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1. Yeast can grow both aerobically and anaerobically on glucose. Explain why the rate of glucose consumption decreases when yeast that has been obtained under anaerobic conditions is exposed to Oxygen?
the amount of glucose consumption required to maintain the proper ATP levels in the cell is greatly reduced in aerobically growing cells. In short, glucose is oxidized completely under aerobic conditions and fewer molecules of glucose must be consumed to produce an amount of ATP equivalent to the amount produced under anaerobic conditions.Yeast can grow both aerobically and anaerobically on glucose.
1. The decrease in glucose consumption when oxygen is present is known as the Pasteur Effect. Under anaerobic conditions , there is a net production of only two molecules of ATP for each molecule of glucose converted to ethanol and CO2 by the anaerobic glycolytic pathway. When Oxygen is introduced, the cell can utilize glucose much more efficiently, producing 30-32 molecules of ATP for each glucose molecule oxidized completely to CO2 and water by glycolysis, the citric acid cycle and the respiratory electron transport chain. Thus
2. Trace the fate of 14CH3 –labeled acetyl CoA through two rounds of the citric acid cycle. Assume that the labeled acetyl CoA enters only in the first round.
2. First round. The carbon atoms are retained and end up as the carbon atoms of oxaloacetate. The CH3 carbon ends up as carbons 2 (C=O) and 3 (CH2) of OAA. In the second round those original acetyl carbons are not lost but get distributed to all carbons of OAA at the succinyl CoA synthetase step. You should determine this answer by going through the reactions of the TCA cycle.
3. Trace the fate of the isotopic label of [2-18 O]-pyruvate through the pyruvate dehydrogenase reaction complex and one round of the TCA cycle.
3. In the pyruvate dehydrogenase reaction the C=O carbon becomes the carboxyl carbon of Acetyl CoA. As in question two, this carbonyl group is not lost and becomes the carboxyl groups of OAA. It remains as only one of the carboxyl groups of citrate, isocitrate, aconitate, ketoglutarate and succinyl CoA. However it gets randomized to the two carboxyl groups of succinate, fumarate, malate and OAA after the succinylCoA synthetase reaction.
4. The following labeled glucose molecules are metabolized to 14CO2 via glycolysis and the TCA cycle. Which labeled molecule yields 14CO2 fastest and which takes longest to yield 14CO2 ? Assume pyruvate only enters the TCA cycle only as acetyl-CoA. A) 1-14C-glucose B) 2-14C-glucose C) 3-14C-glucose.
4. Glc-3 becomes pyruvate carboxyl and is the first released as CO2 in the pyruvate dehydrogenase reaction. Glc-2 becomes the carboxyl group of Acetyl CoA and is retained and becomes the two carboxyl groups of succinate and OAA. In the second round of the TCA cycle they are released as CO2. Glc-1 becomes the CH3 group of acetyl-CoA. As answer 2 shows, the CH3 carbon ends up as carbon 2 (C=O) and 3 (CH2) of OAA in the first round. In the second round those original acetyl carbons are not lost but get distributed to all carbons of OAA at the succinyl CoA synthetase step. Therefore, 3-14C-glucose releases labeled CO2 faster than 2-14C-glucose and 1-14C-glucose releases CO2 the slowest.
5. Which statements are true or false.

a. Dihydrolipoamide dehydrogenase catalyzes the only redox reaction in the pyruvate dehydrogenase complex.
b. Hydrolysis of the thioester bond of acetyl CoA yields insufficient energy to drive phosphorylation of ADP.
c. Even if aconitase were unable to discriminate between the two ends of the citrate molecule, the CO2 released would still come from oxaloacetate rather than the acetyl CoA substrate of the citrate synthase reaction.
d. Malate cannot be converted to fumarate because the TCA cycle is unidirectional.
a. Dihydrolipoamide dehydrogenase catalyzes the only redox reaction in the pyruvate dehydrogenase complex. False. There is a reduction in the dihydrolipoyl transacetylase step.

b. Hydrolysis of the thioester bond of acetyl CoA yields insufficient energy to drive phosphorylation of ADP. False.Acetyl-CoA has a ∆G˚´ of -31.4 kJ/mol.

c. Even if aconitase were unable to discriminate between the two ends of the citrate molecule, the CO2 released would still come from oxaloacetate rather than the acetyl CoA substrate of the citrate synthase reaction. False.

d. Malate cannot be converted to fumarate because the TCA cycle is unidirectional. False.
6. Lipoic acid is bound to enzymes that catalyze oxidative decarboxylation of a-keto acids.

a. What is the chemical mode of attachment of lipoic acid to enzymes?

b. Using chemical structures, show how the lipoic acid participates in the oxidative decarboxylation of a-keto acids.
6. a) Lipoic acid is bound to enzymes through an amide bond with epsilon amino group of a lysine residue. b)See Figs. 16-4 and 16-6 and pages 603 and 605 in 474 in Lehninger or pages 66 and 69 in your coursepack.
7. How is the pyruvate dehydrogenase complex regulated? What are the allosteric effects and the covalent modification effects?
Allosteric effects. Inhibition of enzyme 1 by product inhibition by NADH + acetyl CoA. Thus, high ratios of NADH/NAD and AcetylCoA/ CoA inhibit Enzyme1. Enzyme 3, lipoamide dehydrogenase will also be inhibited. Covalent modification. Pyruvate dehydrogenase kinase phosphorylates a seryl residue of Enzyme 1 and causes Enzyme 1 to be inactive. NADH and Acetyl CoA allosterically activate the kinase. An inhibitor of the kinase is Ca++ which increases in concentration in muscle tissue during muscular activity. A protein phosphatase dephosphorylates the inactive enzyme 1 and the PDH complex becomes active. Ca++ is an activator of the phosphatase. So the products of of PDH activity regulate their own production both by allosteric control and by regulating covalent modification.
8. What is meant by the statement that the TCA cycle is amphibolic? Give examples of processes affected by the TCA cycle intermediates.
The TCA cycle is amphibolic because it paticipates both in synthesis and in catabolism of amino acids, glucose and fatty acids. Succinyl CoA is an intermediate of porphyrin biosynthesis. Alpha ketoglutarate is a precursor for synthesis of the amino acid glutamate and glutamine. Citrate is a precursor for fatty acid synthesis. Oxaloacetate can be utilized for gluconeogenesis or aspartate synthesis.
9. How are ATP, ADP and Ca+2 involved in the regulation of the citrate cycle?
9. ATP is an inhibitor of and ADP is an activator of the isocitrate dehydrogenase. Ca+2 is involved in the regulation of the covalent modification of PDH
10. What are the anaplerotic reactions? Give two examples. What is the rationale for activation of pyruvate carboxylase by acetyl CoA?
The term, “Anaplerotic”, is based on a greek word which means replenishment. Under certain conditions the concentration of OAA is low and in order for the citric acid cycle to be efficient the OAA concentration has to be increased. It is done by the pyruvate carboxylase reaction, Pyruvate + CO2 + H20 + ATP <===> OAA +ADP + Pi. Acetyl CoA is a potent activator of the pyruvate carboxylase. If there is a sudden increase in the acetyl CoA concentration and for it to be metabolized by the TCA cycle the concentration of OAA should be increased. Thus acetyl CoA allosterically activates the pyruvate carboxylase. Another anaplerotic enzyme is found in bacteria. They have the phospho-enol pyruvate carboxylase reaction, PEP + CO2 -> OAA + Pi. Acetyl CoA is also an activator of this enzyme. PEP carboxykinase and malate enzyme are also anaplerotic reactions. The malate enzyme reaction is seen in Table16-2 on page 79 in your course pack. Reaction is pyruvate + HCO3-1+ NADPH -> malate + NADP. Some malate enzymes use NADH instead of NADPH.
1. Cellular respiration is the process by which cells
A. oxidize organic fuels to CO2 and H2O.
B. consume O2 and produce CO2.
C. convert O2 to H2O.
D. breakdown sugars to CO2 and H2O.
B. consume O2 and produce CO2
2. Amino acids, fatty acids, and glucose are oxidized and enter the citric acid cycle as
A. pyruvate.
B. acetate.
C. oxaloacetate.
D. acetyl-CoA.
D. acetyl-CoA.
3. The first reaction of the citric acid cycle, which generates citrate, is
A. a condensation reaction.
B. an oxidative decarboxylation reaction.
C. dehydrogenation reaction.
D. a dehydration reaction.
A. a condensation reaction.
4. For every molecule of glucose, how many molecules of CO2 are released in the citric acid cycle?
A. one
B. two
C. four
D. six
C. four
5. Which of the following is true about the pyruvate dehydrogenase complex?
A. It converts pyruvate to oxaloacetate.
B. It catalyzes oxidative decarboxylation.
C. It is located in the cytosol of eukaryotic cells.
D. It requires NADH.
B. It catalyzes oxidative decarboxylation.
6. What role does coenzyme A play in the citric acid cycle?
A. It is an electron carrier.
B. It carries hydride ions.
C. It is an acyl group carrier.
D. It is an oxidizing agent.
C. It is an acyl group carrier.
7. Which of following is true about all of the dehydrogenase enzymes that participate in the citric acid cycle?
A. They catalyze condensation reactions.
B. They generate CO2.
C. They convert a single bond to a double bond.
D. They generate reduced electron carriers.
D. They generate reduced electron carriers.
8. What types of reactions do phosphorylases catalyze?
A. Displacement reactions in which an attacking phosphate becomes covalently attached at the point of bond breakage.
B. The removal of a phosphoryl group from a phosphate ester.
C. The transfer of a phosphoryl group from a nucleoside triphosphate to an acceptor molecule.
D. Ligation reactions in which phosphate esters join molecules.
A. Displacement reactions in which an attacking phosphate becomes covalently attached at the point of bond breakage.
9. Which of the following enzymes catalyzes a condensation reaction in which no nucleoside triphosphate is required as an energy source?
A. kinases
B. synthases
C. ligases
D. synthetases
B. synthases
10. Which of the following conditions has a negative effect on the pyruvate dehydrogenase complex?
A. a high ratio of [ADP]/[ATP]
B. a high level of Ca2+
C. a high ratio of [NAD+]/[NADH]
D. a high ratio of [acetyl-CoA]/[CoA]
D. a high ratio of [acetyl-CoA]/[CoA]
11. In non-vertebrate organisms, the glyoxylate cycle is needed to convert
A. triacylglycerols to fatty acids.
B. acetate to carbohydrates.
C. glyoxylate to ATP.
D. oxaloacetate to malate.
B. acetate to carbohydrates
12. In what way are the glyoxylate cycle and citric acid cycles linked?
A. NADH produced in the glycoxylate cycle enters the citric acid cycle.
B. Acetyl-CoA produced in the glycoxylate cycle enters the citric acid cycle.
C. Succinate produced in the glycoxylate cycle enters the citric acid cycle.
D. Oxaloacetate produced in the glycoxylate cycle enters the citric acid cycle.
C. Succinate produced in the glycoxylate cycle enters the citric acid cycle.
13. The citric acid cycle is amphibolic pathway, which means that
A. it serves in both anabolic and catabolic processes.
B. it is linked to other cycles.
C. it can catalyze reactions that are both exergonic and endergonic.
D. it can move in both a forward and reverse direction.
A. it serves in both anabolic and catabolic processes.
14. Biotin
A. serves as a cofactor in dehydrogenation reactions.
B. transfers one-carbon groups.
C. is a cofactor that transfers acetyl groups.
D. carries CO2 groups.
D. carries CO2 groups.
15. Which of the following citric acid cycle reaction steps is not inhibited by a high [NADH]/[NAD+]?
A. conversion of alpha-ketoglutarate to succinyl-CoA
B. conversion of succinyl-CoA to succinate
C. conversion of isocitrate to alpha-ketoglutarate
D. condensation of oxaloacetate and acetyl-CoA to form citrate
B. conversion of succinyl-CoA to succinate
16. Some plants that have been genetically engineered to express elevated levels of citrate synthase have increased crop productivity because
A. citric acid increases soil pH.
B. citric acid production is a rate-limiting step.
C. citric acid chelates metal ions.
D. citric acid is toxic to some plant pathogens.
C. citric acid chelates metal ions.
17. Anaplerotic reactions, such as the conversion of pyruvate to oxaloacetate, are useful to the citric acid cycle because they
A. generate a steady supply of intermediates for the citric acid cycle.
B. produce molecules needed to regulate the citric acid cycle.
C. link the citric acid cycle to the glyoxylate cycle.
D. siphon away excess intermediates from the citric acid cycle.
A. generate a steady supply of intermediates for the citric acid cycle.
What is respiration?
Most eukaryotic cells and many bacteria are capable in aerobic conditions of
oxidizing metabolites in the
presence of O2 to CO2 and H2O.
What is cellular respiration?
The molecular processes that cells consume O2 and oxidize carbon atoms of
metabolites to produce CO2
Catabolism of proteins, fats and carbohydrates in three stages of cellular respiration. Stage 1:
oxidation of fatty acids, glucose (pyruvate) and some amino acids yield acetyl-CoA.
Catabolism of proteins, fats and carbohydrates in three stages of cellular respiration. Stage 2:
oxidation of acetyl groups in the TCA cycle. There are 4
steps in which electrons are abstracted and NADH and FADH2 are produced.
Catabolism of proteins, fats and carbohydrates in three stages of cellular respiration. Stage 3:
Electrons of NADH and FADH2 are then funneled into a chain of mitochondrial electron carriers in eukaryotes or, in bacteria, the plasma membrane bound electron carriers.
The citric acid cycle (TCA cycle) is the _______ phase of cellular respiration where …………..
central
acetyl-CoA carbon is metabolized and converted to CO2.
Overall reaction in step 1 of cellular respiration is catalyzed by?
the Pyruvate Dehydrogenase complex.
What enzymes and coenzymes participate in the Pyruvate Dehydrogenase complex?
5 coenzymes and three enzymes participate in this enzyme complex.
CoA,
NAD,
TPP,
Lipoate,
and FAD.
What is the structure of Coenzyme A (CoA)?
A hydroxyl group of pantothenic acid is linked to ADP that also has a phosphate group esterified to the three hydroxy group of its ribose.
In the structure of Coenzyme A, The pantothenic acid carboxyl group is in amide linkage with?
ß mercaptoethylamine.
In the structure of Coenzyme A, The --SH group of the mercaptoethylamine forms?
A thioester with the acetate in acetyl-coenzyme A (acetyl CoA).
In the structure of Coenzyme A, pantothenic acid is what type of vitamin?
Type of Vitamin B
Lipoic acid (lipoate) in amide linkage with?
a Lys residue.
The lipoyllysyl moiety( dihydro-lipoyl transacetylase) is?
the prosthetic group of E2 of the PDH complex
The lipoyl group can exist as?
an oxidized, disulfide form or reduced, dithiol form or in an acetylated form.
Lipoic acid (lipoate) does what?
It acts as a carrier of hydrogen as well as a carrier for acyl groups.
The attachment of lipoate to the end of a Lys side chain in E2 produces?
a long, flexible arm that can move from the active site of E1 to the active sites of E2 and E3
The Pyruvate Dehydrogenase complex consists of _______ enzymes?
three distinct enzymes.
The Pyruvate Dehydrogenase complex consists of three distinct enzymes. What are they?
They are are:
pyruvate dehydrogenase (E1),
dihydrolipoyl transacetylase (E2) and dihyrolipoyl dehyrogenase.
There are how many enzymes in the Pyruvate Dehydrogenase complex depending on the species.
Many copies
The PDH complex in mammals is about 50 nm in diameter
The 3-dimensional structure of PDH shows the core structure in green which is ………………………….. to form a pentagonal dodecahedron.
60 molecules of E2 arranged in 20 trimers
The 3-dimensional structure of PDH shows the lipoyl domain of E2 reaching out to
be in contact with?
the catalytic sites of E1 arranged around the E2 core.
The 3-dimensional structure of PDH shows the E3 subunits are also bound to & do what?
the core where the swinging arm on E2 can reach their active sites.
The 3-dimensional structure of PDH, a lipoyl group is attached to?
the lipoyl domain of E2.
E2 has 3 functionally distinct domains. What are they?
The amino terminal lipoyl domain has the lipoyl
residue(s)

the central E1 binding domain

E3 binding domain

the inner core acyltransferase domain having the acyltransferase active site.
The number of lipoyl domains in diffent species are?
variable
The domains of E2 are separated by ……………… and
interspersed with ……………………… allowing ………………………….. to effectively separate the domains.
by 20-30 amino acid residues rich in Ala and Pro

charged amino acid residues

an extended structure
In PDH, The active site of E1 has bound?
TPP
In PDH, The active site of E3 has bound?
FAD.
This basic E1-E2-E3 structure of the PDH has been conserved in evolution and is seen in a number of complexes used for similar metabolic reactions. One important reaction would be?
the α- ketoglutarate dehydrogenase reaction that also occurs in the TCA cycle.
How does the PDH complex work?
By substrate channeling and the intermediates never leaving the enzyme
surface.
Oxidative decarboxylation of pyruvate to acetyl CoA by
the PDH complex. What are the five steps?
(1) Pyruvate reacts with bound TPP of E1 and undergoes decarboxylation to form the hydroxyethyl TPP

(2) We have transfer of 2 electrons and an acetyl group from E1 to form reduced lipoyllysine of E2 as well
as acetylating one of the lipoyl -SH groups to give an acetyl thio-ester.

(3) we have a transesterification whereby the -SH group of CoA replaces the -SH group of E2 to produce acetyl-CoA and fully reduced lipoyllysine.

(4) E3 oxidizes the reduced lipoyllysine to form FADH2 and

(5) E3 catalyzes the reduction of NAD by reduced FADH2.
Having the enzymes in a complex facilitates
channeling of substrates in Oxidative decarboxylation of pyruvate to acetyl CoA by the PDH complex allows?
A greater efficiency of the reaction and preservation of unstable intermediates.
Oxidative decarboxylation of pyruvate to acetyl CoA by
the PDH complex. What is the first step?
(1) Pyruvate reacts with bound TPP of E1 and undergoes decarboxylation to form the hydroxyethyl TPP
Oxidative decarboxylation of pyruvate to acetyl CoA by
the PDH complex. What is the second step?
(2) We have transfer of 2 electrons and an acetyl group from E1 to form reduced lipoyllysine of E2 as well
as acetylating one of the lipoyl -SH groups to give an acetyl thio-ester.
Oxidative decarboxylation of pyruvate to acetyl CoA by
the PDH complex. What is the third step?
(3) we have a transesterification whereby the -SH group of CoA replaces the -SH group of E2 to produce acetyl-CoA and fully reduced lipoyllysine.
Oxidative decarboxylation of pyruvate to acetyl CoA by
the PDH complex. What is the fourth step?
(4) E3 oxidizes the reduced lipoyllysine to form FADH2
Oxidative decarboxylation of pyruvate to acetyl CoA by
the PDH complex. What is the fifth and last step?
(5) E3 catalyzes the the reduction of NAD by reduced FADH2.
Reactions of the Citric Acid Cycle. The carbon atoms that are at the top of the chemical formulas in steps 1 - 4 came from?
acetate of acetyl CoA.
Note in the first turn of the Citric Acid Cycle, the two carbons released as CO2 __ __ ____ from acetate.
do not come
In the Citric Acid Cycle, ________ & _______ are symmetric molecules.
Succinate and fumarate
In reactions of the Citric Acid Cycle, in what steps is energy conserved in the form of NADH or FADH2 via electron transfer to NAD+ or FAD. ?
NADH – Steps 3, 4 and 8
FADH2 – Step 6
What reactions of the Citric Acid Cycle are irreversible?
Reactions 1,3 and 4.
What is the formation of citrate?
Acetyl CoA + Oxaloacetate are condensed to form citrate.
Is the Citrate synthase reaction is endogonic or exergonic?
The reaction is highly exergonic
What is the transient intermediate of the Citrate synthase reaction and is equivalent to …….?
Citroyl-CoA

a Claisen condensation involving a thioester, acetyl CoA and a ketone, oxaloacetate.
The Citrate synthase reaction mechanism has oxaloacetate binding ___________, which allows?
a conformational change in the enzyme allowing the binding of acetyl CoA
What is Step 2 of TCA?
Formation of isocitrate via the aconitase reaction.
In the formation of isocitrate (step 2 of TCA), Aconitase catalyzes the interconversion between citrate and isocitrate by?
the reversible addition of water to an enzyme bound intermediate, cisaconitate.
What is the enzyme bound intermediate of the formation of isocitrate via the aconitase reaction?
cisaconitate.
The enzyme of the formation of isocitrate via the aconitase reaction has an ____ _____ center (from aconitase) which acts in?
iron-sulfur

binding of the substrate and in catalysis.
An iron from aconitase is bound to ……… of citrate
and interacts with the ______ group of citrate.
one of the carboxyl groups

hydroxyl
Step 3 reaction of TCA?
Oxidation of Isocitrate to α-Ketoglutarate + CO2 is catalyzed by isocitrate dehydrogenase.
Oxidation of Isocitrate to α-Ketoglutarate + CO2 is catalyzed by?
isocitrate dehydrogenase.
What are the two forms of isocitrate dehydrogenase?
one specific for NAD+ and one specific for NADP+.
In eukaryotic cells, the NAD+-specific form of isocitrate dehydrogenase is in the ________ and is the enzyme involved in?
mitochondria
the TCA cycle.
The NADP+ specific enzyme of isocitrate dehydrogenase resides?
both in the mitochondrial matrix and the cytosol.
The two forms of isocitrate dehydrogenase enzymes’ function are believed to be involved in?
NADPH production which are required for anabolic
reactions.
The Oxidation of Isocitrate to α-Ketoglutarate + CO2 reaction requires ____ and _____________ is a reaction intermediate.
Mn2+
Oxalosuccinate
In the Oxidation of Isocitrate to α-Ketoglutarate + CO2 reaction (step 3 TCA), Mn2+ is involved in the ……….. formed during the reaction.
decarboxylation and stabilization of the enol-form
Step 4 of the TCA?
Oxidation of Ketoglutarate to Succinyl-CoA is catalyzed by the α-ketoglutarate dehydrogenase (KDH) complex.
Oxidation of Ketoglutarate to Succinyl-CoA is
catalyzed by?
the α-ketoglutarate dehydrogenase (KDH) complex.
What reaction is virtually identical to the pyruvate
dehydrogenase reaction?
Oxidation of Ketoglutarate to Succinyl-CoA
The α-KDH complex in step 4 of TCA is similar and different to the PDH complex in both structure and function. How are they the same?
It includes three enzymes, homologous to E1, E2, and E3 of the PDH complex, the enzyme bound TPP, the enzyme bound lipoate, FAD, NAD+ and coenzyme A.

The E2 of KDH has a covalently bound lipoyl group similar to E2 of PDH.

The E3 enzyme of both complexes are identical.
The α-KDH complex in step 4 of TCA is similar and different to the PDH complex in both structure and function. How are they different?
While E1 of the PDH complex binds pyruvate, E1 of the KDH complex binds
α-ketoglutarate.
What is step 5 of TCA?
Succinyl-CoA is converted to Succinate by Succinyl-CoA synthetase
In step 5 of TCA, Succinyl-CoA is converted to Succinate by?
Succinyl-CoA synthetase
What are the three steps of the The succinyl CoA synthetase reaction mechanism (step 5 of TCA).
(1) A phosphoryl group replaces the CoA of succinyl-CoA bound to the enzyme forming a high energy acyl-P.

(2) The succinyl-P donates its Phosphoryl group to
a His residue forming a high-energy phosphohistidyl enzyme.

(3) The phosphoryl group is transferred from the
His group to the terminal Phosphate of GDP or ADP forming GTP or ATP
The transfer of Pi to GTP or to ATP in the succinyl CoA synthetase reaction mechanism is known as?
substratelevel Phosphorylation.
The succinyl CoA synthetase (step 5 TCA) has two subunits.
the α-subunit (Mr, 32 kD) has the P-His residue and binding site for CoA

the β-subunit (Mr 42 kD) confers specificity for either ADP or GDP
It is important to note that GTP and ATP of the succinyl CoA synthetase reaction are?
interconvertible.
It is important to note that GTP and ATP of the succinyl CoA synthetase reaction are interconvertible. The GTP formed by succinyl CoA synthetase can?
transfer its terminal phosphate to ADP to form ATP in a reaction catalyzed by nucleoside diphosphate kinase.
The GTP formed by succinyl CoA synthetase can transfer its terminal phosphate to ADP to form ATP in a reaction. What is the formula rxn?
GTP + ADP ←→ GDP + ATP

Delta G’O = 0 kJ/mol
What is step 6 of TCA?
Succinate Dehydrogenase oxidizes succinate to fumarate.
What oxidizes succinate to fumarate (step 6)?
Succinate Dehydrogenase
In eukaryotes, succinate dehyrogenase (of TCA: step 6) is tightly bound to?
the inner mitochondrial membrane.
In prokaryotes, succinate dehyrogenase (of TCA: step 6) is tightly bound to?
The inner membrane.
succinate dehyrogenase (of TCA: step 6) has 3 different
____________ and one molecule of ……...
iron-sulfur clusters

covalently-bound FAD
In succinate dehyrogenase (of TCA: step 6), What passes from succinate through FAD and iron-sulfur clusters in the molecule. And then they are transferred to the ?
Electrons

The electrons are then transferred to the electron chain.
What is a is a strong competitive inhibitor of
Succinate (step 6 TCA)?
Malonate
What is step 7 of TCA?
Fumarate is hydrated to L-malate by the enzyme fumarase or fumarate dehydratase.
In step 7 of TCA, Fumarate is hydrated to L-malate by?
the enzyme fumarase or fumarate dehydratase.
In step 7 of TCA, Fumarase reaction of Fumarate is specific for ________ and not _____ .
L-malate and not for D-malate
What is step 8 of TCA?
L-malate is oxidized to oxaloacetate via the L-malate dehydrogenase that is NADspecific.
What is step 8 of TCA, L-malate is oxidized to oxaloacetate via the?
L-malate dehydrogenase that is NAD specific.
Is the L-malate is oxidized to oxaloacetate via the L-malate dehydrogenase (step 8 of TCA) endergonic or exergonic?
quite endergonic.
The L-malate is oxidized to oxaloacetate via the L-malate dehydrogenase (step 8 of TCA) endergonic. However the reaction moves freely in the direction of _________ since …….
oxaloacetate (OAA) formation

OAA is quickly consumed in the citrate synthase reaction.

Thus the OAA concentration in the cell is low (< 10-6 M).
The L-malate is oxidized to oxaloacetate via the L-malate dehydrogenase (step 8 of TCA) is one of the few examples in nature where a ?
symmetrical molecule citrate reacts in an enzyme reaction asymetrically.
When acetate, labeled in the carboxyl group ( [1-C14] acetate), is incubated in animal tissues it is converted to.________ and the label in the TCA cycle intermediates can be?
acetyl CoA


traced.
What is the reason for this non-labeling of the 8th step of TCA?
It was wrongly concluded that citrate could not be in the pathway from acetate to α-ketoglutarate.

even if citrate has no chiral center it has the potential to react asymmetrically if the enzyme that it is reacting with, has an asymmetric active site.

Thus it was suggested that aconitase may have three points to which citrate must be bound and citrate must undergo a specific three-point attachment to these binding points.

the binding of citrate to three such points can happen in only one way.


citrate is called a prochiral molecule and that is, a molecule that has no chiral center but is potentially capable of reacting asymmetrically with an asymmetric active site.
What is a prochiral molecule?
a molecule that has no chiral center but is potentially capable of reacting asymmetrically with an asymmetric active site. (like citrate)
How is the energy of TCA cycle oxidations are
efficiently conserved?
two CO2 molecules are released and the energies released in these oxidations are conserved in the reduction of three
NAD+, and one FAD and synthesis of 1 ATP or GTP.
oxidation of the 3 NADH and FADH2 by the mitochondrial
electron transfer chain (like in Chapter 19) will yield how many molecules of ATP for each molecule of glucose which will be completely oxidized to form 6 molecules of CO2.
30-32
What Products are obtained in one turn of the TCA Cycle.
In one turn, 3NADH, 1 FADH2, 1 GTP (or ATP)and 2 CO2 are formed.
TCA cycle _______ are important
biosynthetic intermediates.
Metabolites
the TCA cycle is an ________ pathway.
amphibolic
Besides TCA role in the oxidative catabolism of
carbohydrates, fatty acids and amino acids, the cycle provides?
precursors for many biosynthetic pathways.
Besides TCA role in the oxidative catabolism of
carbohydrates, fatty acids and amino acids, the cycle provides precursors for many biosynthetic pathways.
What are 4 of them?
α- ketoglutarate and oxaloacetate (OAA) can serve as precursors of amino acids, glutamate and aspartate,
respectively.

OAA can also be used for glucose synthesis in gluconeogenesis.

Succinyl CoA is a precursor for synthesis of the porphyrin ring of heme groups seen in hemoglobin and in cytochromes.

Citrate is a precursor for fatty acid synthesis.
What is the role of TCA cycle in anabolism?
Intermediates of the TCA cycle are drawn off as precursors in many biosynthetic pathways.
How many anaplerotic reactions replenish the depleted TCA cycle intermediates?
4
Anaplerotic reactions are needed to replenish?
TCA Cycle intermediates.
Since TCA cycle intermediates are removed to serve as biosynthetic precursors there must be ………………….. in order for the cycle to continue.
reactions to replenish them
Anaplerotic comes from the greek word anaplerosis which means?
“to replenish”.
What is the role of biotin in the reaction catalyzed by pyruvate carboxylase?
Biotin is attached to the enzyme through an amide bond with the ε-amino group of a lys residue forming biotinyl enzyme.
What is the steps of biotin in the reaction catalyzed by pyruvate carboxylase
First carboxy-P is formed from ATP and HCO3.

The carboxy group is transferred to biotin to form carboxybiotinyl-enzyme.

The carboxy group is transferred to another biotin
at another catalytic site.

Pyruvate is bound to the enzyme and is converted to its enol form.

The carboxy group which is an activated form of CO2, is then transferred to the enolpyruvate to form oxaloacetate.
The biotinyl-lysine chain acts like a long flexible arm in transferring?
the activated CO2 from one catalytic site to another.
biotinyl-lysine chain behaves in a similar way as the lipoyllysine in E2 of PDH acting as?
a flexible tether transferring bound reaction intermediates to different active sites in enzyme complexes.
What are the biological tethers of the biotinyl-lysine chain?
The cofactors lipoate, biotin and ß-mercatoethylamine
and pantothenate form long, flexible arms in the enzymes to which they are covalently bound, acting as tethers that
move intermediates from one active site to the next
The TCA cycle is under tight regulation at two
Levels. What are they?
Conversion of pyruvate to Acetyl CoA at the pyruvate dehydrogenase complex level

Conversion of pyruvate to Acetyl at the entry of acetyl CoA into the cycle that is at the citrate synthase level.
What is the regulation of metabolite flow from the PDH complex through the TCA cycle?
The PDH complex is allosterically inhibited when [ATP/ADP], [NADH/NAD+], and [acetyl-CoA/CoA] ratios are highly indicative of an energy-sufficient metabolic state.

availability of acetyl- CoA and oxaloacetate would limit citrate synthase activity.

In muscle tissue, Ca+2 signals contraction and thus stimulates energy-yielding metabolism to replace the
ATP consumed.
The TCA is also regulated at the _______ & _______ reactions.
isocitrate dehydrogenase and at the α-ketoglutarate dehydrogenase
there is a PDH kinase and a PDH phosphatase in the PDH complex. How does The E1 and PDH activities get activated?
The kinase phosphorylates a Ser residue in E1 and inactivates E1 activity.

The kinase is allosterically activated by ATP.

High [ATP] reflects a sufficient supply of energy
and PDH activity is not needed.

When [ATP] declines the kinase activity decreases and the protein phosphatase action increases to dephosphorylate E1.

The E1 and PDH activities are now active.
Both plant and and mammalian PDH complexes are regulated by _______/_________ action but the Escherichia coli PDH complex is not.
kinase/phosphatase