Tissue Specificity of Amino Acid Metablolism
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- Which enzyme is need to convert BCAA to BCKA?
- BCAA aminotransferase
- Do muscles have a high concentration of BCKA dehydrogenase? What is the consequence of this?
- a) No⬦ b) after BCAA --> BCKA, the BCKA is sent into the circulation for use by other tissues.
- Besides BCKA, what is the other immediate product of BCAA aminotransferase?
- Glutamate
- What are the 4 possible outcomes for glutamate derived from the BCAA aminotransferase in the muscle? (Hint: think in terms of what can you do with glutamate)
- 1. Transamination with pyruvate to make alanine⬦ 2. Transamination with oxaloacetate to form aspartate, whose amino group can be liberated as ammonia⬦ 3. NH4 can be added to its side chain to form Gln (via glutamine synthase and ATP)⬦ 4. It can be used as a substrate by glutamate dehydrdogenase to yield ammonia (urea cycle)
- What is the take home message of BCAA to the muscles?
- muscles can use BCAA for protein synthesis or transaminate to BCKA⬦ and the glutamate will be used to form Gln or Ala
- What happens to Gln and Ala produced in the muscle as a result of BCAA to BCKA transamination?
- transported out of the muscle
- What stimulates glutamine synthase? (Hint: this is not intuitive... it's just an added detail of this Nitrogen addition rxn in muscle)
- high [H+] and [glucocoritcoid]
- Where does the second NH4 come from in glutamine synthesis?
- 1. From a glutamate molecule itself using glutamate dehydrogenase⬦ 2. From aspartate formed from the oxaloacetate when transaminated by glutamate
- What is a way BCKA can be metabolized in muscle, even though the BCKA dehydrogenase concentrations are low? (expanation should include specific amino acids and (?) intermediates.)
- Through anapleurotic rxns of the TCA cycle: Val and Ile can enter the TCA cycle through Succinyl CoA⬦ they are then converted to pyruvate from malate by decarboxylating malate dehydrogenase.
- What are possible fates of pyruvate?
- alanine or acetyl CoA
- What is the fate of alanine's nitrogen produced in the muscle through BCAA to BCKA metabolism?
- The glucose-alanine cycle: alanine in the liver can be transaminated to pyruvate, the nitrogen is used either in aspartate (plug into the urea cycle) or glutamate (deaminated by glutamate dehydrogenase)⬦ in either case the nitrogen can enter the urea cycle.
- What is the energetic use of pyruvate as a consequence of BCAA? (Hint: genesis)
- it can support glucogenesis: pyruvate --> oxaloacetate (via pyruvate carboxylase); then oxaloacetate --> PEP (via PEPCK) --> glucogenic pathway⬦ Glucose can be sent back to tissue, which in turn can convert to pyruvate and then back to alanine, then sent back to the liver... thus a cycle.
- What are two useful purposes of the glucose-alanine cycle?
- 1. continuous supply of glucose to tissues⬦ 2. safe transport of nitrogen in the circulation.
- What is the preferred fuel source for tissue that have a high rate of cell turnover, such as the gut or immune system? Why? (Hint: what do cell's with high turn do? so what do they need?)
- glutamine⬦ DNA synthesis, where glutamine is the major source for nitrogen
- Where does the gut deliver ammonia? Why is this okay?
- the circulation⬦ (portal circulation) to the liver where it is packaged as urea
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(a) What does the oxidation of glutamine in the intestinal epithelial cell result in?
(b) Where does the product go?
(Hint: the intestines work with the kidneys on this one) -
(a) glutamine --> citrulline and ornithine + NH+
(b) intestines -> Kidney - Describe arginine synthesis by the intestines and the kidneys. (hint: think urea cycles ÷ 2 organs)
- a. glutamine enters gut⬦ b. converted to ornitine (enters mitochondria)⬦ c. converted to citrulline (like the urea cycle)⬦ d) citrulline is exported and enters the kidney⬦ e. citrulline (+ aspartate) is converted to arginosuccinate by arginosuccinate synthase⬦ f. arginosuccinase converts arginosuccinate to arginine and fumarate... arginine enters circulation.
- Why can't the intestinal epithelia make arginine?
- it lacks arginosuccinate synhtase
- How do the kidneys use glutamine?
- it uses it as a pH buffer in the urine
- What does a decrease in pH produce in the kidneys?
- renal glutamase, which causes the deamidation of glutamine
- Why is it necessary to maintain a proper pH in the renal tubules?
- membrane transporters wil not function out of their pH range.
- Can the brain use BCAA? What makes this possible?
- yes, the brain has BCAA transaminase
- What is one of the uses the brain has for glutamate (produced from the metabolism of BCAA or glutamine in the circulation)?
- Glutamate can be decarboxylated by neurons (by glutamate decarboxylase) to form GABA (a NT)... (Note this is the GABA shunt from the TCA cycle)
- In terms of export of BCKA, which organs are similar in their use of BCAA?
- brain and muscle
- Which organs export and which import glutamine?
- import: intestine (cell turnover) /kidney (pH control)⬦ export: brain/muscle
- The following questions are from the Pernicious Anema Lecture:
- Continue to next question
- What happens after the IF-B12 complex is taken up by receptor mediated tranport in the ileum?
- B12 is release from IF and bound to transcobalamin (TC)
- What causes the accumulation of dUMP, abberant DNA replication and inaccurate DNA repair?
- insufficient B12 (no recycling of Folate)⬦ megaloblastic anemia may result
- What is the common cause of pernicious anemia?
- vitamin B12 deficiency
- What are the histological presentation of pernicious anemia?
- hypersegmented neutrophils, panyctopenia (fewer of all cells), Megaloblastic precursors with large nuclei and increased apoptosis. (larger, yet fewer cells).
- What are the physiologic causes of the inability to absorb B12 in pernicious anemia?
- Atrophic gastric epithelia: loss of parietal cells (produce IF), achlorhydria or hypochlorhydria and minimal IF production.
- Why is it that achlorhydria or hypochlorhydria can cause a deficiency in B12?
- failure to degrade B12 binders in food.
- What causes atrophic epithelia (no longer able to produce needed factors and/or HCL) in pernicious anemia?
- chronic gastritis, which may cause an autoimmune rxn, and/or a breakdown of the gastric barrier to stomach acid.
- In pernicious anemia, what is the target of the autoimmune attack?
- parieta cell proton pumps, or IF itself.
- What are people with pernicious anemia prone to?
- gastric epithelia may be metaplastic⬦ and thus have a higher rate of cancer.
- Name 3 function of B12.
- 1. Folate recycle: DNA replication and repair is affected here⬦ 2. Homocysteine conversion to methionine (cardiovascular disease)⬦ 3. Fatty acid metabolism: deficiencies may lead to FA acculmation
- In the stomach, what happens to intrinsically bound B12 in food stuff?
- low pH breaks down food binder on B12, the R-Binder has high affinity to B12.
- What happens in the neurtal pH of the duodenum?
- degradation of R-binder and binding of B12 to IF
- What are the neurological effects of a B12 deficiency
- spinal cord demyelination⬦loss of axons, numbness, tingling, ataxia, memory loss
- can the neurological effects caused by B12 deficiency be reversed?
- no