Strong muscles, fast nerves and good memory......
Working hypothesis about the role of amino acids availability on proteins synthesis
Proteins synthesis requires 2 steps
- mRNA synthesis (the "wishful thinking" of the cell under the effect of hormones and cytokines)
- mRNA translation that requires ATP and all the AA required for full mRNA translation
As mRNA has a limited lifespan, in many conditions the availability of one or more specific amino acids and not the amount of mRNA can became the limiting factor for proteins synthesis
As the cells have plenty of mRNAs we can assume that the Percentage of AA in the proteins expressed by a cell is representative of the local AA concentration.
Cytokines are signaling molecules: which is their information content?
IL6 and TNF have low Tryptophan - Trp
IL6 has high Leu, an inducer of mTOR that activates protein synthesis
TNF has low Met, that is high in mTOR (ca 4%)
AA % Proprietary Free Software
Aminoacids (AA) are mostly supplied by dietary proteins.
There are many Essential Aminoacids that cannot be synthesized by man:
Isoleucine
Leucine
Lysine
Methionine
Phenylalanine
Threonine
Tryptophan
Valine
Proteins are fully digested in the gut and aminoacids are carried to liver by portal vein.
The liver uses free AA to sinthesize plasma proteins that are released into the blood stream
- Albumin 35/55 g/l (half life: 21 days)
- Acute Phase Protein, negative
- Transferrin 2,04/3,6 g/l (half life 8/10 days)
- Acute Phase Protein, negative
- Fibrinogen 2,5/4,5 g/l (half life 7 days)
- Acute Phase Protein, positive
- free AA ca 0,3 g/l (mostly from tissues to liver)
Fibrinogen (average of the 3 chains: A, B, G)
Open Questions:
- Why to use proteins insted of free aminoacids?
- Why the liver is altruist and produces proteins for the other tissues and not for itself?
- Why albumin?
- How is albumin synthesis regulated?
From blood to tissues
- Inhibitor of neutral protease 40 kDa
- Albumin 66 kDa
- Transferrin 76.5 kDa
- Fibrinogen 340 kDa (FbA 70, FbB 56, FbC 51)
From extracellular fluid to cell interior
Plasma proteins cannot leave the blood unless the vessels became permeable.
Vascular permeability is regulated by local HIF/VEGF system.
Smaller stress induces small permeability increase (up to 70 Kd) higher stress induce increase of permeability up to 400 Kd, allowing fibrinogen efflux.
Local AA concentration affects protein synthesis
Availability of essential amino acids according to local conditions (starvation, low or high oxygen, tissue, cell cycle phase etc.) may be a limiting factor in protein synthesis, whatever the mRNA level. (Human Protein Cluster Analysis Using Amino Acid Frequencies, 2013) The clustering of proteins may prove a valuable tool in identifying so far unknown metabolic connections and constraints.
Fibrinogen as a nutrient
Fibrinogen is synthesized mainly in the liver and its synthesis is regulated by IL-6 via the STAT3 system in liver.
Bone Marrow Graft (Federico Sizzano Thesis 2004)
Fibrin fragments are the best nutrient for proliferating cells
Amorphous patch of fibrin with cells embedded in the matrix (normal bone marrow.
Breast Cancer Graft in c/balb mouse
Albumin as a nutrient
- Albumin in vitro inhibits cell proliferation and favours differentiation (personal data)
- Low serum albumin like in cirrhosis leads to sarcopenia
Albumin is the best nutrient for differentiated cells
Regulation of proteins uptake and digestion in Lysosomes
To get this.....
you need a lot of acid....
Back to the First Rule
PPI are inhibitors of V-ATPases
1,25(OH)2 Vitamin D is a powerful activator of V-ATPases
CFTR may be genetically different or locally up and down regulated.
Regulation of Albumin/Fibrinogen ratio in Liver
- the total amount of proteins depends on dietary proteins supply
- both synthesis requires ATP
- IL-6 serum level drives Fibrinogen synthesis
- lowering serum IL-6 should decrease Fibrinogen and increase Albumin. How?
