10: TCA Flashcards
TCA cycle function
Oxidizes carbon fuels for harvesting high energy electrons
Is TCA catabolic or anabolic?
Amphibolic
Where does TCA take place?
Mito
Acetyl coA is the active form of what?
Acetate
What macromolecules can form acetyl CoA?
Carbs, lipids, and proteins
Two ways lipids can form acetyl CoA
TAGs -> FAs -> acetyl coA
Ketone bodies -> acetyl coA
Five PDC coenzymes and the vitamins they are derived from
TPP: B1 FAD: B2 NAD+: B3 CoA: B5 Lipoic acid: not from a vitamin
Where does phosphorylation occur on the PDC?
E1 complex, via TPP
What happens in a phosphatase deficiency?
PDC always inactive -> glucose goes to lactate -> lactic acidosis -> affects CNS
What does TCA do when there’s low cellular ATP?
Increases
Reducing power of a cell
NADH:NAD+ ratio
Two major things high citrate does
- Inhibits PFK-1 in glycolysis
2. Activates ACC in FA synthesis
What does high citrate indicate in a cell?
ATP-rich state
How does fluoroacetate work?
Reacts with CoA -> fluoroacetyl CoA -> competitive inhibitor of aconitase -> inhibited aconitase leads to citrate buildup -> inhibits citrate synthase
Two major anaplerotic reactions of TCA
- Degradation of AAs
2. Carboxylation of pyruvate
Degradation of AAs replenishes what four molecules in TCA?
- OAA
- a-ketoglutarate
- Succinyl CoA
- Fumarate
Carboxylation of pyruvate replenishes what molecules in TCA?
OAA
What cofactor does pyruvate carboxylase require?
Biotin
Are lipids anaplerotic?
No, they are degraded exclusively to acetyl CoA
Two classic TCA disorders and two recently discovered ones
Two classic: fumarase deficiency, 2-oxoglutaric aciduria
Two new: SCS deficiency, mitochondrial depletion syndrome
Overview of the two classical TCA disorders
Rare disorders with global developmental delays and severe neurological issues, with variable severity and typically lethal in first ten years of life
How to diagnose the two classic TCA disorders?
Urinalysis
Oncometabolites
Compounds that can be harmful if they build up
Two oncometabolites of TCA
- Citrate
2. 2HG (2-hydroxyglutarate)
PEP carboxykinase abormalities does what?
Promotes cancer cell growth
What type of cancer has been found linked to TCA dysfunctions?
Non-metastatic breast carcinoma
Citrate as an oncometabolite
- Reduces PDC activity -> more glycolysis
- Increased pyruvate accumulation -> lactic acid -> cancer growth
- activates ACC -> lipid synthesis -> tumorigenesis
What mutations cause accumulation of 2HG (2-hydroxyglutarate)?
Mutations in IDH1 and IDH2
Precursor of 2-hydroxyglutarate
A-ketoglutarates
What does excess 2HG lead to?
Gliomas
