Authentic Biochemistry

Glutaminase breaks down glutamine into glutamate and ammonia. Glutamate also yields additional urea 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.

Sirtuin mediated control over glutamate dehydrogenase and carbamoyl-P synthetase via discrete and potentiating  ADP ribosylation and deacylation is associated with pancreatic insulin secretion, hepatic amino acid utilization and the potential for pathobiochemical sequalae

SIRT5 causes deglutarylation and functional activation of glutamate dehydrogenase 1  which is  essential to cellular glutaminolysis.Indeed, SIRT5 supports the anaplerotic transamination entry of glutamine and other amino acids as alpho ketoglutarate into the TCA cycle in malignant phenotypes of colorectal cancer via activation of the glutamate dehydrogenase1.

Sirt5 is known to regulate the activity of the urea cycle enzyme, carbamoyl phosphate synthase 1 (CPS1). SIRT5 mediated de-glutarylated CPS1 is elevated in activity to maintain urea cycle competency during active amino acid incorporation into the bioenergetic machinery thus promoting the potentiation of tumorigenesis.

Science. 2011 Nov11; 334(6057): 806–809

Cell Metab 2014 Apr 1;19(4):605-17.

Nat Commun. 2018 Feb7;9(1):545

Cell. 2006 Sep 8;126(5):941-54

Mol Cell. 2013 Jun 6; 50(5): 686–698

The Pyruvate dehydrogenase hydrated E1-E2 interface is  enthalpy driven, while the dehydrated  E3-peripheral subunit binding domain complex is driven by entropy obtaining a favourable  delta G= delta H-T delta S=  -33.4kj mol where the domain interfacial hydration obtains surface  thermal complementarity  and contributes finally to an aggregate  strength of multiple affinities of individual non-covalent binding interactions via enthalpy-driven catalysis.

Lipoamidase activity of mitochondrial Sirtuin 4 modulates cellular fate by generating a  debilitating removal of PDH-E2 dihydrolipoyllysine acetyltransferase-bound lipoic acid  thus driving glutaminolysis over glucose oxidation.

Cell. 2014 Dec 18; 159(7): 1615–1625.

PNAS | August 23, 2016 | vol. 113 | no. 34

Structure VOLUME 13, ISSUE 8, P1119-1130, AUGUST 01, 2005

•Free energy change(chemical potential difference) for transporting 1 mole of a substance from region where its concentration is C1 (e.g., Cout) to region where its concentration is C2 (e.g., Cin):

∆G= RTln(C2/C1)

(favorable with ∆G< 0 if C2< C1)

•Transport of ionsacross membrane (must consider electrical potential in addition to concentration difference):

∆G= RTln(C2/C1) + ZF ∆Y

(Z=charge of ion, F=Faraday’s constant, ∆Y=membrane  electrical potential in volts)

•Coupled transport (active transport):

∆G= RTln(C2/C1) + ∆G´

(∆G´ of coupled process, such as ATP hydrolysis, may be  negative enough to compensate for unfavorable transport  against concentration gradient when RT ln (C2/C1) > 0)

•Diffusional transport: movement of substance from high to low concentration across membrane (down concentration gradient)

–Non-facilitated diffusion across lipid bilayer (slow for most biological substances)

–Facilitated diffusion (accelerated diffusion by making membrane more permeable to specific transported substance, e.g., channels and carriers)

•Active transport: Actively driven (generally directly or indirectly coupled to ATP hydrolysis) transport against concentration gradient from low to high concentration across membrane (e.g., pumps)

Mini Lecture 1 on Membrane Physiological Biochemistry.

The amino acid sequence of membrane associated polypeptides obtains secondary structure, glycosylation, acylation and hydropathy which confer functionality (in part) by targeting specific membrane domains.

For Valentine's Day Eve. A bouquet assortment of  biochemical  thermodynamic principles and  metaphysical event ontologies.

To finish my thoughts:

 Is life necessary? How to answer this question? One way is to ask if there is sufficient reason for its existence. Outside of spiritual or theological discussion, the answer is compellingly obscure especially since we find no authentic examples except on our planet. 

If life is contingent, where does it come from, how does it come about and why does it exist? You see where this is going. Why is there a physical universe? Why isn’t there just nothingness?

Answering with the typical “it just is!” only further confounds the question. The word “just” here, operates syntactically with contingency. By that I mean,  proposing that the modality of an event, life in this context, simply "is" a state function, makes no claim that the event "must be". And so…we are back to the beginning. A beginning that has no source.

The Big Bang could be such a beginning, but then again, some event had to proceed it , even if time itself had this event as its source.

As a biochemist I authentically and humbly do not obtain sufficient reason to obtain life from the non-living and so I will to be content, on finding how biochemical events happen. As an existing individual, I believe in God.

*Oncogenesis eventuates genetic mutation to epigenetic gene expression mechanisms with molecular signatures either inappropriately proscribed, incorrectly prescribed upon writing as  dangerous and deleterious, or erasure;  leaving a corrupted  chromatin result.

 *Tumor cells obtain proliferative autonomy, autophagous –self-maintenance in growth and signaling, neovascularization for nutrient and oxygen supply, and resistance to anti-proliferative and apoptotic stimuli 

*In resting cells, the cell cycle is strictly managed by a set of regulatory proteins that control the various cell cycle checkpoints and this will become dysfunction during the early transforming stage of the tumorigenesis via the unregulated dismantling of tumor suppressor genes 

*Suppression is the programmed deliberative  inhibition of biochemical events while repression is the unintentional inhibition of biochemical events

*When a biochemical  event is de-repressed it is brought back to register, regardless of valence

*In effect this dismantling is a repression of tumor suppressor gene transcription and/or  translation, post-translational modifications or final agency 

*This loss of gene suppressor “activity” can result from deletion, inactivating mutations, epigenetic silencing, incoherent post-translational modification(s) including glycosylation/acylation/prenylation/phosphorylation/aggregation etc.or lipid mediated transport aberrations as with membrane lipid rafts from Sphingomyelinase mediated ceramide synthesis.

*The typical biomedical result is oncogenesis(transformative) and ultimately tumorigenesis (committed), metastasis (mobilized and transactional) and either death or repair to healthy state.

*The progression of the mammalian cell cycle from G1 to mitosis is regulated by cyclins with their cogent catalytic subunits, the referred to as cyclin-dependent kinases (CDKs) 

*A family of cyclin–CDK inhibitor proteins (CDIs), which bind and inactivate the CDKs, includes the p16INK4a, p21CIP1, p27KIP1, and associated proteins p15INK4b, p18INK4c, p19INK4d and p57KIP2 

*These proteins potentially act as tumor suppressors and their inactivation corresponds with human carcinogenesis.

*Selective removal of CDK inhibitors may ablate senescent cell lineages in a process known as senolysis which may promote healthy cardiac muscle aging in the elderly

* In balance the square of opposition logical conclusion is to distinguish between contrarion vs. contradictory physiological and pharmaco-therapies.

Dr Daniel J. Guerra Authentic Biochemistry  Published on 10 February 2021

Refs

 EBioMedicine 2016 830-39DOI: (10.1016)

BMC Cancer volume 20, Article number: 882 (2020)

J Cardiol. 2019 Oct;74(4):313-319

Front. Neurosci., 24 July 2019 | https://doi.org/10.3389/fnins.2019.00728

Intra abdominal adiposity (IAA)  linked obesity may be the most significant contributory factor to high mortality human disease after aging.

IAA  presents with systemic and chronic inflammation and enlarged White Adipose Tissue (WAT) adipocytes that have been infiltrated with lymphocytes and macrophages that secrete pro-inflammatory cytokines, chemokines, growth factors and inappropriate levels of pro-inflammatory adipokines.

 Aging combined with chronic obesity not only promotes cardiovascular disease and cancer but further promotes autoimmune disease, dementia and high morbidity metabolic dysfunction, respiratory disease, and hyperimmune response to otherwise non-virulent pathogens linked to mortality.

International Scholarly Research Notices, vol. 2013, Article ID 139239, 12 pages, 2013. https://doi.org/10.1155/2013/139239

*Adipose tissue is the endocrine organ that secretes “adipokines”

*Nothing new to the Authentic Biochemistry crew; adipokines have been very well discussed here and their function as mediators of the feeding/appetitive/satiety response through the arcuate nucleus of the hypothalamus (POMCvNPY neurons) was most recently addressed.

*Adipokines mediate the BMI, heart rate, serum glucose &fatty acid/TAG, and pro- inflammatory cytokine production;they are released by adipocytes (e.g. leptin and adiponectin) or preadipocytes, adipose tissue-infiltrated immune cells, or the gastric system

Indeed, Th2 lymphocytes promote adipose glucose homeostasis by enhancing insulin sensitivity in adipocytes and browning/brown adipose tissue (BAT) activation but chronic inflammation of white adipose tissue (WAT) leads to the activation of pro-inflammatory pathways in adipocytes and resident immune cells following obesity involving the shutting down of Tregs and anti-inflammatory cytokines.

Front Physiol. 2020; 11: 578966

Indian J Pharmacol. 2012 Mar-Apr; 44(2): 155–156.

Cells. 2019 Mar; 8(3): 227.

Proceedings of The Nutrition Society.2012 71(4):521-33

Autophagy. 2009 May; 5(4): 558–560

Molecular and Cellular Endocrinology Volume 472, 5 September 2018, Pages 40-49

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