TCA cycle Flashcards
What does the TCA cycle produce
Where does the TCA cycle occur
What is the main Rate deteriming enzyme and what are its regulators
The TCA cycle produces 3 NADH, 1 FADH2, 2 CO2, 1 GTP for every molecule of AcetylCoA
(when the NADH and FADH got to the ETC, they yield 10 ATP)
TCA Reactions occur in the mitochondria
Main Rate determining enzyme: Isocitrate dehydrogenase (inhibited by ATP and NADH, activated by ADP)
Purpose of TCA cycle and outcomes
Central Role in intermediary metabolism
Oxidation of common metabolic intermediates to CO2
Energy released released by oxidation is captured by NADH, FADH2, and GTP
Energy of NADH and FADH2 is transformed into energy of ATP by oxidative phosphorylation
AcetylCoA (from pyruvate or fatty acid) is the primary substrate
The pathway also uses carbon skeletons of many AAs and other metabolites for energy production
TCA regulated to balance production and need for energy /metabolic intermediates
Redox Rxns
oxygen is a good primer for redox reaction
Lactate is oxidized to pyruvate
Pyruvate is reduced to lactate
Which reactions account for most of the CO2 made by the body
isocitrate–> aKG (via isocitrate dehydrogenase)
aKG-> succinylCoA (via aKG dehydrogenase)
Both make CO2 + NADH + H
Citrate synthase
catalyzes the condensation of Acetyl CoA and OAA
it has a thioester bonds so its thermodynamically favored forward directions
Aconitase
reaction is redily reversible has an Iron sulfer center at its active site
Isocitrate dehydrogenase
NADH captures the energy of OH oxidation
removes a CO2
forms a KG
alpha Keto glutarate dehydrogenase
complex contains 5 cofactors:
- thyamin pyrophosphate
- Lipoic Acid
- CoA
- FAD
- NAD
3,5 are stereometric, 12 4 are the catalytic cofactors
Regulated by alpha ketoglutarate dehydrogenase by products (CO2, NADH, succinyl CoA, ATP)
It still has energetic potential (a thioester bond is formed)
Succinyl CoA synthase
harvests the energy of the thioester bond thru making GTP and Succinate
It shows substrate level phosphorylation
Succinate is symetric
Succinate Dehydrogenase
makes fumarate
energy is captured by FADH2 (Fadh2 is made with Fumarate)
Only enzyme of TCA cycle thats not in the mito matrix but in the inner mito membrane
Contains FeS (like aconitase)
succinate dehydrogenase is complex 2 of ETC, FADH2 feeds its electrons to mito ETC downstream from NADH and therefore generates one less ATP than NADH
Fumarase
adds water make malate
malate dehydrogenase
reaction is similar to that catalyzed by lactate dehydrogenase and is reversible
equilibrium is unfavorable in the forward direction but TCA constantly uses up OAA so it pulls it forward, also NAD is high in Mito so it pushes the reaction forward because it makes NADH
Regulation of TCA cycle
regulated to maintain ATP, ADP, NAD, NADH levels
Succinyl CoA is an additional regulatory signal
3 major sites of regulation (4th not in TCA)
PDH
Citrate synthase (inhibited by ATP/NADH/ succinyl CoA and availability of OAA)
Isocitrate dehydrogenase (the key regulatory step, inhibited by ATP/ NADH, activated by ADP/ AMP)- inhibition of isocitrate dehydrogenase leads to an increase in Citrate which leads to FA synthesis
alpha KG dehydrogenase: inhibited by (ATP/GTP/NADH/ Succinyl CoA) some tissues activated by Ca++. NOT regulated by phosphorylation
Isocitrate dehydrogenase regulation
negatively regulated by ATP/ NADH
positively regulated by AMP/ ADP
Controlling isocitrate is important bc you can increase citrate and therefore inhibit PFK1 (and stop glycolysis to stop making pyruvate and acetyl CoA)
Sources of Acetyl CoA
PDH complex (takes carbs and AAs to degrade to pyruvate)
FA oxidation: FAs yield acetyl CoA when catabolized/ oxidized
Amino acids: isoleucine, leucine, tryptophan are catabolized to acetyl CoA
Ethanol (yields acetyl CoA, 2 NADH, using an ATP)
with heavy alcohol use you increase NADH rxns and interferes with gluconeogenisis and makes them hypoglycemic
