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What are the 3 stages of pyruvate carbon oxidation?
- 1) pyruvate dehydrogenase reaction: oxidation of one carbon atom of pyruvate to CO2, electron transfer to coenzyme NAD+, & 2-carbon fragment activation by forming acetylCoA
- 2) tricarboxylic acid cycle (citric acid cycle): 2 more CO2 are formed and 4 more pairs of electrons are transferred from the substrate to coenzymes NAD+ & FAD (8 reactions)
- 3) electrons are transported through a series of electron carriers & are ultimately transferred to molecular oxygen with the formation of water. The free energy of electron transfer is conserved by forming ATP, & the net result is up to 38 moles ATP per mole glucose
What are the alternative fates of pyruvate?
- can undergo transamination to form alanine
- can be reduced to lactate
- undergo carboxylation to form oxaloacetate
- *can undergo oxidative carboxylation to form acetyl CoA, which gets translocated into the mitochondria, and enters the TCA cycle!
when an energy-rich intermediate transfers its phosphate group to ADP, forming ATP, without requiring oxygen
- the production of ATP via the electron transport chain and ATP synthase
- the phosphorylation step is separated from the oxidation step
In which cellular compartment does the TCA cycle occur?
pyruvate dehydrogenase complex
- multienzyme aggregate that irreversibly oxidizes pyruvate to acetyl-CoA
- one carbon of pyruvate is oxidized to CO2, & electrons are transferred to NAD+ (forming NADH)
Which three enzymes constitute the pyruvate dehydrogenase complex?
- Pyruvate decarboxylase (E1)
- dihydrolipoyl transacetylase (E2)
- dihydrolipoyl dehydrogenase (E3)
What are the coenzymes of the pyruvate dehydrogenase reaction?
- CoASH (Coenzyme A/acetyl Coenzyme A)
- TPP (thiamine pyrophosphate)
Coenzyme A/acetyl Coenzyme A (CoASH)
a pyruvate dehydrogenase coenzyme that accepts an acyl group from lipoate, forming acetyl-CoA
- a central intermediate of metabolism that can also be formed from the breakdown of fatty acids and from some amino acids
- coenzyme A carries the acyl groups via a thiol ester linkage; synthesis of acyl CoA is a way of activating an acyl group by thiol ester bond formation (a high energy bond = to the pyrophosphate bond in ATP)
Coenzyme A serves as a carrier of acyl groups in many metabolic reactions. What high energy bond is formed between CoASH and acyl groups?
thiol ester bond
thiamine pyrophosphate (TPP)
the coenzyme binds and rapidly decarboxylates the ketoacid pyruvate which leaves the residual 2-carbon hydroxyethyl fragment bound to the coenzyme
Thiamine pyrophosphate (TPP) is bound to which enzyme in the pyruvate dehydrogenase complex?
pyruvate decarboxylase (E1)
From which vitamin is the coenzyme thiamine pyrophosphate (TPP) derived?
Vitamin B1 (thiamine)
Name two medical conditions associated with thiamine deficiency
Beri-beri & Wernicke-Korsakoff syndrome
- a coenzyme of dihydrolipoyl transacetylase (E2) which receives the 2-carbon hydroxyethyl from TPP, and proceeds to transfer the acetyl group to CoA and the electrons to FAD [which can be found on E3 (dihydrolipoyl dehydrogenase)]
- the transfer of electrons to FAD returns lipoate to its usual oxidized state
FAD (flavin adenine dinucleotide)
- accepts electrons from the reduced lipoate, regenerating oxidized lipoate and forming FADH2, which stays bound to the enzyme complex
- derived from the riboflavin (a B vitamin)
accepts electrons from FADH2, regenerating enzyme-bound FAD
What are inhibitors/activators of the pyruvate dehydrogenase complex?
- Inhibitors: NADH, acetyl CoA, phosphorylated serine
- Activators: pyruvate, insulin, Ca2+
- acetyl CoA inhibits E2 (dihydrolipoyl transacetylase)
- NADH inhibits E3 (dihydrolipoyl dehydrogenase component)
- acetyl CoA & NADH promote a specific kinase to phosphorylate a serine on E1 --> inhibits the complex
- pyruvate inhibits the kinase --> activating the complex
- insulin activates a phosphatase that removes the serine phosphate group --> activating complex
- Calcium activates enzyme complex (linking its activity to exercise)
- caused by pyruvate dehydrogenase deficiency (or mutations in mtDNA)
- symptoms: loss of motor skills, neurological effects, seizures, lactic acidosis
- if there's a deficiency of pyruvate dehydrogenase, thiamin (vitamin B1) is given
- high-fat, low-carb diet may be recommended
- sodium bicarbonate to combat acidosis
partial pyruvate dehydrogenase deficiency
- leads to metabolic acidosis from buildup of pyruvate (as well as lactate & alanine which equilibrate with pyruvate)
- enzyme deficiency is associated with neurological disorders, particularly cerebellar dysfunction
What types of molecules affect pyruvate dehydrogenase's ability to function?
thiol-reactive agents (eg. trivalent arsenic or organic mercurials) are potent inhibitors of the enzyme
Which structural group on coenzyme A forms a thiol ester linkage with acyl groups?
the sulfhydryl group
The coenzyme lipoate is bound to which enzyme in the pyruvate dehydrogenase complex?
dihydrolipoyl transacetylase (E2)
Which enzyme in the pyruvate dehydrogenase complex catalyzes the rapid decarboxylation of pyruvate?
pyruvate decarboxylase (E1)
Which component of the pyruvate dehydrogenase complex is a target for trivalent arsenic poisoning?
the lipoate coenzyme
What kind of bond covalently links lipoate to the enzyme dihydrolipoyl transacetylase (E2)?
an amide bond
The coenzyme flavin adenine dinucleotide (FAD) is derived from which vitamin?
vitamin B2 (riboflavin)
What is the function of the FAD coenzyme bound to the dihydrolipoyl dehydrogenase enzyme (E3) of the pyruvate dehydrogenase complex?
- FAD accepts electrons from the reduced form of lipoate, regenerating oxidized lipoate and forming FADH2
- FAD/FADH2 is covalently bonded to E3
What is the function of the coenzyme NAD+ with regards to the series of reactions catalyzed by the pyruvate dehydrogenase complex?
NAD+ accepts electrons from the FADH2 that is bound to E3, regenerating FAD and producing NADH
What inhibits each enzyme (E1, E2, and E3) of the pyruvate dehydrogenase complex (PDH)?
- Acetyl-CoA inhibits PDH at the E2 component
- NADH inhibits PDH at the E3 component
- Phosphorylation of a specific serine residue inhibits E1
How do elevated concentrations of pyruvate regulate the activity of the pyruvate dehydrogenase complex (PDH)?
pyruvate actives PDH because it INHIBITS the kinase that phosphorylates E1 inactivating it
What regulatory effect does insulin exert on the pyruvate dehydrogenase complex (PDH)?
insulin activates PDH by activating a phosphatase that removes the phosphate group from the serine on E1
X-linked Leigh's disease is caused by a deficiency of which enzyme?
What clinical sign would you expect to observe in a patient with partial deficiency of pyruvate dehydrogenase?
metabolic acidosis due to the buildup of lactate and alanine from the interconversion of pyruvate
TCA Cycle Mnemonic
- C citrate
- I isocitrate
- K alpha-Ketoglutarate
- S succinylCoA
- S succinate
- F fumarate
- M malate
- O oxaloacetate
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Acetyl-CoA: What is it good for?
- TCA cycle enzyme that catalyzes the irreversible condensation of acetyl-CoA with oxaloacetate to form citrate
- inhibited by NADH and succinyl CoA
- reaction rate increases as amount of oxaloacetate & acetyl-CoA increases
Fluoroacetate is able to inhibit which TCA cycle enzyme?
- catalyzes the reversible two-step conversion of citrate to isocitrate
- first water is removed from citrate to form cis-aconitate, the intermediate
- then water is re-added to cis-aconitate in a different orientation to form isocitrate
Why does aconitase treat the two ends of citrate differently?
- Although citrate appears to be a symmetrical molecule, its two ends are handled asymmetrically (the Ogston effect) by aconitase because it can bind in only one way in the asymmetric binding site in the enzyme
- asymmetric enzyme binding sites treat achiral molecules as if they were chiral
- converts isocitrate --> a-ketaglutarate
- GENERATES NADH & CO2
- activated by substrate isocitrate, ADP & Ca2+
- inhibited by NADH and ATP
- converts a-ketaglutarate --> succinyl-CoA
- GENERATES NADH & CO2
- analagous to pyruvate dehydrogenase
- it's activated by Ca2+
- inhibited by NADH, ATP & product succinyl-CoA
Which coenzymes are required for proper activity of the enzyme alpha-ketoglutarate dehydrogenase?
- Thiamine pyrophosphate (TPP), lipoate, coenzyme A (CoASH), FAD and NAD+
- it's analagous to pyruvate dehydrogenase
- turns succinyl-CoA --> into succinate
- carries out a substrate-level phosphorylation (GTP is formed directly with GDP as a substrate)
Which TCA cycle enzyme catalyzes a substrate-level phosphorylation?
Succinyl-CoA synthetase (makes GTP from substrate GDP)
What is the chemical equation for the reaction catalyzed by succinyl CoA synthetase?
succinyl-CoA + GDP + Pi --> succinate + GTP
- reversibly oxidizes succinate --> fumarate while FAD is reduced (FAD is the electron-accepting coenzyme) and FADH2 is released as a product
- succinate dehydrogenase is bound to the inner mitochondrial membrane (unlike other enzymes of the TCA cycle which are in the mitochondrial matrix)
The enzyme succinate dehydrogenase requires which coenzyme?
- it's reduced and FADH2 is produced
- fumarate <--> malate
- catalyzes the reversible addition of water to fumarate or the removal of water from malate
- malate --> oxaloacetate
- catalyzes the reversible formation of oxaloacetate from malate, releasing NADH in the process
- oxaloacetate is regenerated another round of the cycle
Which TCA cycle enzymes catalyze IRreversible reactions?
- citrate synthase (oxaloacetate --> citrate)
- alpha-ketoglutarate dehydrogenase (alpha-ketoglutarate --> succinylCoA)
in each turn of the TCA cycle, 2 ______ atoms enter as __________ and 2 ______ atoms are released as ___. The metabolism of one pyruvate through both the ________________ reaction and one turn of the cycle leads to the release of _ ___ and the transfer of _ pairs of _______ to coenzyme carriers
- In each turn of the TCA cycle, 2 CARBON atoms enter as ACETYL CoA and 2 CARBON atoms are released as CO2. The metabolism of one pyruvate through both the pyruvate DEHYDROGENASE reaction and one turn of the cycle leads to the release of 3 CO2 & the transfer of 5 pairs of electrons to coenzyme carriers.
- *don't forget for each glucose glycolysis-ed, there are two molecules of pyruvate
Which two enzymatic steps in the TCA cycle result in production of CO2 through oxidative decarboxylation?
- isocitrate dehydrogenase step
- alpha ketoglutarate dehydrogenase step
Which TCA cycle intermediate is also a precursor for fatty acids and sterols?
Which TCA cycle intermediate is also a precursor for amino acids and purines?
alpha-Ketoglutarate is reversibly interconverted with the amino acid glutamate
Which TCA cycle intermediate is also a precursor for heme synthesis?
fumarate is formed in the breakdown of:
tyrosine and phenylalanine & in the urea cycle
Which TCA cycle intermediate may be exported to the cytoplasm for synthesis of glucose?
Which TCA cycle intermediate is also a precursor for amino acids, purines and pyrimidines?
- oxaloacetate can be turned into aspartate, which is a precursor for amino acids, purines and pyrimidines
- oxaloacetate is also reversibly interconverted with malate
- aspartate & malate can be exported to cytoplasm as substrates for gluconeogenesis
What are three metabolites that can be directly converted to oxaloacetate?
- Pyruvate (by action of the enzyme pyruvate carboxylase)
a reaction that is not part of the TCA cycle but whose product is a TCA cycle intermediate; it's meant to replenish the TCA cycle intermediates
- catalyzes the formation of oxaloacetate from pyruvate
True or False: reactions of the TCA cycle are slowed by an increase in NADH compared to NAD+
True: they are also slowed by an increase in ATP
Which TCA cycle enzymes are subject to allosteric regulation? 3
- 1. citrate synthase
- 2. isocitrate dehydrogenase
- 3. alpha-ketoglutarate dehydrogenase
Which TCA cycle enzymes produce NADH?
- Isocitrate dehydrogenase
- alpha-ketoglutarate dehydrogenase
- malate dehydrogenase
Which TCA cycle enzyme produces FADH2?
Which TCA cycle enzyme(s) produce GTP via substrate-level phosphorylation?
List the allosteric activators and inhibitors of citrate synthase:
- Activators: ADP
- Inhibitors: NADH, ATP, succinyl-CoA, citrate
List the allosteric activators and inhibitors of isocitrate dehydrogenase:
- Activators: isocitrate, ADP, AMP, Ca 2+
- Inhibitors: NADH, ATP
List the allosteric activators and inhibitors of alpha-ketoglutarate dehydrogenase:
- Activators: Ca 2+
- Inhibitors: NADH, succinyl-CoA
Which TCA cycle substrates and coenzymes cannot cross the mitochondrial membrane?
- Acyl-CoA compounds (such as acetyl-CoA)
Mutations in succinate dehydrogenase or fumarase can result in:
- severe neurological impairment
- certain types of cancers such as fibroids(leiomyomatosis)
- renal cell cancer
What are the two shuttle systems used to transfer the NADH reducing equivalents generated in glycolysis into the mitochondrion to generate energy?
- Since NADH does not cross the mitochondrial membrane, two shuttle systems are used to:
- 1) malate-aspartate
- 2) the glycerol phosphate shuttle
- Liver primarily uses the malate aspartate shuttle
- Muscle relies more on the glycerol phosphate shuttle
Do I need to know the amino acids that can be converted to TCA intermediates and used for energy production in times of starvation?