Glycogen, TCA Cycle and Mitochondria (Lecture 9) Flashcards
what does pyruvate dehydrogenase do and where is it found?
found in the mitochondria
this enzyme catalyzes the reaction of pyruvate + CoA + NAD+ –> acetyl-CoA + CO2 + NADH
how does pyruvate get into the mitochondria?
since glycolysis occurs in the cytoplasm, pyruvate will enter ht mitochondria via a pyruvate translocate (H+ symport)
what is the carbon entry point in CAC?
acetyl CoA
what’s the purpose of CAC?
make reducing equivalents to donate electrons to the ETC
pyruvate dehydrogenase complex is
a massive multi-enzyme complex
contains E1, E2, E3, E3 -binding protein, pyruvate dehydrogenase kinase, pyruvate dehydrogenase phosphatase
5 coenzymes are required:
TPP, lipoid acids, CoA, FAD, NAD+
why re the active sites of pyruvate dehydrogenase complex in close proximity to one another?
so that the product of E1 is passed onto the second and so on
E1 reaction
nucleophilic attack but thiamine pyrophosphatate (TPP) leadidn to a decarboxylation
C1 of pyruvate released as CO2
C2 and C3 attached to TPP as a hydroxyethyl group
this commits the PDC to generate acetyl coa, since its irreversible. it is irreversible because CO2 diffuses out of the mitochondria
in other words E1 is bound to TPP, which is required for catalysis. E1 will decarboxylate the pyruvate molecule and generate hydroxyethyl TPP
E2
catalyzes the reversible steps 2 and 3
I step the hydroxyehtyl group of hydroxyethyl-TPP is oxidized to acetic acid to form acetyl-dihydrolipoamide
these 2 electrons removed in the oxidation will reduce the S-S of the lipoyl group to SH. this thirster bond is a high energy intermediate
step 2 regerates TPP to decarboxylate another pyruvate
step 3: the trans-esterification to CoA to form acetyl coa
lipoamide is E2’s swinging arm because it is used to
perform substrate channeling between E1-E3
coenzyme A fucntion
carrier of acetyl and other acyl groups
E3
catalyses the reversible reactions of steps 4 and 5
the aim is the reset E2 and E3 in their active states and regernaets FAD and produces NADH
- oxidation-reduction reaction that generates the oxidized E2 lipoamide (done via FAD)
- enzyme bound FADH2 reoxidizes to FAD via NAD+ thus generating NADH 9transfer of e-)
PDC generates and where do these substrates go?
acetyl coa for CAC
NADH oxidative phosphoryaltion
CO2 diffused out of mitochondria
advantages of multi enzyme complexes
minimize distance for subtracters in between the active sites. this increases the reaction rate without having to maintain large pools or intermediates
metabolic intermediates are channeled between successive enzyme sites
- side reactions are minimized
- protection for them,ically labile intermediates
coordinate the control of reaction by shutting one enzyme off, it’ll shut the system off
conversion of pyruvate to acetyl coa will
commit glucose carbons to oxidation in CAC or FA synthesis as for animals cant synthesize glucose from acetyl coa
regulation of the PDC
2 levels:
product inhibition via NADH and acetyl coa (produced in steps 5 and 3)
covalent modification via phosphorylation of E1 (pyruvate dehydrogenase)
the phosphorylation of E1 makes it inactive
what occurs during product inhibition
when acetyl coa or NADH levels are high the reactions 3 and 5 run backwards
- acetyl coa + dihydrolipoamide –> coa + acetyl dihydrolipoamide
- FAD-SS + NADH –>NAD+ + FADH2
this prevents useless consumption of pyruvate
when pyruvate builds up in the liver, then gluconeogensis can occur, thus increasing eh lactate in muscle to go through the cori cycle
regulation of PDC via phosphorylation
inactivation via PDK
- PDK allosterically activated but acetyl coa and NADH
- PDK phosphorylated E1
- E1 is inactive and shuts down he PDC
PDK is allosterically inhibited by ADP, Ca2+
reactivation via PDP
- PDP allosterically activated by Ca2+
- PDP dephosphoryaltes E1
- E1 active
utilization of pyruvate is controlled by
PDC and LDH
what occurs in cancer cells with PDC activity
PDC activity is suppressed by PDK phosphorylation.
pyruvate is instead converted into lactate via the Warburg effect
cancer cells have hyper active PDK, which inactivates the conversion of pyruvate to acetyl coa , thus resulting in an accumulation of lactate
regulation of PDC when stop running
muscle at rest
no need for ATP
acetyl coa and NADH accumulate, E2 E3 are off via product inhibition
E1 is off via phosphorylation
regulation of PDC when start running
need to produce ATP
activate glycolysis to produce pyruvate
blocks PDK active E1
Ca2+ increases for mscuel contraction, thus activates PDP to keep E1 on
