Authentic Biochemistry

What is involved to make a sound decision?

Biochemistry is a scientific discipline; one that examines and interprets the foundational structures and functions of living systems.

As with any judgment, as there are reasons for believing, there are also reasons for disbelieving, and the freely willed decision to choose which, should involve the discovery of truths to use as exemplars for seeking coherence and foundation to the premises that necessarily and sufficiently support the better argument for that decision

Listen to my lecture to learn the details of this unfolding discussion that recombines epistemology with metaphysics as re-purposed to find Authentic Biochemistry.

DJGPhD

31 March 2021

Annual Review of Cell and Developmental Biology Vol. 34:111-136

Journal of Neuroscience 23 October 2019, 39 (43) 8576-8583

Archivum Immunologiae et Therapiae Experimentalis 2013 Apr;61(2):119-25.

 In this foundational lipid absorption lecture,  Dr. Guerra address the roles of apo- lipoproteins, triacylglycerol and cholesteryl esters with membrane associated caveolae transport in adipocytes, endothelia and skeletal muscle. An Authentic Biochemistry Podcast Production. 25 March 2021.

Electron transport and the anapleurotics of intermediary metabolism. Dr. Daniel J. Guerra

Authentic Biochemistry Studios

21.3.21

•Impaired immunological responsiveness is common in the elderly

•The immunological competence of an individual is determined by the presence of mature lymphocytes formed in primary lymphoid organs, and secondary lymphoid tissues such as the liver, lung and GI tract.

•Immunological equilibrium requires steady lymphocyte output, and controlled expansion

•Thymic and lymph-node stromal microenvironments thus represent key elements in the development of the adaptive immune system. Consequently, impairment of the lymphoid microenvironment will ultimately lead to insufficient primary and secondary immune responses or to the decline of thymic selection, manifesting in immune senescence accompanied by late-onset autoimmune disorders, often observed in elderly.

•Self-tolerant cytotoxic and helper T-lymphocytes, the crucial regulator cells in adaptive immune responses, develop in the specialized epithelial network of the thymus. The thymus, however, gradually loses its capacity to support lymphopoiesis in an involution process that results in a decline of de novo T-cell production.

•Cancers of epithelial origin (carcinomas) are the most frequent type of malignancy in humans, with their incidence and aggressiveness increasing with age

•This observation raises the question as to whether the aging process itself contributes to tumor progression

•. In this regard, telomere biology seems to play a pivotal role since shortening of telomeres has been associated with cellular senescence and organismal aging as well as with cancer incidence and mortality .

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•In the multistep carcinogenesis model, telomere shortening has been observed together with increased chromosome instability (CIN) in early precancerous conditions

•Experimental models have also shown that a transient period of telomere instability followed by reactivation of telomerase contributes to the acquisition of the metastatic phenotype

•Cytokines regulate the intensity and duration of the immune response, and  they can act as growth factors or stimulants or even inhibitors of T cell amplification and differentiation.

•Cytokines are glycoproteins that are synthesized through a dolichol PP mediated pathway in the ER and are thus dependent upon prenyl lipid metabolism

Endoplasmic reticulum localized ADPGK serves glycoprotein synthesis and also functions to control glycolytic vs. aerobic bioenergetic intermediary metabolic agency in lymphocytes.

Scientific Reports volume 9, Article number: 14248 (2019)

1. Glucokinase- GK is in the neuron

2.Control over glycolysis via GK mediates neural transmission

3.  Neuronal GK further functions on  the appetite/satiety axis thus partially regulating the HPA axis

4. Aging and immune associated dysfunction of these glycolytic systems are associated with neurodegeneration and the loss of neuronal action potential mediated learning, memory, and mood.

Therefore, metabolic control over the severity of chronological age and the immunosenescence of the CNS can be exacerbated by visceral obesity thus linking CNS decline to the major causes of morbidity and mortality in the aging human population.

Curr Opin Lipidol. 2015 Apr; 26(2): 88–95

Am J Physiol Endocrinol Metab. 2016 Jul 1; 311(1): E42–E55

If  γ-aminobutyric acid (GABA) concentration drops significantly in the synaptic cleft, excitotoxicity can obtain, sometimes presenting with epileptic convulsions.This can be reversed by decreasing the concentration of L-glutamate via control over the activity of glutamate dehydrogenase, glutamine synthetase and glutamate transporters or by  the inhibition of  γ-aminobutyric acid aminotransferase (GABA-AT), which catalyzes the conversion of GABA to the excitatory neurotransmitter l-glutamic acid.

Trends in Cell Biology 2020. 30.6: 440-451.

Chem. Rev. 2018. 118. 7: 4037–4070

A basic lecture on reactive oxygen synthesis and reduction coupled with glutathione, folic acid and amino acid metabolism.

This lecture is foundational for subsequent synthesis with neural transmission, microglial activation and exicitotoxicity leading to neurodegeneration in the aging human CNS.

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Published 9 March 2021 by Dr Daniel J. Guerra.

CPS-1 activity is regulated by liver enriched transcription factors as well as Sirtuin-mediated de-acylation.

Glutaminase breaks down glutamine into glutamate and ammonia. Glutamate also yields additional NH4+ via the enzyme glutamate dehydrogenase. From here, ammonia is initially incorporated into hepatocyte mitochondria and ultimately results in the formation of urea. Urea subsequently leaves the hepatocyte cytoplasm and is ultimately excreted in urine.

Glutaminase-1 (GLS1) is a mitochondrial enzyme found in endothelial cells (ECs) that metabolizes glutamine to glutamate and ammonia and glutaminolysis modulates the function of human umbilical vein endothelia.Glutamine deprivation or GLS1 inhibition also stimulated the production of reactive oxygen species and this was associated with a marked decline in heme oxygenase-1 (HO-1) expression. GLS1 inhibition also sensitized umbilical endothelia to the cytotoxic effect of hydrogen peroxide; a process that is blocked by the overexpression of Heme oxygenase 1. In summary, GLS1 promotes human endothelial  proliferation, migration, and survival.

SIRT4 might prevent CNS excitotoxicity and subsequent apoptosis by  reducing glutamine synthesis while and upregulating glutamate transport into astrocytes where increased  glutamate dehydrogenase activity removes the ultimate source of this neural degeneration mechanism.

In the small intestine, SIRT5 causes deglutarylation and functional activation of glutamate dehydrogenase 1 leading to poor prognosis in colorectal cancer.

Combined, this experimental evidence suggests that the modulation of mitochondrial Sirtuin activity to pharmacologically circumvent CNS pathophysiology may not be appropriate for cancers in the digestive system and that Sirtuin isoform expression and activity is highly nuanced. 

J Cell Mol Med. 2017 Sep; 21(9): 2036–2045

Hum Exp Toxicol. 2020 Jul;39(7):938-947