Fates of pyruvate Flashcards
What are the major metabolic fates of pyruvate?
Pyruvate can be converted into:
1)Lactate in anaerobic conditions.
2) Acetyl-CoA for entry into the citric acid cycle.
3) Oxaloacetate for gluconeogenesis or the citric acid cycle.
4) Alanine through transamination.
draw pyruvate
What role does pyruvate play in the Cori Cycle?
In the Cori Cycle, lactate produced by anaerobic glycolysis in muscles is transported to the liver, where it is converted back to pyruvate and then into glucose through gluconeogenesis
What is the role of lactate in anaerobic metabolism?
In anaerobic conditions, pyruvate is reduced to lactate to regenerate NAD+, which allows glycolysis to continue producing ATP when oxygen is limited
how is excess lactate production by the muscle cells dealt with?
in the cori cycle
-lactate is taken to the liver to be converted to glucose
what cells always produce lactate? why?
RBC’s because they lack mitochondria
what 2 pathways is oxaloacete an intermediate in?
CAC and gluconeogenesis
what enzyme converts pyruvate to lactate? what does the direction of the rxn depend on?
lactate dehydrogenase (LDH)
-depends on the [P/R]
why can’t lactate be used as fuel in the muscle cells during anaerobic conditions?
in aerobic conditions, lactate would build up and rxn would go in reverse (generating pyruvate and NADH) there is no way to reduce NADH as the ETC will not be working in anaerobic conditions
Why does transport of lactate cause decreases in pH?
because it it transported with H+
what transporter transfers lactate out into the bloodstream?
H+ linked monocarboxylate transporter
explain metabolically why people who excercise more are better at handling lactate metabolism?
exercise increases transription of the gene that produced the transporter respondible for lactate transport
how does pH changes from lactate production affect oxygen affinitty for Hb?
affinity of O2 for Hb decreases when pH decreases
-H+ binds to the heme group in Hb which stabilizes the T state and increases the ability for 2,3BPG to bind (causing O2 affinity to decrease)
how efficient is glycolysis (in a percent) ?
31%
what is the overall rxn from glucose to lactate?
where does the conversion of pyruvate to lactate occur?
cytosol
how does pH change from the prodcution of lactate in the blood cells vs muscle cells?
decreased pH in blood cells and increased pH in muscle cells
when lactate is converted to pyruvate what kind of metabolic reaction is this?
oxidation
during the cori cycle, where does the energy needed to synthesize glucose in the liver come from?
from the oxidation of fatty acids
where does the oxidation of pyruvate to acetyl coA occur?
mitochondrial matrix
how is pyruvate transferred from the cytosol to the mitochondrial matrix?
1) transfer across outer mitochondrial membrane
2) transefer across inner mitochondrial membrane using pyruvate translocase
what kind of transporter is the pyruvate translocase? what does this mean in terms of how it transports glucose?
H+ linked monocarboxylate transporter
-uses a H+ to transport pyruvate
what 3 types of reactions occur during the conversion of pyruvate to acetyl coA?
1) oxidation
2) Decarboxylation
3) Transacetylation
what 5 cofactors are present in the PDH complex? how are they differentiated?
Loosley bound: CoA and NAD+
-leave as NADH and Acetyl-coA
Tightly bound: TPP, Lipoamide, FAD
what prosthetic groups regulate E1, E2 and E3?
E1-TPP
E2-Lipoamide
E3-FAD
what is the primary way the PDH complex is regulated?
phosphorylation and dephosphorylation
what kind of enzymes are E1 and E3?
dehydrogenases
how does lipodamides structure relate to its name? (what is it comprised of)
Lipoic acid + lysine
(bound by an amide bond)
what forms can the lipoamide swinging arm exist in?
1) reduced form (dihydrolipoamide)
2) oxidized form (disulphide bond in ring structure)
3) Acetylated bond (contains thioester bond)
what is the rate limiting step of the PDH complex rxn?
The removal of CO2 and attachment of hydroxyethyl group to TPP
-slowest step
What cofactor is required for rxn 1 of the PDC?
TPP
what occurs in step 2of the PDC? what cofactor is required?
Reductive acetylation of lipoamide
Catalyzed by E2 using TPP and lipoamide
(TPP giving up, lipoamide accepting the Hydroxyethyl group)
what occurs in step 3 of the PDC?what cofactor is required?
Transesterification of coA to break a thioester bond and create a new one
-transfer of acetate to coA
catalyzed by E2 uses lipoamide and coA
(transfer from lipoamide to coA)
Why does dihydrolipoamide need to be reoxidized in the PDC? what catalyzes this?
required for step 2 to occur again
E3 uses FAD to oxidize
whe Acetyl-coA is produced from the PDC, where does it go?
has many options:
CAC
FA, cholesterol and ketone synthesis
what occurs in step 4 of the PDC? what cofactor is needed?
the reduced lipoamide from step 3 is reoxidized by the reactive disulphide group (very similar to FAD)
- E3 uses reduced lipoamide and FAD as cofactor
how is the reduced cyclic amide bond (FAD) oxidized to allow step 4 to continue to occur?
NAD+ picks up 2H+ from the reduced cyclic bond (FADH2) and becomes NADH + H+
-oxidized the cyclic amide back to FAD to be able to be used in step 4 again
why is NADH needed in the PDC? why cant FADH2 be used?
FAD is a prosthetic group and cannot leave the complex, electrons must be transferred to NADH so it can leave the complex
how many protons are produced overall from the PDC?
none
a proton is needed to start the reaction, and a proton leaves the complex with the generation of NADH
TRUE or FALSE: E1 catalyzes step 1 and 2 of the PDC?
true
what is the initial substrate of the PDC?
pyruvate
how is the PDC regulated?
Through phosphorylation and dephosphorylation of E1
Phosphorylation: inactivates E1
Dephosphorylation: activates E1
what enzyme removes the phosphate on E1? how does this affect the reaction?
Pyruvate dehydrogenase phosphotase
- activates the enzyme at E1 to allow the reaction to proceed
what enzyme adds a phosphate on E1? how does this affect the reaction?
Pruvate dehydrogenase kinase
-inactivates the enzyme in E1 to prevent the reaction from occuring
what substrates act as allosteric activators of the PDC? how do they do this?
ADP, Pyruvate and coA INHIBIT the kinase, preventing phosphorylation of E1
Ca2+ and insulin ACTIVATE the phosphotase
what substrates are allosteric inhibitors of the PDC? how do they do this?
Acetyl-coA and NADH activate the kinase, causing phosphorylation of E1 enzymes, inactivating the PDC
How dooes product accumlation affect E2 and E3?
Acetyl-coA inhibits E2
NADH inhibits E3
what is beriberi?
Cluster of diseases resulting from vit B1 deficiency
-Vit B1 needed to make TPP
How does Beriberi cause neurological disorders?
Beriberi results from Vit B1 deficiency which is needed to make TPP, TPP is essential for E1 to function
-If E1 can’t function the PDC complex activityy is reduced, leading to an inibility for glucose to be broken down and sent to CAC
-Energy supply for the brain would be lilited causing neroligical disorders
