TCA and OxPHOS Flashcards
What is the TCA cycle? where does it happen?
-Oxidizing carbon fuels for
harvesting high energy
electrons (e-)
-Source of precursors for
biosynthesis
-in mitochondria matrix!
Where doe Acetyl CoA come from?
Carbs, lipids, proteins
How does pyruvate enter TCA cycle and what happens to it?
using MPC,
PDC makes it acetyl CoA
What does PDC need to have to be used?
Needs TPP from 1 complex, needs to be dephosphorylated
What is the clinical significance of PDC?
-In a phosphatase deficiency PDC is always in
phosphorylated form
-Glucose becomes Lactate rather than
Acetyl CoA
-Results in constant lactic
acidosis
-Alanine intake should be
restricted
What is step 1 of TCA cycle?
Acetyl CoA + Oxaloacetate becomes citrate (citrate synthetase)
What is step 3 of TCA cycle? what is made
Isocitrate becomes a ketoglutarate (isocitrate dehydrogenase)
makes NADH and CO2
What is step 4 of TCA Cycle ? what is made
a ketoglutarate goes to succinyl CoA (a ketoglutarate deydrogenase)
makes NADH and CO2
what is the rate limiting step of TCA cycle
Isocitrate becomes a ketoglutarate (isocitrate dehydrogenase) step 2
Regulated steps?
1, 3 and 4
When is TCA cycle most active?
When ATP levels are low in the cell, high ATP is opposite
What aa fill up fumarate?
Phe Tyr Asp
What aa fill up oxaloacetate?
Asn Asp
What aa fill up a keto glutamate ?
Gln, Pro, His , Asg
What aa fill up succinyl coa?
Thr, Met, Ile, Val
What is citrate used to make?
fatty acids
what is malate used to make?
glucose
what is 2-Oxoglutaric aciduria?
A rare disorder with global
developmental delay and
severe neurological
problems in infants
what is Fumarase deficiency?
Issue with fumarase gene
Characterized by severe
neurological impairment.
Fatal outcome within the
first 2 yrs. of life
Increased urinary
excretion of fumarate,
succinate, aketoglutarate, and citrate
Oncometabolites of TCA cycle?
- Citrate
- 2-hydroxyl glutarate
What does lower Eo mean?
has a lower affinity for
electrons; hence gives
them up easily to a redox
pair with a higher E0
inverse of G0
What is the purpose of Oxphos?
To transfer electrons from
NADH and FADH2 to O2
To establish a proton
gradient across the inner
mitochondrial membrane
To synthesize ATP
How does transfer of electrons work in oxphos?
The electron flows from the molecules with lower E0
to
that with highest E
ΔG0’ = -nƑ Δ E0
proton gradient established in oxphos? how?
Electron transfer through
the respiratory chain lead
to the pumping of H+ from
matrix to the innermitochondrial space
Two factors constitutes a
proton-motive force, what are they?
1) pH gradient (ΔpH)
2) Membrane
potential (ΔΨ)
How is ATP synthesized in oxphos?
Catalyzed by a large
membrane-bound protein
• ATP synthase (Complex V)
uses pmf to make ATP
Oligomycin disrupt what?
proton
transport through the complex v
What does coenzyme Q do?
receives electrons from complex 1 and 2, passes them to complex 3
not a prosthetic group btw
What does cytochrome c do?
takes electrons from complex 3, gives them to complex 4
what happens when electron transport is prohibited?
-A decrease in the pumping protons -A decrease in the protein gradient -Inhibition of ATP synthesis
what is oxphos sensitive to?
- O2
- [ATP/ADP] ratio
what does uncoupling do?
generates heat, not ATP made
-Protons (H+) reenter the mitochondrial
matrix from the intermembrane space
- TCA cycle and electron transfer to
O2 are accelerated
What does Malate-aspartate shuttle do?
NADH cannot enter into mitochondria so it does it
Malate from cytosol enters mito, becomes oxaloacetate to release NADH, cycle starts again
Operates in the heart, liver, and
kidneys
what does Glycerophosphate-shuttle do?
Generates FADH2
in the inner mitomembrane
Operates in skeletal muscle and
brain
What is Luft’s Disease?
first mitochondrial disease ,
– Uncoupling of oxidative phosphorylation was found
– High levels of Cytochrome-c oxidase
Causes of mitochondrial diseases
Primary cause :
– Defect in nuclear DNA (nDNA) encoding the mitochondrial proteins
– Defect in mitochondrial DNA (mDNA)
Secondary causes:
– Ischemia
– Reperfusion
– Cardiovascular diseases
What do mitochondrial diseases look like?
– Nervous system: seizures,ataxia,dementia, deafness, blindness
– Eyes : ptosis, external ophtalmolplegia,retinis pigmentosa with visual loss
– Skeletal muscle : Muscle weakness, fatigue, myopathy, exercise
intolerance, loss of coordination and balance
– Low energy production
– Increased free radical production
– Lactic acidosis
CoA what is it?
activator of acyl
groups
Energy from glucose versus fatty acids
Fa have more energy. 36 in glucose vs 129 in pal acid
Arsenite and lipoic acid ?
lipoic acid subunit (E2) of PDC is modified by arsenite , limits availability of lipoic acid
Beriberi and Wernicke-Korsakoff ? why do they happen?
body does not
have sufficient thiamine
PDC doenst work well
effects of citrate on rate-limiting enzymes?
High concentrations of citrate in a cell are indicative of an ATP-rich state, limits glucose catabolism
Rat poison inhibits the TCA cycle , how?
Fluoroacetate is a rat poison that inhibits the TCA cycle
Fuoroacetate
reacts with CoA to form fluoroacetyl CoA, which (instead of acetyl CoA)
condenses with oxaloacetate to produce fluorocitrate
Inhibis aconitase, citrase accumulates
Pyruvate carboxylase deficiency ?
A disruption in pyruvate carboxylase activity causes more pyruvate
to be converted to lactic acid than oxaloacetate, the fanner of which accu- mulates in the blood.
what are ferredoxins?
electron carriers in p450 systems mito
Ubiquinone radical , why is it relevant?
intermediate in the
transfer of electrons from CDmplex I to ubiquinone, as well as in the transfer from reduced ubiquinone to CDmplex Ill.
The ‘Q- can pass an electron
to 0 2 to generate the free radical superoxide ( ·O;Z) anion
what is cytochrome c and what does it do?
Cytochrome-c., induces a cascade of biochemical
reactions that result in the activation of a subfamily of cysteine proteases called caspases
causes apoptosis, can be a marker for apoptosis
LHON, what is it what does it do?
Complex 1 and 3 not working
Degenerated Optic nerve
Leigh syndrome
Complex 1 and 4
weak motor skills
What do ARAC and AZT do?
drugs that are uncouplers
Chemisosmosis theory?
transfer of electrons down a chain releases energy
what does rotenone do?
Rotenone is a potent inhibitor of NADH dehydrogenase (Complex I) of the mitochondrial electron
transport chain
Respiratory chain components encoded by mtDNA ?
every complex but complex II
Cyanide ? what does it do?
noncompetitive inhibitor of complex IV, rapid cell death
aspirin overdose? what happens?
At high concentrations, salicylate uncouples oxidative phosphorylation by disrupting the
proton gradient across the inner mitochondrial membrane and causes
the dissipation of energy as heat
Other electron transport systems?
P450, in ER, uses NADPH
Nucleoside analogue treatments, what do they do?
The activated drugs inhibit mitochondrial DNA polymerase and deplete mitochondrial DNA.
As a result, the synthesis of locally produced components of the respiratory chain, particularly in CDmplex I, is inhibited, leading to a loss of ATP
production.
what do Antiporters for phosphate/OH do?
phosphate imported in exchange for OH
Antiporter for ADP / ATP exchange what does it do?
translocase moves one ATP out and one ATP into matrix
Where do NADH and FADH2 come from?
NADH comes from TCA cycle, pyruvate oxidation and ketone body oxidation
FADH2 comes from multiple sources, such as succinate dehydrogenase
