mitochondria produces exhibition of cdp-ethanolamine antihistamine pathway which promotes cleaning of the environment while impaired mitochondria also perform this activity to the benefit of version of PEMT this not a regulator of growth. This characterizes, not only a potential for unregulated growth but also explains the reprogramming of cellular entities toward immortal phenotypes during parthanatos and increasingly so when PEMT2 function becomes deteriorated correlatively to increasingly impaired mitochondrial function.

Anaerobic glycolysis is a syndrome that impose a systematic, increasingly detrimental and increasingly burdensome requirements on systemic buffering mechanisms and on mitochondria, in a way that is similar in producing increasing isolation of such components, increasing potential for deteriorated function and increasing susceptibility to disease. Aerobic glycolysis with the protection of the regulatory capabilities of PEMT2 seem to promote the most optimal physiological conditions even is only regularly sustained instead of being always enabled.

Information) “The Synthesis of Methyl Groups from Serine.” J Am Chem Soc. Volume 73. Number 11. Page 5509 to 5510.

Information) “Phosphatidylethanolamine Homoeostasis rebalanced through Mitochondria-Endoplasmic Reticulum Exchange.” Volume 16. Number 10. October 2020.

Information) “The CDP-Ethanolamine Pathway and Phosphatidylserine Decarboxylation Generate Different Phosphatidylethanolamine Molecular Species.” Volume 282. Number 39. Pages 28362 to 28372.

Deterioration of mitochondrial function and correlated deterioration of PEMT2 function, result in deterioration of the cdp-choline pathway which occurs in mitochondria.

Hepatic oxidation of choline can occur with import of choline from cytoplasm to the mitochondria, where choline dehydrogenase catalysis synthesis of H+ and betaine aldehyde, followed by betaine aldehyde and NAD processing by betaine aldehyde dehydrogenase into NADH and Betaine, while the literature in some instances suggests that this pathway can be inverted by thermodynamics and increased NADH compared to NAD. BHMT and methylene bridge cysteine can catalyze translation of betaine into 2methylglycine and methionine, followed by 2methylglycine/THF/FAD translation into sarcosine/5methyltetrahydrofolate/FADH2 by 2methylglycine dehydrogenase. Sarcosine, tetrahydrofolate and FAD can become glycine, 5-methyltetrahydrofolate, and FADH2 through catalysis by Sarcosine dehydrogenase. Glycine, tetrahydrofolate, and FAD can then become CO2, NH3, 5-methyltetrahydrofolate and NADH through catalysis of the glycine segmentation system which includes FAD and lipoate.

Glycine betaine, betaine, n,n,n, glycine betaine or trimethylglycine is an osmolyte regulation molecule which stabilizes the quaternary structure of proteins and enzymes to prevent pressurization or hydrostatic change, thermodynamic change and other challenging conditions from deteriorating, changing, impairment or permanently impairment enzymes and proteins.

Trimethylaminenoxide is utilized by aquatic organisms to stabilize proteins, enzymes and systems and changing depths, which is why its exhibition potentiates changes in vascular pressure and flow, requiring proactive and persistent management. The risks linked to trimethylamine oxide suggests that meat, chicken, eggs and fish usage as nutritional factors was a social and conscious adaptation to nutritional inadequacy in the environment and the P53 enabled shunting of glucose into actively exercising muscle tissue redirected focused development of the cerebral cortex and conscious capacitance toward immediate required focus on obtaining more sparsely accessible, more complicated access conditions and more choline nutrient dense sources of nutrition.

Information) Nutrient Metabolism. ISBN 978-0-12-387784-0.

P53 downregulates pentose phosphate pathway production of nucleotides used in DNA repair and DNA replication. P53 downregulate glycolysis from about 32 molecules of energy per cycle to about 6 to 9 molecules of energy per cycle. P53 also downregulates GLUT endocytosis of glucose, causing glucose to accumulate in circulation except in actively exercising muscle tissue where glucose is shunted to improve ability to obtain nutritional resources dense in choline and methyl groups.

P53 causes available glucose to be trapped in glycogen cycling, being integrated into amyloid fibrils and free from amyloid fibrils according to energy requirements. Amyloid fibrils are interesting because like generally ubiquitylation and other modalities of clearing proteins, proteins tagged for removal can be aggregated in bundles and then the bundles can be removed using autophagic autophagosomes or proteolytic deterioration. However, oxidative distress, unfolded protein response, other features of PEMT downregulation, glycation end products, lipoxidation end products, ascorbylation end products, other end products, peroxynitrite and from uncoupled nitric oxide synthases, methylene bridge cysteine metabolites, all can occupy, deteriorate or fuse together these bundles in a way that prevents enzyme access to the segmentation loci. These processes are the most simplistic factors in conditions such as alzheimer’s in which autophagy and proteolysis or impaired, autophagosome or lysosomes are not emerging, Bag1/Bag3 balances promote either proteolysis or autophagy over one another, or these processes tag and remove the protein and enzymes which are required to rapidly remove amyloid, tau, and other proteins or bundles.

Sirt1 and Sirt2 are oppositely potentiated with age, while sirt2 is correlated particularly with brain tissue and Sirt1 is considered to be a general deacetylase.

P53 promotes, through its regulatory activity, what is known of as anaerobic glycolysis which some of the literature observes as de facto directing of glycolysis’ pyruvate toward lactate in a way that causes pyruvate and NADH to become translated into Lactate and NAD+, although some of the other literature attributes this directing of pyruvate to lactate as being the result of PARP signaling at loci of DNA impairment which occurs persistently until enough nucleotides and material for DNA repair are recruited to loci of DNA impairment. DNA repair occurs a million times or more in each cellular entity and PARP signaling occurs persistently while it removes the ribose from nicotinamide to attach the ribose local molecules and proteins to produce a gradient upon which material for repair can be recruited to PARP.

This ribose excision from NAD+ may be source of sugar that can participate in diabetic pathology although ribose is considered to lower blood sugar. Nonglucose diverse hexose sugars can circumvent P53 downregulation of GLUT.

The literature observes that ribose is an efficient glycation vector for haemoglobin, suggesting that exposure to DNA impairing particulate, RF and EMF, or toxic factors that impair DNA or inhibit PEMT to downregulate nucleotide synthase, along with inadequate in NADH or NAD+, all can promote increased levels of HbA1c. A glycation of haemoglobin by d-ribose results in 10 carboxylmethyllisines and incipient rate of d-ribose translation into fructosamine as experimentally confirmed as being 60 times higher than d-glucose. Benfotiamine abrogated the atypical increase in HbA1c linked to d-ribose availability.

Information) “Dextrorotatory – Ribose is a Contributor to Glycated Haemoglobin.” EBioMedicine. Volume 25. Pages 143 to 153. November 2017.

P53 downregulation of the pentose phosphate pathway or hexose monophosphate shunt, deprives PARP of nucleotides and the result can be a syndrome in which PARP signals consistently until enough nucleotides are available to perform repair. Similar conditions can occur during DNA replication, including impaired telomerase activity and impaired replication. PARP must experience adequate substrate for DNA repair, enabling it to dissociate from the locus of repair in order that Homologous highly accurate repair might occur. Inadequate substrate results in diminished accuracy of repair.

P53 also downregulates Insulin receptors. P53 also potential downregulates phosphofructokinase which is a mechanism that can be used to counteract decreased insulin receptor activity.

PARP consistent signaling depletes NAD+ in the microenvironment and results in a strong gradient upon which lactate and NAD+ are more strongly potentiated from NADH and Pyruvate, explaining the strong directing of NADH to NAD+ and pyruvate to lactate during anaerobic glycolysis. However, the literature observes that this promotes disruption of the foundational disequilibrium of physiological ph at 7.4 and intracellular pKa of 7.21 which requires systemic involvement in managing ph as a result. Along with the accumulation of glucose in circulation, hyperactivation of islet beta cellular entities that then typically must occur in hepatic, renal and pancreatic tissues to produce insulin which must then be redistributed to physiology reliant upon L-arginine availability and arginase activity.

Importantly, this increased systemic involvement in managing ph occurs in context in which PEMT is downregulated in its integration of hydride or H2e1p as CH3, or as CH2 that has integrate an electron that has been integrated into hydrogen. This diminishes the exhibition of CH3 integrated hydride or (H2e1p)- which assists oxyhydroxide in promoting background alkalinity which helps ph stabilize near 7.2 to 7.6, near ph 7.35 to 7.45, and ph at 7.4. PEMT results in diminished requirements for buffering systems, splanchnic organs and major organs while performing as integral factors that enable such major organs and tissues themselves to exhibit homeostasis.

Alkaline fatty acids at the sn-1 position of phospholipids such as PEMT synthesized phosphatidylcholine also promote balancing of polarity along with promoting alkalinity. Alkaline fatty acids and molecules such as phosphatidylethanolamine, newly produced, unglycosylated, or lightly glycosylated, plasticity enhancing phosphatidylethanolamine, typically exhibiting DHA, Omega-3, extended length arachidonic acid, oleoylate, highly combustible palmitate which is the first fatty acid in fatty acid beta oxidation, and ether linked insulating fatty acid species, characterize the catalytic output of PEMT. PEMT produces metabolites that perform as inorganic to organic phase transfer agents which separate biotic phase from abiotic phase, sequester useful factors from the abiotic phase for transfer to the biotic phase, promotes serine protease activity and super “clot buster” tissue plasminogen activator, deteriorate the structural basis of pervasive oncology potentiating molecules, and are used to clean industrial wastes in diverse environments. The three stepwise methylations performed by PEMT, remove CH3 from s-adenosyl methionine and use the lone pair of CH3 to integrate into three locations within phosphatidylethanolamine to change the ethanolamine lead group to be a choline lead group. The result of PEMT catalysis is 1methylethanolamine or PMME, 2methylethanolamine or PDME, and enriched phosphatidylcholine known as PC.

S-adenosyl methionine and alkaline fatty acids are known to cause ordinary proteins to become transformed into enzymes merely be exposure to these molecule’s alkalinity which promotes a disequilibrium in ph. Disequilibrium in ph promotes animate biological activity particularly when the foundation, such as water, has ph that is at equilibrium as water is at 7.0 ph at thermodynamic level of 77 Fahrenheit, thermodynamic level of 37 Celsius and with pCO2 level of 40 mmHg. Levels cations and anions, pressurization, thermodynamics, fluid content, and other factors can be managed by buffering systems to maintain adequate ph disequilibrium. Importantly, disequilibrium can be translated by biological systems in pressure, thermodynamics and most importantly, mechanical force and capacitance. Release of hydride from NADH is known to release 2eV- of current, e- and fluorescence which are reasonably correlative or constitutive of some aspects of capacitance.

A useful example is the freeing of hydride from NADH in the electron transport pathway or oxidative phosphorylation. Hydride is oxidized from NADH releasing 2eV-, fluorescence, per molecule of hydride that is oxidized, each of which is evenly distributed in a democratized modality to the phases of oxidative phosphorylation. About 58 percent of the freed hydridic resources are used for operations within the pathway, while about 42 percent is integrated into the oxonium nestled between the phosphate groups of ATP and within the oxonium integrated at the conclusion of the phosphate groups in the structure of ATP. Atp, integrated into s-adenosylmethionine, results attachment of hydridic resources, followed by a typical carbocation rearrangement in which the hydridic center is moved from atp to the central structure of methionine, resulting in an ionization of the sulfur. PEMT removes CH3 from this rearrangement and produces a special radical known as methylene bridges cysteine that is considered inert and tagged for inclusion in biosynthesis when PEMT produces methylene bridge cysteine, although when other methyltransferase used for detoxification, immunology, allergic response, and xenobiotic response utilize methionine’s CH3, the result is highly toxic methylene bridge cysteine that is integral to all disease, impairment and the detrimental nuances of aging, including deterioration of the neurological basis of social behavior. Thus, in many ways, methylene bridge cysteine and persistent cortisol, both are integral, central and in many instances required nuances of subversion.

S-adenosyl methionine used as substrate for PEMT is also accompanied by methylene bridge cysteine. S-adenosyl methionine is produced by methionine synthetase which is now known as s-adenosyl methionine synthase.

Nicotinamide is increased when PARP signaling removes the ribose from NAD+. The dynamics in this context that result in directing of pyruvate to lactate is known as parthanatos and involves deterioration of already completely differentiated cellular entities and an increasingly immortal phenotype among progenitor cellular entities, and is linked to potential for pathology, upregulation of survival signaling in the upregulated cdp-choline pathway including choline kinase alpha production of phosphocholine that is used by diverse pathology, which activates platelets and cause complements immunological signal at subclinical levels. Also upregulated is supply of phosphocholine to 26s/20s/19s proteosomes which exhibit resilience and enhanced activity, while releasing choline for a tight cycle of phosphocholine supply and regeneration. Also upregulated is S1P the nonresolution survival signaling molecule that activates S1P receptors, GPCR receptors, GSK3 and other molecules linked to pathology, including upregulation of phosphorylating kinases.

Upregulation of P53 results in activation puma and bax with potentiate apoptosis in the P53 regulatory decision pattern. However, DBC1 is required to be integrated into P53 in order for puma and bax to be transactivated. However, DBC1 also displaces NAD+ from Sirt1 and potentially Sirt2 by integrating into the Nicotinamide pocket of Sirt.

DBC1 in the form of dn-DBC1 displaces itself from the Sirt1 and Sirt nicotinamide pocket.

DBC1, when displaced from the sirt nicotinamide pocket, results in freed hydride in the form of NAD+, other nad metabolites, and freed carriers of Nad+ in particular. The literature does not consistently differentiate between NAD+ pockets and NADH pockets, suggesting that redox status and balance of NAD+/NADH might be persisted when NAD metabolites, or NAD carriers integrate into the sirt nicotinamide pocket.

Thus, sirt integration with DBC1, impairs puma activation of apoptosis and impairs bax activation of apoptosis, which change the balance of Bax and Bak to BCL2, such that Bcl2 may promote cellular survival and such that the Bag1 proteolytic upregulator/Bag3 autophagy upregulate paradox emerges upon this context of BCL2 prevalence. DBC1 displacement from P53 by sirt also prevents transactivation of P53 or transcription and posttranscriptional modification of P53, deteriorating the P53 regulatory lattice.

Cytoplasmic LDH and Mitochondrial EDC complex I are major interconversion pathways for NAD+/NADH, while there are some enzymes that directly interconvert NAD+ and NADH. Enzymes such as sirtuins regenerate NAD+ from nicotinamide using a base exchange reaction that can cause the sirtuin to abdicate its acetylation transaction ability, although arginine adjacent to the nicotinamide integration loci (sirtuin nicotinamide “c pocket”) can regulate or toggle sirtuin nicotinamide recycling compared to deacetylation activity.

Information) “Protein Kinase.” Journal of Dairy Science. Volume 86. Issue 4. Pages 1147 to 1156. 4th Month, 2003.

Sirt2 is described in the literature as being as being dissociated from DBC1 or prevented from being integrated with DBC1 by CK2 phosphorylation of the ESA domain which results in increased interaction with ESA domain with the central catalytic domain of Sirt2.

Information) “Regulation of Sirtuin Function by Posttranslational Modification.” Frontiers in Pharmacology. Volume 3. Article 29. Page 29. 2nd Month, 2012.

Sirt5 deacetylates pyruvate dehydrogenase complexes and deacetylates succinate dehydrogenase complexes, resulting in upregulation of the production of their substrate or their products correlated with balance of NADH compared to NAD+. Sirt3 and sirt7, thus, can activate succinate dehydrogenase. Succinate promotes the transsulfuration pathway through which methylene bridge cysteine is structurally deteriorated. The condition ALS, in one of its versions, is characterized by upregulated transsulfuration activity or translation of glucose into succinate, contrasting with the typically beneficial effect of depleting methylene bridge cysteine. Succinate becomes fumarate through succinate dehydrogenase. Sirt3 and Sirt7 also both interact with phases of the cellular respiration pathway. SIRT5 and generally among sirtuins, nicotinamide performs as an inhibitor of deacetylation by receiving acyl groups from sirtuins in a way that conforms the role in PARP production of nicotinamide during signaling in which it removes ribose from NAD+ to distribute ribose to local substrate to cause a gradient upon which material and nucleotides for DNA repair might be recruited. Arginine adjacent to the nicotinamide pocket in sirt5, as an example or as a subgroup of Sirtuins, interacts with succinate to cause sirtuins or Sirt5 to become desuccinylases.

The literature suggests that any of these substrates for the Krebs cycle can be added and then can upregulate or start the Krebs cycle.

Importantly, the literature is inconsistent in presenting the role of Rub P carboxylase or rubisco in its shunting of ribulose metabolites into the glycolysis to enhance, upregulated or start glycolysis at the juncture between pyruvate and the Krebs Cycle, along with the shunting or ribulose into the Krebs cycle directly, upregulated, enhancing or staring the Krebs cycle. The debate is not the function of rubisco in carbon fixation into biology but, instead, the debate is if rubisco exists in Human physiology, particularly because rubisco was included in the Human genome databanks until recently when it has been obscurely presented in this context. Rubisco is the most abundant enzyme in the biome. Rubisco was a participant in the great oxygenic event which resulted in enhanced availability of oxygen and is linked to the ability of organisms to increase in size. The current biome exhibits inadequate exhibition of CO2 for rubisco to fully exhibit its catalytic potential in carbon fixation into biology, such that Rubisco is diminished its translation of CO2 into biology, which debunks theories about the biomes ability to support life. Biomass thus, from a rubisco perspective, removes CO2 from the atmosphere and produces enhanced substrate for Life while Human PEMT function is a strong detoxification pathway for the atmosphere through atmospheric respiration and PEMT. THMT, INMT, methylthioglycolic acid catalytic structural deterioration of oncology potentiating factors and ability of these pathway metabolites to be instrumented to clean industrial wastes.

Neuromelanin is known to interact in electromagnetic spectrum and extraelectromagnetic spectrums of field and influence to produce balance and coordination, while impaired neuromelanin is linked disease with impaired movement and coordination and while early development exhibits incomplete coordination in correlation with developing, enhancing and increasing levels of neuromelanin in the Suprachiasmatic Nucleus.

Rubisco may benefit biology by providing substrate that can be shunted into multiple entry points into the Krebs cycle.

The Krebs cycle is known to be omitted during anaerobic glycolysis, greatly downregulating biosynthesis of numerous factors including proteins that are well known in physiology. Its omitting is strong reason why energy molecule output decreases from about 32 molecules per cycle to about 9 to 6 molecules per cycle.

Aerobic glycolysis occurs when PEMT continues to be downregulated, P53 continues to be increasingly potentiated or increasingly expressed, while energy metabolisms increase above 9 to 6 energy molecules per cycle, resulting in imbalanced translation of mined hydride from structure and membranes into circulation and metabolism. Aerobic glycolysis is beneficial when PEMT is active and functional because PEMT exhibits diverse genomic and metabolic stability mechanisms, PEMT integrates methyl groups into cellular membranes and phospholipids to regulate growth/development/homeostasis, PEMT integrates resolution phase stabilizing fatty acids at enhanced focus rates into cellular membranes and structure, and PEMT2 in particular emerges near birth to impose systemic and structural regulation that can even require 1 to 1 ration of methyl groups with catalytic, metabolic, growth and development factors.

PEMT downregulations invokes systemic involvement at enhanced levels to maintain homeostatic, and these systemic capabilities become targets of disease, pathology promoting factors, and other vectors of risk, including deterioration of brain, conditioning, lucidity, cognitive capacitance, and integration of the less than conscious and conscious mind in regulation of physiology and in regulation of how physiology interacts with environment to the benefit self, group, species, Life, biome and the universes.

The literature observes that sirtuins generally integrate with NAD, particularly as NAD+ and this integration is in the sirtuin C pocket which promotes alkylimidate formation and nicotinamide release. Nicotinamide, after release, can reintegrate in the C pocket and depotentiate or inhibit deacetylase activity sirtuins that have already released nicotinamide. The sirt5 desuccinylation catalytic potential is downregulated by nicotinamide, presented in the literature as being enabled to deactivate desuccinylation through a sirt5 specific arginine that is able to ascertain distal carboxylate substrates. GW5074 specifically abrogates sirt5 desuccinylation while allowing sirt5 to exhibit deacetylase activity. Thus, the C pocket can have isoform specific characteristics that can occupied, changed, drugged, modulated otherwise, downregulated by inhibitors, upregulated or otherwise used to impose isoform specific regulation. These suggest that a system including redox factors is superimposed on basal physiology, perhaps suggesting that the systems represented in physiology are layered upon one another, providing increasing benefit, and perhaps providing benefit that is specific to changes in environment.

Sirt6 exhibits deacetylase, adp-ribosyltransferase, and defattyacylase activity.

Desuccinylation is has been experimental observed in with sirt5, sirt3, sirt7 and sirt4.

Generally, desuccinylation activity is different when differentiation occurs while diacylation is consistent with differentiation.

General cellular lysate catalytic rates for desuccinylation were observed to be biphasic, changing after initial rates of desuccinylation.

Proliferating muscle and adipose tissue exhibited increased levels of desuccinylation activity but do not exhibit increased deacetylase activity in experimental conditions.

Cellular entities that are proliferation exhibit reprogramming toward desuccinylation by sirt that increases sirt desuccinylation but does not upregulated deacetylation. The literature observes nicotinamide integrate as counteractively downregulating a particular sirt proteins performance of deacetylation but did not observe a specific downregulation of deacetylation during proliferation that exhibits upregulated desuccinylation. These suggest that cellular lysate performance of deacetylation can occur independently of the bolted-on catalysis of sirtuins. The systems seem to be layered. Generally, nicotinamide downregulates sirt deacetylase activity.

Cellular lysate desuccinylases activity can likewise use NAD+, other than sirt performance of desuccinylases activities using NAD+.

Information) “Sirtuin Activators and Inhibitors.” Pharmacol Ther. Volume 188. Pages 140 to 154. 8th Month, 2018.

Information) “Desuccinylase.” Scientific Reports. Volume 10. Article number 17030. 2020.

Desuccinylation levels for cellular level lysates were 10 times lower than NAD+ linked desuccinylation, revealing how obscure different in redox enabled transactions and transactions without assisted energetics may be different in volume.

Downregulation of nucleotide availability, canonical anaerobic glycolysis or PARP depletion of NAD+ directs pyruvate and NADH from glycolysis toward lactate and NAD+. Resultant of ribose removal from NAD+ by PARP, persistently because of inadequate nucleotides caused by downregulated pentose phosphate pathway enabled production of 5 carbon sugars for nucleotide and NADPH synthesis, and the occurrence of DNA repair invoking of persistent PARP signaling in a million or more instances each day in each cellular entity, it is able to be concluded that nicotinamide is available enough to downregulate sirt deacetylase activity generally.

Generally, sirt deacetylase activity is downregulated in canonical anerobic glycolysis that occurs when PEMT is downregulated. This downregulation of deacetylase activity can occur with de facto upregulation of desuccinylases activity when the sirt involved are sirt5, sirt3, sirt7 and sirt4.

Uniprot presents Human SIRT5 as a demalonylase, desuccinylases and deglutarylase which is able to remove malonyl groups, glutaryl groups and succinyl group from proteins. Sirt5 regulates circulatory fluid ammonia levels particularly during fasting. Sirt5 actives CPS1. Sirt5enables desuccinylation and deglutarylation of CPS1. Sirt1 frees CPS1 to increase catalytic activity by CPS1. CPS1 catalytic activation occurs correlative to NAD+ availability. Superoxide Dismutase 1 or SOD1 is activated bySirt5 desuccinylation, disrupting reactive oxygen species, but promoting the reactive oxygen mediation cascade from superoxide to H2O2 requiring catalase and peroxiredoxins or vitamins and n acetyl l cysteine. H2O2 can become peroxynitrite when involving Nitric Oxide Synthase uncoupling. Catalase diminishes H202 particularly but is deactivated by upregulated methylene bridge cysteine.

Sirt5 enables SHMT2 activation through desuccinylation. SIRT2 desuccinylates HMGCS2 to activate HMGCS2 and activate ketogenesis.

Sirt5 has minimal deacetylase activity although it can deacetylate cytochrome c cycs, uox and other proteins.

The specific catalysis of sirt5 for desuccinylation includes H2O, N6-usccinyl-L-lysyl-[protein] + NAD+ translation by sirt5 bidirectionally into 2’-O-succinyl-ADP-D-Ribose, l-lysyl-[protein], and nicotinamide. Glutaryl proteins and malonyl proteins can be substituted for succinyl in this reaction to constitute their respective catalytic patterns performed by sirt5.

The literature observes remarkable and even extreme duration of vital being in correlation of metabolic characteristics that include depletion of methylene bridge cysteine through the nonrecycling pathway known as the transsulfuration pathway. Interestingly aerobic conditions required exhibition of improved redox capable proteins including lysine, phenylalanine, cysteine, tryptophan, tyrosine and selenocysteine, all of which counteract the debatable exhibition of anaerobic glycolysis as a homeostatic status particularly because anaerobic glycolysis occurs when PEMT is most active and particularly because anaerobic glycolysis includes lactate increase, NAD+ increase and PARP signaling persistence that result in increased required activity by systemic buffering systems, organs and tissues. It is interesting how the upregulation of lactate and persistent depletion of NAD+ could have reasonable been regarded as homeostatic status.

Sulfur exhibiting amino acids, cysteine and methionine, both of which perform as components of buffering systems, and can become impaired or deactivated when used by buffering systems to manage ph and homeostasis, are both correlated with extreme duration of being in Animalia. Duration of being is linked to decreased methionine in Animalia, although it not clear if this decrease is because upregulated metabolisms of methionine by PEMT, other methyltransferases and transsulfuration depletion of methionine production by recycling pathways, or if this correlation is the result of methionine nutritional decreases. A study observed nutritional decreases in methionine as vector of enhanced duration of being, although the clinical data differentiates methionine direction toward methylene bridge cysteine by PEMT as being harmless compared to other pathways that produce methylene bridge cysteine from methionine.

Methionine is a primary substrate and indicator of production of methylene bridge cysteine, while oxidative distress is lower in contexts of extreme duration of being, while lower levels of sulfur exhibiting amino acids seems circumstantial, although the great oxygenic event which downregulated atmospheric ratio of sulfur compared to oxygen seems relevant in adaptive replacement of reactive oxygen counteractance compared to focus on reactive sulfur counteractance management. Observations regarding sulfur and oxygen exposure differences during phases of hibernation and no hibernation are revealing in this regard. Hibernation may result in decreased oxygen utilization and increased exposure to enclosed areas where sulfur may have an opportunity to increase in ratio compared to oxygen.

Methionine can be translated into s-adenosyl methionine followed by s-adenosyl methionine becoming s-adenosyl methylene bridge cysteine, while subsequently s-adenosyl methylene bridge cysteine can become methylene bridge cysteine through the activity s-adenosyl methylene bridge cysteine, s-adenosyl methylene bridge cysteine can become s-adenosyl methionine through the activity of INMT, and s-adenosyl methylene bridge cysteine might also be regulated by proteolysis or autophagy. Methylene bridge cysteine can then be recycled by THMT according to sulfur availability and thetin substrate availability into methylthioglycolic acid, representing another pathway of methionine bereft producing nonrecycling pathway for methylene bridge cysteine. Methylene bridge cysteine might also become methionine through B12 and 5 methyltetrahydrofolate and methionine synthase activity, BHMT2 and s-methylmethionine sulfonium activity, betaine/n,n,n glycine betaine/trimethylglycine and BHMT activity, and other pathways that may not be clearly elucidated in the literature.

The transsulfuration pathway is interesting because it results in nonrecycled methylene bridge cysteine metabolism. Methyltransferases are pervasively used to detoxify hormones, toxins, toxic metals, xenobiotics, histamine increases, and other factors, all resulting in a sequester CH3 from s-adenosyl methionine which becomes methylene bridge cysteine known to be a radical involved in all disease, diminished behavior and correlated in serum um/L with aging and detrimental nuances of aging. A study of centenarians observed that at about 80 years, increases in abated vital being correlated with age, abate, the sigmoid graph flattens, and metabolic characteristics of the most aged included perturbed B12 levels and increased levels of methionine. Extreme aging may involve stabilization of these two parameters, but certainly involves management of methylene bridge cysteine or practices that are interventional at habitual and clinical levels. Methylene bridge cysteine reflect toxicity exposure, xenobiotic exposure, allergen exposure, increase in toxic metabolites, cytokines which downregulated PEMT to cause de facto upregulation of methylene bridge cysteine because PEMT recycles methylene bridge cysteine into itself but promotes flux and tagging of homocysteine to prevent it from participating in detrimental toxic pathways.

However, methylene bridge cysteine deactivates biologically active molecules by enabling polymerization linked to pathology, sequestering the hydride from biological active molecules, deteriorating atom level interactions and adhesions that are functional within biology, causes upregulation of free fibrin, occupies fibronectin to cause deposits in cardiomyocytes, agrin, and other tissues, as well as deactivates catalase, and is able to produce almost every symptom observed in disease without aspects of disease being exhibited otherwise. An analysis in this compendium of research found 3 or more, single-spaced pages of detrimental factors caused by methylene bridge cysteine in only a limited, cursory consideration of these potentialities. An objective review of methylene bridge cysteine, including a search on the internet for virtually any diminished outcome whatsoever, pervasively reveals a correlation to levels of methylene bridge cysteine, also revealing that diminished neurological basis of social behavior, all beginning with brain deterioration from methyl group and choline inadequacy beginning at gestation, clearly presents that human misfortune and diminished outcomes are centered upon allowed exhibition of the effects of upregulated methylene bridge cysteine.

Since 1878 the ability to downregulated methylene bridge cysteine is characterized in the clinical literature, suggest that methylene bridge cysteine has been allowed to flourish because it generates massive opportunity to benefit from the diminished outcomes of Human populations. The omitted opportunities of antecedent eras are now being supplanted by the limitless opportunity of imputing Human priority in such contexts in a way that allows Human advancement to what is next in the continuation of the Human experience.

The transsulfuration pathway directs methylene bridge cysteine to cystathionine and cysteine, generally including vitamin B6 as a cofactor.

Extreme duration of being is correlated with methylene bridge cysteine becoming cystathionine, followed by directing of cystathionine toward succinyl-CoA of the Krebs/citric acid cycle, or directing of cystathionine toward cysteine then either glutathione or taurine although it is known that cysteine can become cystine, H2S, HS, sulfate, methanethiol and other metabolites.

It should be observed that glutathione, zinc and other factors are used to detoxify the production of dimethylthetin by BHMT and BHMT2 to prevent dimethylthetin from downregulating BHMT and BHMT2.

Desuccinylation by sirt5, sirt3, sirt7 and sirt4 supplies succinate which can be shunted directly into the Krebs cycle where succinate potentiates fumarate, fumarate potentiates malate, malates potentiates oxaloacetate although oxaloacetate is also produce as a possible metabolites of pyruvate when PEMT/P53 are functional and all pyruvate is not being directed toward lactate, oxaloacetate becomes citrate correlative to pyruvate being directed toward acetyl-CoA/CO2 when all pyruvate is not being directed toward lactate, citrate becomes isocitrate, isocitrate becomes alpha-ketoglutarate although arginine/glutamine/proline/histidine all become alpha-ketoglutarate, followed synthesis of succinyl-CoA although, again, Acetyl-CoA is downregulated when pyruvate is directed to other outcomes such as phosphoenolpyruvate, alanine, acetaldehyde and ethanol, Acetyl-CoA toward Citrate and CoA, and oxaloacetate.

Thus, succinate provides two loci for insertion into the Krebs cycle as succinyl-CoA and sugar exhibiting succinate in a way that enables the Krebs cycle to potentiate directing of cystathionine into the Krebs cycle, thereby promoting substrate cycling through the transsulfuration pathway. Succinate is known otherwise to potentiate the transsulfuration pathway.

Succinyl-CoA Synthetase bidirectionally performs catalytic interconversion of ATP, CoA and Succinate with ADP, phosphate and succinyl-CoA.

Heretofore, these analyses have not made observations regarding the role phosphorylation and phosphorylation cascades. Thus, it is now important to observe that phosphorylation of molecules introduces molecules into participation in the intracellular pKa balance, allowing more molecules to participate in determining cellular pKa or extending pKa homeostatic balancing interactions to molecules which were not included before phosphorylation.

Succinyl-CoA is a precursor to cystathionine and heme.

Succinyl-CoA enables entry and exit of proteins from the pKa balancing and homeostatic oscillation.

Experimental microbial observation of aerobic conditions reveals a 1000 percent increase in production of succinyl-CoA when succinate is the substrate compared to when glucose is the substrate for biosynthesis.

The following study observes metabolic and enzyme factors that are correlated with and in some instances explain extreme duration of being.

Information) “Methionine Transsulfuration Pathway is Upregulated in long-‘living’ Humans.” Volume 162. Pages 38 to 52. January 2021.

Information) “Succinyl-CoA Synthetase.” The Enzymes. Volume 10. Pages 581 to 606. 1974.

Uniprot. Q9P2R7. Succinate-CoA Ligase. ATP – Specific Succinyl-CoA Synthetase.

Information) “Differential Sensitivities.” PLoS ONE. Volume 7. Number 9. E45098. 2012.

Information) “Sirt5.” ‘Mol ‘Cellular Entity.’ Volume 50. Number 6. Pages 919 to 930. 6th Month, 2013.

Information) “Transsufluration.” Neurobiol Dis. Volume 144. 105025. 10th Month, 2020.

Information) “Sirtuin 3 Deacetylase Activity.” PLoS One. Volume 6. Number 8. E23295. 2011.

Information) “Sirt3.” Front Pharmacol. Volume 13. 871560. 2022.

Information) “Nicotinamide.” PLoS One. Volume 7. Number 9. E45098. September 2012.

The succinate dehydrogenase enzyme or succinate - coenzyme Q reductase or respiratory complex is exhibited in the inner mitochondrial membrane and participates in both the electron transport pathway and the citric acid cycle.

Managing methylene bridge cysteine toward 3.7 um/L or lower may be a therapeutic objective to alleviate effect to the strong ion gap or strong ion balance.

The literature observes that pyruvate is converted to acetyl-CoA during aerobic conditions and pyruvate is converted into lactate within anaerobic conditions, while it is known P53 downregulates pentose phosphate pathway and downregulates glycolysis from about 32 energy molecule synthesis per cycle to about between 9 and 6 molecules of ATP synthesis per cycle, resulting in canonical exhibition of anaerobic glycolysis. Anaerobic glycolysis causes competition of diminished pyruvate which is strongly potentiated as pyruvate and NADH toward lactate anion and NAD+ because of PARP signaling except in active muscle tissue and except in nonconditioned muscle tissue. Lactate dehydrogenase performs the translation of pyruvate and NADH into lactate anion and NAD+.

Information) "Bag 3." Autophagy. Volume 10, Number 9. Pages 1603 to 1621. September 1, 2014.

Information) "Bag 3." 'Cellular Entities.' Volume 9, Number 3, Page 574. 3rd Month, 2020.

Information) "Anti-Aging." Clin Interv Aging. Volume 15. Pages 387 to 393. 2020.

Information) "DBC1." US Patent Number US20090036375A1

Thus, a clear perspective emerges. PEMT downregulation causes P53 to be promoted in determining cellular outcomes for apoptosis potential or survival potential. Although P53 has a complex lattice for directing cellular outcomes, the potential for apoptosis by P53 relies upon P53 transactivation of puma and bax. DBC1 integration into P53 is essential for P53 to transactivate puma and bax. Sirt1 integration into DBC1 frees NAD+ to promote mitosis while DBC1 is prevented from integrating with P53 in a way that prevents apoptosis to enhance potential for survival and proliferation.

PEMT downregulation promotes parthanatos when pyruvate and NADH are directed toward lactate and NAD+ in which parp signaling overproducing nicotinamide and a strong gradient of NAD+ depletion, ribose attachment to local metabolites to PARP, delayed DNA repair/replication, and upregulation of nicotinamide availability emerge. Already differentiated cellular entities are increased in susceptibility for apoptosis and newly produced or developing progenitor cellular entities increasingly acquire an immortal phenotype.

Upregulated nicotinamide causes increase in nicotinamide methyltransferase production of methylene bridge cysteine which also promotes apoptosis using other mechanisms. Upregulated nicotinamide also deactivates deacetylase activity by some sirtuins and promotes desuccinylases activity in sirtu5, sirt7, sirt3 and sirt4.

Desuccinylase activity promotes transsulfuration pathway depletion of methylene bridge cysteine, such that the complete cycle presented in this context seems to promote circumvention of biosynthetic pathways when PEMT is downregulated by avoiding recycling of methylene bridge cysteine into methionine and depleting methylene bridge cysteine through the transsulfuration pathway.

The reason that this cycle or pathway is important, seems to be that anaerobic glycolysis is presumed to be a homeostatic status, but it inherently increases the involvement of systemic buffering mechanisms, organs and tissues in sustaining intracellular pKa at 7.21 and ph near 7.2 to 7.6, ph of 7.35 to 7.45 and ph of 7.4. This emerges because it is ionic balances of that emerge as determinants when PEMT is not integrating hydride int cellular membranes to produce and sustain the background ph of 7.4 that is a foundational anatomical, tissue, and systemic exuding influence of the 7.4 ph disequilibrium from both the 7.0 ph of pure water and the acid gradient between 7.4 and H+ or hydronium H3.

The sirtuin interaction with DBC1 occurs regardless of PEMT status. Other mechanisms of cellular cycle regulation including confluence YAP/TAZ, Agrin signaling, other mitogenic pathways, pRb modulation, cyclins, and CDKs.

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