Metabolism: TCA Cycle Flashcards
List 3 sources of acetyl-CoA
- glycogenolysis/glycolysis (glucose => pyruvate oxidation)
- triglyceride lipolysis and fatty acid beta oxidation
- proteolysis and deamination/oxidation of amino acids
What do deficiencies in PDH coenzymes lead to?
- deficiencies in B1, B2, B3, B5 cause inhibition of TCA cycle due to decreased levels of aCoA
- reduced energy production
How many ATP molecules are generated by 1 glucose molecule?
1 glu = 2 pyr = 2 aCoA
1 aCoA = 10 ATP
1 glu = 20 ATP
What is different about acetyl-CoA supplied by glycolysis vs fatty acid oxidation?
FA oxidation provides MANY more acetyl-CoA molecules => MUCH MORE ATP made
List fates of acetyl-CoA.
- TCA => ETC => ATP
- ketone body synthesis during starvation
- fatty acid and sterol synthesis
What is Coenzyme-A? (structure, function)
Structure: ATP + pantothenate + mercaptoethylamine + acetyl group (of various carbons)
Function: acyl carrier; transfers acetyl groups for degradation and synthesis
List net production of TCA.
3 NADH (2.5ATP/1 NADH) = 7.5 ATP 1 FADH2 (1.5ATP/1 NADH) = 1.5 ATP 1 GTP = 1 ATP (total 10 ATP) 2 CO2
Where does the TCA cycle occur?
mostly mitochondrial matrix, except succinate dehydrogenase on the inner membrane
What are the 3 stages of ATP production? Where do they occur?
- aCoA production (glycolysis occurs in cytosol; pyruvate transported into mitochondria => acetyl-CoA)
- TCA (matrix)
- ETC and oxidative phosphorylation (inner membrane)
What general reactions lead to ATP production?
- NADH/FADH2 oxidation to NAD+/FAD
- ADP + Pi => ATP
- 1/2 O2 => H2O
occurs simultaneously
What are the 2 ways to regulate TCA?
- fine control via allosteric regulation of enzymes
- coarse control via cellular environment
What 2 enzymes are involved in fine control of TCA?
- isocitrate dehydrogenase
- alpha-ketoglutarate dehydrogenase
Describe allosteric regulation of isocitrate dehydrogenase.
reaction: isocitrate => alpha-ketoglutarate
- activators: high ADP (need more energy)
- inhibitors: high ATP, NADH (sufficient energy; NADH inhibits PDH)
Describe allosteric regulation of alpha-ketoglutarate dehydrogenase.
reaction: alpha-ketoglutarate => succinyl-CoA
- activators: high Ca2+ (indicator of low energy)
- inhibitors: high ATP, NADH, GTP, succinyl-CoA (feedback inhibition, energy indicators)
What factors are involved in coarse control of TCA?
ATP, ADP, NADH, NAD+
aCoA
OAA
How does ATP/ADP/NADH/NAD+ affect coarse control?
Since reoxidation of NADH and ATP synthesis are joint, supply of ADP and ATP synthesis are rate-limiting steps.
How does cellular activity affect coarse control?
increased activity would deplete ATP stores and increase ADP supply => activate TCA
How do oxygen levels affect coarse control?
anaerobic conditions would prevent reoxidation of NADH => inhibition of TCA enzymes, PDH
=> can’t continue TCA without enough NAD+
How does OAA affect coarse control? Give 2 examples of things that affect its supply.
OAA is the substrate for the first step. OAA supply is affected by the amphibolic intertwining of TCA with other biosynthetic pathways.
ex: OAA used for AA synthesis
ex: OAA generated by AA breakdown
What are the 2 forms of PDH deficiency and their etiology?
- X-linked dominant mutation in E1 alpha
2. autosomal recessive various mutations
What can you expect in the serum of children with PDH deficiency?
elevated lactate, pyruvate, alanine
lactic acidosis
How do you treat PDH Deficiency?
thiamine
carnitine
lipoate
Describe etiology, symptoms, and tx of fumarase deficiency.
reaction: fumarate => malate
- autosomal recessive mutation
- symptoms = neurological deficits, encephalomyopathy, dystonia, elevated TCA intermediates in urine
- tx = nutritional supplementation, PT, wheelchair
What is fluoroacetate?
rat poison
blocks aconitase => blocks TCA
LETHAL
