Metabolism 3: CAC Flashcards
Where is Acetyl CoA formed?
Mitochondria
What can Acetyl-CoA be used for?
ketone bodies, CAC, fatty acids, sterols
What can form Acetyl-CoA
Pyruvate (oxidaiton) Fatty Acids (beta ox) Amino acids (Deamination and oxidation)
What are the 3 places we get NADH in the TCA cycle?
Isocitrate ->a-ketoglutarate
a-ketoglutarate->succinyl-CoA
Malate -> Oxaloaceteate
Where do we get GTP formed in TCA cycle?
Succinyl CoA -> Succinate
Where do we get FADH2 formed in TCA cycle?
succinate -> fumarate
List the sequence of substances of hte TCA cycle starting from Pyruvate
pyruvate -> Acetyl CoA -> citrate -> isocitrate ->a-ketoglutarate -> succinyl CoA -> succinate -> fumarate -> malate -> oxaloacetate
Where does CAC take place?
Primarily in the mitochondria inner membrane and matrix where hte CAC enzymes are located
How do we go from a 6C compound to oxaloacetate, a 4C compound at the end of CAC
Lose 2 C in form of carbon dioxide via oxidation
What happens to the NADH generated?
Used within mitochondria in the ETC rxn to generate ATP, which is then exported out of the mitochondria as ADP is imported in
In total, what is generated in cycle of the CAC
3 NADH, 1 FADH2, 1 GTP, 2CO2
How many ATP/GTP is generated by 1 round of CAC
10 (9 ATP: 7.5 from 3 NADH, 1.5 from FADH2 and 1 GTP)
Where does the ATP come from?
Electron transfer from substrates to molecular Oxygen provides energy to create ATP as well as water
What are the course control regulations of the citric acid cycle?
Major mechanism for regulation; important for exercise, flight or fight response
levels of ADP(rate limiting):
NADH, FADH2,
Acetyl CoA: related to PDH and transport of fatty acids to mitochondria
Oxaloacetate: affected by pathways depleting CAC intermediates
What are the fine control regulators of the CAC?
Under baseline condition: no desperate need for energy
Allosteric regulation
Isocitrate dehydrogenase
a-ketoglutarate dehydrogenase
Does higher concentration of ATP, GTP, and NADH stimulate or inhibit CAC?
inhibits
Does higher concentration of ADP and calcium stimulate or inhibit CAC?
stimulate
What are the activators /inhibitors for isocitrate dehydrogenase
Fine control regulation
Activator: ADP
Inhibitors: ATP, NADH
What are the activators/inhibitors for a-ketoglutarate dehydrogenase?
Fine control regulation
Activator: Calcium
Inhibitor: NADH, Succinyl CoA, ATP, GTP
What happens wiht high cellular activity in course control
ATP decreases and ADP increases -> increases CAC activity
What happens with low oxygen in course control
Increased NADH, FADH2 -> lack of NAD+ and FAD will decrease CAC
What CAC intermediate contributes to fatty acid and sterol synthesis?
Citrate
What CAC intermediate contributes to amino acid synthesis?
a-ketoglutarate
Oxaloacetate
What CAC intermediate contributes to gluconeogenesis?
Malate
What CAC intermediate contributes to heme synthesis?
Succinyl CoA
What can replenish a-ketoglutarate in the CAC
amino acid (glutamate)
What can replenish succinyl coA in the CAC
Valine and Isoleucine -> propioniyl CoA -> Succinyl CoA
What can replenish fumarate in the CAC
amino acids (aspartate, phenylalanine, tyrosine)
What can replenish oxaloacetate in the CAC
Aspartate
What can replenish pyruvate?
Amino acids
What casues PDH deficiency?
mutations in E1 alpha gene -> E1 becomes inactive
Inherited in X linked dominant (all others are autosomal recessive)
What is typically seen with PDH deficiency in children?
inc serum lactate, pyruvate, alanine
chronic lactic acidosis
cyst formation
How is PDH deficiency treated?
dietary supplementation with thiamine, carnitine, and lipoic acids
What causes fumarase deficiency?
Mutations in the fumarase gene and disrupts the conversion of fumarate to malate and thus the CAC
What are some sx seen with fumarase deficiency?
Severe Neurological Impairment: Encephalopathy, Dystonia
Increased urinary excretion of fumarate, succinate, a-ketoglutarate, citrate
What are treatments for fumarase deficiency
no effective treatment currently
What can fluoroacetate (rat poison) do?
Directly inhibits aconitase which converts citrate to cis aconitate in the CAC before changing to isocitrate
Inhibits the CAC
