Authentic Biochemistry

Cellular long chain acyl-CoA concentrations are controlled by multiple networked and coherent  metabolic pathways ( including mitochondrial β-oxidation versus Golgi-ER-PL complex lipid synthesis versus glyceropholipid and sphingolipid hydrolysis), which functionally associate  resident  acyl-CoA in cellular bioenergetic and signaling pathways. Thus, the regulation of PFK-1 by its direct interaction with acyl-CoA generates downstream interconnected alterations in metabolic flux through glycolysis, the OPP and mitochondrially associated oxidative metabolism plus  vesicular trafficking and directed  subcellular localization  associated with porosomes.

Biol Open. 2019 Oct 15; 8(10): bio040311.

Biochem Soc Trans. 2015 Apr;43(2):193-8.)

J of Molecular and  Cellular Medicine 2014. 18: pp.1927

Naive T lymphocytes, as opposed to memory  T cells(which are more common in aging) carry out homolactate fermentitive glycolysis. 

Memory cells are operating under complete aerobic metabolism involving  mitochondrial bioenergetics including the TCA cycle but also fatty acid oxidation as a source for reducing equivelents to drive the electrontransport chain and oxidative phosphorylation.

The regulation of these alternative pathways involves allosteric modification of key enymes and trafficking proteins intracellularly.

The acid sphingimyelinase and protein palmitoylation enzymatic machinery coordinates this regulation by changing the membrane micro-environment.

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Dr Dan Guerra 

 Early stage TCR activated T cells with rampant lactic acid fermentation, fail to  maintain adequate ATP levels , especially when glucose is limiting.This decrease in ATP relative to ADP+AMP results in the activation of AMPK, which inhibits mTOR activity and all subsequent anabolism especially assocaited for  T cell proliferation. Indeed, induced Loss of AMPKα1, will sythetically restore  mTOR signaling and T cell cytokine production, but not proliferation. Although loss of AMPK can restore some functions in glucose-restricted T cells, the cells do not initiate metabolic adaptations necessary to recover ATP levels. In vivo, AMPKα1-deficient T cells have decreased mitochondrial respiration, flux of glutamine into the mitochondria, and ATP:AMP ratios, and therefore fail to proliferate and function effectively.

In cardiac and skeletal muscle, AMPK phosphorylates the bifunctional enzyme at a unique SER residue which induces the PFK-2 activation over the phosphatase activity thus stimulating glycolysis and overcoming hypoxia. Hypoxia renders the mitochondrial electron-transport chain-oxidative phosphorylation pathway non-functional as molecular oxygen is the ultimate electron acceptor becoming reduced to water. With depleted oxygen as in stress and in heavy skeletal muscle contraction, glycolysis must be stimulated as AMP levels rise. AMP also controls PFK-1 directly

In tumors, the rate of translation of HIF-1a mRNA in cancer cells is dependent upon the activity of the mammalian target of rapamycin (mTOR), which in turn is determined by the activity of upstream tumor suppressor proteins and oncoproteins. HIF-1α plays a key role in stimulating glycolytic enzymes and in blocking mitochondrial activity. LncRNAs can also regulate Akt and AMPK pathways. Akt may increase oxidative phosphorylation by enhancing metabolic coupling between glycolysis and oxidative phosphorylation.

Relevant Research References

Cell Research volume 30, pages649–659(2020)

 Molecular Cancer July 2017. 16(1)DOI: 10.1186/s12943-017-0699-3

Genomics, Proteomics & Bioinformatics Volume 14, Issue 1, February 2016, Pages 42-54

J BiolChem. 2011 Apr 8; 286(14): 11937–11950.

Authentic Biochemistry Podcast 29 December 2020

Daniel J. Guerra Ph.D.

•All scientific inquiry should start with dialectical method that uses the current knowledge base to generate various specific Theses and then follow each with the counter-argument by employing the Square of Opposition thus producing Anti-theses and then, making the third movement, which allows for a Synthesis that has the flavor of rejection, acceptance or indifference.

*Downstream of co-stimulation and PI3K-AKT, the mammalian target of Rapamycin (mTOR) kinase pathway integrates multiple signals and regulates anabolic metabolic reprogramming in T cells exiting quiescence. mTOR complex 1 (mTORC1) is required for cell cycle entry and coordination of early metabolic changes that occur upon T cell activation.

*T cells deficient in Raptor, an essential component of mTORC1, fail to upregulate the expression of Glut1 and other glycolytic enzymes when activated.

*Raptor-deficient T cells also exhibit defects in de novo lipid synthesis and oxidative phosphorylation, suggesting the mTOR pathway is a global regulator of T cell metabolic programs.

*mTORC1-mediated signaling is also required for proteomic remodeling of pathways including one-carbon metabolism(SAM and Folic acid), FAO, and the electron transport chain (ETC) that occurs early in activating T cells.

Human neuroscientific research seeks to uncover patterns of commonality and uniformity to help define mechanisms which reliably result in the experience of thinking and interacting with the world. This scientific mindset is in opposition to real life experience where human bonding is unique to a specific relationship. This may be best understood as a compatibilist approach, where neuroscience may affirm the very real experience of an individual when he makes a judgment or chooses to imagine his next move while the neurocircuitry is providing the means to have that experience without an agentic causal connection. This view as stated is not a contradiction, since it doesn’t assert there is no experience of free will or directed emotion or thought but rather that it is coincidental to the neurophysiology and the grounding provided by neurobiochemical networking.

In my view, there is an alternative to this theory; it is based on the principal of “first causes”.

Merry Christmas Everyone!

T cell agency initiates upon the stimulation of the TCR via presentation of cognate peptide-MHC complexes in associative ligand-mediated membrane co-receptor CD28 with co-stimulatory molecules presented on the surface of the APC: this event is called T cell licensure and essentially quits quiescence.

The TCR signals through the ERK/MAPK pathways and calcium flux; where as CD28 signaling activates the PI3K-AKT-mTOR axis, and both pathways synergistically engage the NF-κB organon of pleitropic T lymphocyte agency.

Merry Christmas from AUTHENTIC BIOCHEMISTRY!

Thank You!

In this episode Dr Guerra provides a concise description of  T lymphocytic fatty acid synthesis from glucose via cytosolic glycolysis,  mitochondrialpyruvate dehydrogenase, pyruvate carboxylase, and citrate synthase and a return to the cytosol for ATP citrate lyase and the homodimeric polyprotein complex FAS to generate palmitoyl-ACP.

This ability of  antigen-MHC Antigen Presenting Cell  TCR - activated T lymphocytes to prepare for massive cytokine and chemokine expression requires a biochemical poise to use newly synthesized intracellular triacylglycerol to drive cellular exapnsion and effector-mediated immune responses.

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Metabolic syndrome  (MetSyn)is a dyslipidaemic chronic and aging  linked sedentary life-style constellation of disease presentations including metabolic disorganization, prodromal Type 2 diabetes and a prominent connection to hypertension-most prominently associated with over-eating and obesity. MetSyn is often  prolegomena to middle-age onset CVD, cancer and neurodegeneration. High caloric density soluble carbohydrate nutrition, lack of fasting and the species-specific metabolic inability to convert fatty acids into glucose via gluconeogenesis, provide a pathobiochemical poise toward MetSyn.

As Nicotinamide Adenine Dinucleotide (NAD+) levels decline with age and obesity a potential suppression of NAD (H)-dependent enzymes in oxidative phosphorylation, the TCA cycle, and glycolysis resulting in suppressed  ATP production can trigger the AMPK mediated transcriptional activation of the senescence-associated secretory phenotype (SASP) leading to morbidity and mortality in the advanced aged human.

However, NAD+ essential DNA Damage Repair and Sirtuin-mediated deacetylation of histone-associated chromatin may exacerbate aging and both neurodegeneration and tumorigenesis.

Published and produced by Dr. Daniel J. Guerra, Authentic Biochemistry 17 December 2020.

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J Biomed Sci. 2019; 26: 34

Front. Genet., 12 March 2015

BioEssays, 2017. Volume: 39, Issue: 5,

Both the innate and acquired immune systems become senescent during chronological aging. While T cell activation may become disenfranchised from its co-stimulatory control apparatus during aging, the potential for hyper or hypo-immune responses becomes more common. At the same time,   CNS microglia and peripheral resident and circulating macrophages are activated following the stimulation of various pattern recognition or phagocytic receptors.  In the CNS, this activation state is subsequently controlled by proximal neurons, which secrete regulatory ligands. The end result of these interactions is the release of cytokines, neurotoxins, and/or growth factors by microglia/macrophages and  the activation of cellular pathways including phagocytosis. Aberrant function of these pathways can result in significant degeneration during aging. 

Cell Rep. 2018 Feb 6; 22(6): 1509–1521.

FEBS Journal. 2009.Vol. 276, 1 Pages: 13-26

Experimental & Molecular Medicine volume 51, Article number: 80 (2019)

Frontiers in Immunology · February 2013

Cell cycle (Georgetown, Tex.) September 2008  7(15):2296-8

Dr. Guerra reminds and extends his decade-long hypothesis that The Immune Response could function to generate the networked synaptic connections in the brain during  initiation, development, learning, and aging.

The question considered is how do immune cells and immuno-regulatory proteins such as cytokines and chemokines and immunoglobulins recognize certain neurons and not others? The mechanism for maintaining and increasing synaptic strength vs. obsolescence and programmable cell death could be mediated by cellular phenomena known as pattern recognition.

The bioenergetics of T lymphocyte activation and subsequent effector mediated inflammatory responses  involves a conversion of glucose to lactate via aerobic glycolysis as coordinated through the early TCR activation stage phosphorylation of pyruvate dehydrogenase via PDHK1 and axial coordination of NAD+ synthesizing LDH.

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