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citric acid Flashcards

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1
Q

What are reactive oxygen species (ROS), and why did the accumulation of atmospheric O₂ around 2 bya pose a challenge to early life?

A

ROS are toxic oxygen ions and peroxides formed from molecular oxygen, which damage or destroy biomolecules. The rise of atmospheric O₂ presented a significant selection pressure, forcing organisms to evolve ROS defenses or face extinction.

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2
Q

What are the four classifications of modern organisms based on their strategies for coping with oxygen and ROS?

A

Obligate anaerobes: Cannot grow in O₂; rely on fermentation.
Aerotolerant anaerobes: Fermentative but possess ROS-detoxifying enzymes.
Facultative anaerobes: Can ferment or use O₂; have ROS defenses.
Obligate aerobes: Require O₂ for energy and have elaborate ROS detox systems.

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2
Q

How is acetyl-CoA generated and used in aerobic metabolism?

A

produced from the degradation of glucose, fatty acids, and amino acids. It enters the citric acid cycle to generate NADH and FADH₂, which fuel the ETC for ATP synthesis.

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3
Q

Describe the three interconnected biochemical processes of aerobic metabolism in eukaryotes and where they occur.

A

Citric Acid Cycle (CAC) – In the mitochondrial matrix; oxidizes acetyl-CoA to CO₂ and produces NADH/FADH₂.
Electron Transport Chain (ETC) – In the inner mitochondrial membrane; transfers electrons from NADH/FADH₂ to O₂.
Oxidative Phosphorylation – Also in the inner membrane; uses the proton gradient to synthesize ATP.

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3
Q

What role does O₂ play in aerobic metabolism, and what is its final fate in the electron transport chain?

A

O₂ acts as the terminal electron acceptor in the ETC, where it combines with protons to form water (H₂O), completing aerobic respiration

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4
Q

What are the structural and functional features of the mitochondrial inner membrane that support aerobic metabolism?

A

The inner membrane is highly folded (cristae), increasing surface area for ETC complexes, ATP synthase, and transport proteins. It maintains the proton gradient necessary for oxidative phosphorylation.

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5
Q

What are VDACs, and what is their role in mitochondrial function?

A

VDACs (Voltage-Dependent Anion Channels) are pores in the outer mitochondrial membrane that permit the diffusion of small hydrophilic molecules (e.g., pyruvate, ADP, ATP, Ca²⁺) between the cytosol and intermembrane space.

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6
Q

What types of energy and reducing equivalents are produced by the citric acid cycle, and how are they used?

A

The CAC produces NADH and FADH₂ (electron carriers) and CO₂. NADH/FADH₂ donate electrons to the ETC, which drives ATP synthesis via oxidative phosphorylation.

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7
Q

How do facultative anaerobes differ metabolically from aerotolerant anaerobes?

A

Both possess ROS defenses, but facultative anaerobes can utilize O₂ for respiration, switching between fermentation and aerobic metabolism, whereas aerotolerant anaerobes rely solely on fermentation.

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8
Q

Why is the classification of organisms based on O₂ utilization relevant to understanding their energy metabolism and evolutionary adaptations?

A

It reflects how organisms adapted to oxygen-rich environments through metabolic flexibility and antioxidant defenses, shaping energy efficiency, ecological niches, and survival strategies over evolutionary time.

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8
Q

What is a redox reaction, and what are the roles of the electron donor and electron acceptor?

A

A redox (reduction-oxidation) reaction involves the transfer of electrons from a donor (reducing agent), which becomes oxidized, to an acceptor (oxidizing agent), which becomes reduced.

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9
Q

What happens to copper (Cu⁺) and iron (Fe³⁺) in the redox reaction described?

A

Cu⁺ donates an electron and is oxidized to Cu²⁺, while Fe³⁺ accepts the electron and is reduced to Fe²⁺.

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10
Q

What is a conjugate redox pair? Give an example.

A

A conjugate redox pair consists of two forms of the same species differing by one or more electrons. Example: Cu⁺/Cu²⁺ is a conjugate redox pair.

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11
Q

In biological redox reactions, what is often transferred in addition to electrons?

A

In many biological redox reactions, both electrons and protons (H⁺) are transferred. For example, hydride ions (H⁻)—a proton with two electrons—are often moved between molecules.

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12
Q

Describe the redox reaction catalyzed by lactate dehydrogenase.

A

NADH donates a hydride ion (H⁻) to pyruvate, reducing it to lactate. A proton (H⁺) from the environment is also added. Simultaneously, NADH is oxidized to NAD⁺.

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13
Q

Why is it helpful to break down redox reactions into half-reactions?

A

Splitting redox reactions into half-reactions makes it easier to identify which species is oxidized and which is reduced, emphasizing the electron flow as the linking mechanism.

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14
Q

What is the function of an electrochemical (galvanic) cell in studying redox reactions?

A

It separates oxidation and reduction into half-cells, allowing observation of electron flow, measurement of voltage (potential difference), and assessment of energy changes in redox reactions.

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15
Q

How is the voltage in an electrochemical cell related to the energy of the redox reaction?

A

The magnitude of the voltage reflects the amount of energy released or required by the reaction. A positive voltage indicates a spontaneous reaction (energy-releasing).

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16
Q

Define standard reduction potential (E°) and the conditions under which it is measured.

A

E° is the measure of a substance’s tendency to gain electrons under standard conditions: all solutes at 1.0 M, gases at 1 atm, and 25°C, measured relative to the standard hydrogen electrode (0.00 V).

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17
Q

What is the significance of the standard hydrogen electrode in measuring redox potentials?

A

It serves as the reference point (E° = 0.00 V) for measuring the standard reduction potentials of other substances, allowing consistent comparison of electron affinity.

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18
Q
A
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19
Q

In an electrochemical cell, in which direction do electrons flow, and what completes the circuit?

A

Electrons flow from the Cu²⁺/Cu⁺ half-cell (cathode) to the Fe³⁺/Fe²⁺ half-cell (anode) through a voltmeter. A salt bridge containing KCl completes the electrical circuit by allowing ion flow.

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20
Q

. What does a voltmeter measure in an electrochemical cell, and what does it indicate?

A

voltmeter measures the electrical potential (ΔE°) between two half-cells, which reflects the driving force for electron flow from the reductant to the oxidant.

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21
Q

What is the standard reduction potential (E°) of the hydrogen electrode at pH 7, and how does it compare to the standard hydrogen electrode?

A

The reduction potential (E°) of the hydrogen electrode at pH 7 is –0.42 V, compared to 0.00 V for the standard hydrogen electrode, which is at pH 0 ([H⁺] = 1 M).

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22
How is the direction of electron flow determined between two redox half-cells?
Electrons flow from the half-cell with the more negative reduction potential to the one with the more positive reduction potential. This results in a positive ΔE°, driving the reaction spontaneously.
23
What is the relationship between ΔE° and ΔG° in redox chemistry?
ΔG° = –nFΔE°, where n is the number of electrons transferred, F is Faraday's constant, and ΔE° is the cell potential. A positive ΔE° gives a negative ΔG°, indicating a spontaneous reaction.
24
What are the oxidized and reduced forms of NAD and NADP, and what vitamin are they derived from?
Oxidized forms: NAD⁺ and NADP⁺ Reduced forms: NADH and NADPH They are derived from niacin (nicotinic acid), a form of vita
25
How do NAD⁺ and NADP⁺ structurally differ?
NADP⁺ contains an additional phosphate group attached to the 2′-OH of the adenosine moiety, which is absent in NAD⁺.
26
What type of reactions do NAD⁺/NADH and NADP⁺/NADPH typically participate in?
NAD⁺/NADH: Mostly used in energy-generating catabolic reactions NADP⁺/NADPH: Used in biosynthetic reactions (e.g., fatty acid synthesis) and ROS detoxification
27
In the alcohol dehydrogenase reaction, what role does NAD⁺ play?
NAD⁺ acts as an electron acceptor, accepting a hydride ion (H⁻) from ethanol, oxidizing it to acetaldehyde and becoming NADH.
28
Are NAD⁺/NADP⁺ tightly or loosely bound to enzymes?
they are transiently bound, meaning they associate temporarily with the enzyme, are reduced, and then released to deliver electrons elsewhere.
29
What vitamin is the precursor for FAD and FMN, and what is their major structural component?
Riboflavin (vitamin B₂) is the precursor. The major structural feature is the isoalloxazine ring, which participates in redox reactions.
30
How do FAD and FMN differ from NAD⁺/NADP⁺ in terms of enzyme binding?
FAD and FMN are tightly bound prosthetic groups—they remain permanently associated with the enzyme, often forming part of the flavoprotein structure.
31
What kind of reactions can flavoproteins catalyze, and what is unique about FMN's function in mitochondria?
Flavoproteins act as dehydrogenases, oxidases, and hydroxylases. FMN can accept or donate one electron at a time, allowing it to bridge two-electron and one-electron transfer systems like those in the electron transport chain.
32
What is a key example of a flavoprotein enzyme, and what is its role in metabolism?
Succinate dehydrogenase is a flavoprotein that catalyzes the oxidation of succinate to fumarate in the citric acid cycle, reducing FAD to FADH₂ in the process.
33
How do living organisms use electron flow in both aerobic respiration and photosynthesis?
In aerobic respiration, electron flow from NADH to O₂ is used to generate ATP in the electron transport chain (ETC). In photosynthesis, light energy drives electron flow from H₂O (low potential) to high-energy carriers, capturing energy in the bonds of sugars and other molecules.
34
What redox pair represents the final electron acceptor in aerobic respiration, and why is it important?
The final redox pair is ½O₂/H₂O. Oxygen’s high reduction potential allows it to accept electrons from NADH via the ETC, releasing substantial free energy that is used for ATP synthesis.
35
in general, how do electrons flow in aerobic metabolism, in terms of reduction potential?
Electrons flow from redox pairs with more negative reduction potentials (e.g., NADH/NAD⁺) to those with more positive reduction potentials (e.g., ½O₂/H₂O), releasing energy.
36
How does electron flow differ in photosynthesis versus aerobic respiration?
In aerobic respiration, electron flow follows the natural gradient (high to low energy); in photosynthesis, energy from light is required to drive electrons against the gradient, from water (low potential) to higher-energy carriers.
37
What is the overall function of the citric acid cycle in metabolism?
The citric acid cycle oxidizes acetyl groups from acetyl-CoA to CO₂, capturing high-energy electrons in NADH and FADH₂, and producing GTP (or ATP) through substrate-level phosphorylation.
38
What two types of hydrogen transfer are common in biological redox reactions, and which coenzymes are involved?
Hydride transfer (H⁻): Used by NAD(P)⁺/NAD(P)H Hydrogen atom transfer (H*): Used by FAD/FADH₂
39
What are the sources of acetyl-CoA that enter the citric acid cycle?
Acetyl-CoA is derived from: Pyruvate (product of glycolysis) Fatty acid β-oxidation Some amino acids
40
Describe the structure and role of coenzyme A in the citric acid cycle.
An ADP 3′-phosphate derivative A pantothenic acid unit A β-mercaptoethylamine with a reactive –SH group It forms high-energy thioester bonds with acyl groups, making it an effective acyl carrier (e.g., in acetyl-CoA)
41
Why is the thioester bond in acetyl-CoA considered high-energy?
The carbon–sulfur bond in thioesters is more reactive than a carbon–oxygen ester bond because sulfur is a better leaving group, making the bond easier to cleave and more energy-releasing.
42
What happens during the first step of the citric acid cycle?
A two-carbon acetyl group from acetyl-CoA condenses with oxaloacetate (4C) to form citrate (6C), catalyzed by citrate synthase.
43
How many CO₂ molecules and reduced coenzymes are produced per turn of the citric acid cycle?
2 CO₂ molecules 3 NADH, 1 FADH₂ 1 GTP (or ATP)
44
What happens to oxaloacetate at the end of the citric acid cycle?
Oxaloacetate is regenerated at the end of the cycle, allowing it to condense with another acetyl-CoA and continue the cycle.
45
Besides energy production, what other role does the citric acid cycle play in the cell?
Citric acid cycle intermediates serve as substrates in biosynthetic reactions, including amino acid synthesis, gluconeogenesis, and heme biosynthesis.
46
47
What is the net type of reaction catalyzed by the Pyruvate Dehydrogenase Complex (PDHC), and what is the standard free energy change associated with it?
The PDHC catalyzes an oxidative decarboxylation of pyruvate to acetyl-CoA. The reaction is highly exergonic with a ΔG° of −33.5 kJ/mol.
48
Pyruvate dehydrogenase
Decarboxylates pyruvate (uses TPP).
49
Dihydrolipoyl transacetylase
Transfers the remaining 2-carbon unit to coenzyme A (CoA).
50
Dihydrolipoyl dehydrogenase
Regenerates the oxidized form of lipoic acid using FAD and NAD⁺
51
What is the job of lipoic acid in PDHC?
Lipoic acid carries acetyl groups and electrons during the conversion of pyruvate to acetyl-CoA. It’s attached to E2 on a flexible arm.
52
TPP (from vitamin B1)
Helps remove CO₂ from pyruvate.
53
Lipoic acid:
Transfers acetyl groups and electrons.
54
Coenzyme A (CoASH)
Carries the acetyl group as acetyl-CoA.
55
FAD
Picks up electrons from lipoic acid.
56
NAD⁺
Picks up electrons from FADH₂ to form NADH.
57
Why does PDHC need both FAD and NAD⁺ for electron transfer?
FAD helps first by accepting electrons from lipoic acid. Then NAD⁺ takes electrons from FADH₂. This two-step process is needed due to how the energy levels (redox potential) work.
58
What happens first when pyruvate meets PDHC?
E1 uses TPP to remove a carbon from pyruvate as CO₂, forming a 2-carbon intermediate called hydroxyethyl-TPP (HETPP).
59
What happens to the hydroxyethyl group after it’s formed?
E2 transfers it to lipoic acid, making acetyl-lipoamide, then transfers the acetyl group to CoA, forming acetyl-CoA.
60
How is lipoic acid restored so the cycle can repeat?
E3 reoxidizes lipoic acid using FAD, which becomes FADH₂, then NAD⁺ takes electrons from FADH₂ to make NADH.
61
What activates PDHC when the cell needs energy?
NAD⁺, CoA, AMP, and calcium (Ca²⁺) activate PDHC. These signals mean the cell needs more ATP.
62
What inhibits PDHC when the cell already has enough energy?
High levels of ATP, acetyl-CoA, and NADH inhibit PDHC to stop more acetyl-CoA from being made.
63
How is PDHC turned off by phosphorylation?
PDK1 (pyruvate dehydrogenase kinase) adds a phosphate to PDHC, inactivating it. PDK1 is turned on by acetyl-CoA and NADH.
64
How is PDHC turned back on when energy is low?
PDP (pyruvate dehydrogenase phosphatase) removes the phosphate. PDP is activated by low ATP, insulin, and Ca²⁺.
65
What’s special about the structure of PDHC?
It’s a huge complex with multiple copies of E1, E2, and E3 enzymes. Lipoic acid “arms” help move molecules between enzyme sites.
66
Why is PDHC so important in metabolism?
It controls the flow of carbon from glycolysis into the citric acid cycle, making it a key control point for energy production.
67
Reactions 1–4:
Introduce and oxidize the 2-carbon acetyl group, releasing 2 CO₂ molecules.
68
Reactions 5–8
Regenerate oxaloacetate (OAA) to allow the cycle to continue.
69
What are metabolons, and why are they important in the citric acid cycle?
Metabolons are noncovalently-associated multienzyme complexes that facilitate substrate channeling, improving efficiency by directly transferring intermediates between active sites.
70
What initiates the citric acid cycle, and which enzyme catalyzes the first reaction?
The cycle begins with the condensation of acetyl-CoA (2C) with oxaloacetate (4C) to form citrate (6C), catalyzed by citrate synthase
71
What is the structural organization of citrate synthase and how does substrate binding affect it?
Citrate synthase is a homodimer. Binding of oxaloacetate causes a conformational change from open to closed form, creating the acetyl-CoA binding site.
72
How is the enol intermediate of acetyl-CoA formed in the citrate synthase mechanism?
A side-chain carboxylate (Asp) deprotonates the methyl group of acetyl-CoA to form an enol. A histidine side chain donates a proton to the carbonyl oxygen, stabilizing the transition state. The histidine then removes a proton from the enol, forming an enolate, which attacks the carbonyl carbon of oxaloacetate.
73
What is citroyl-CoA, and how is it converted to citrate?
Citroyl-CoA is the intermediate formed after enolate attacks OAA. It is hydrolyzed by nucleophilic acyl substitution: a water molecule, activated by a second histidine, attacks the thioester bond, forming citrate + CoASH.
74
Why is the formation of citrate thermodynamically favorable?
The hydrolysis of the high-energy thioester bond in citroyl-CoA makes the overall reaction highly exergonic (ΔG° = −33.5 kJ/mol).
75
Why must citrate be isomerized in the citric acid cycle?
Citrate has a tertiary alcohol, which is hard to oxidize. It is converted to isocitrate, which has a secondary alcohol that can be more easily oxidized.
76
Which enzyme catalyzes the isomerization of citrate to isocitrate, and what kind of reaction is this?
Aconitase catalyzes the reversible isomerization via a dehydration–rehydration mechanism through the intermediate cis-aconitate
77
Histidine
protonates the C3 hydroxyl group → water is eliminated deprotonates water → water attacks C2.
78
Serine
abstracts a proton from C2, forming cis-aconitate.
79
If the ΔG° for citrate to isocitrate is +13.3 kJ/mol, how does the reaction proceed in cells?
Although endergonic under standard conditions, the reaction proceeds forward in vivo because isocitrate is rapidly consumed by the next step, pulling the reaction forward.
80
Which enzyme catalyzes the oxidative decarboxylation of isocitrate, and what is the ΔG° of this reaction?
Isocitrate dehydrogenase (IDH) catalyzes the reaction. The ΔG° is –8.4 kJ/mol, making it exergonic.
81
What are the products of isocitrate oxidation?
The products are α-ketoglutarate, CO₂, and NADH (or NADPH).
82
What is the mechanistic sequence of the isocitrate dehydrogenase reaction?
C2 hydroxyl of isocitrate is deprotonated → forms a ketone (oxalosuccinate). Hydride is transferred from the α-carbon to NAD⁺/NADP⁺ → yields NADH/NADPH. Mn²⁺ stabilizes the carbonyl in oxalosuccinate. Decarboxylation occurs: tyrosine polarizes the C3 carboxyl group → forms enol intermediate. The enol rearranges → forms α-ketoglutarate.
83
What are the three isoforms of isocitrate dehydrogenase, and where are they located?
IDH3: NAD⁺-dependent, in mitochondria (linked to ETC). IDH1: NADP⁺-dependent, in cytosol. IDH2: NADP⁺-dependent, in mitochondria.
84
What role does NADPH (from IDH1/2) play in the cell?
NADPH is used in biosynthetic reactions and in detoxifying ROS (e.g., via glutathione reductase).
85
What enzyme complex catalyzes the conversion of α-ketoglutarate to succinyl-CoA?
The α-ketoglutarate dehydrogenase complex (α-KGDH).
86
What are the products of the α-KGDH reaction, and how exergonic is it?
Products: succinyl-CoA, CO₂, NADH.ΔG° = –33.5 kJ/mol, very exergonic.
87
What cofactors are required by α-KGDH?
Same as pyruvate dehydrogenase complex: TPP, lipoic acid, CoA, FAD, NAD⁺.
88
What is structurally and functionally analogous to this reaction in glycolysis-linked metabolism?
The conversion of pyruvate → acetyl-CoA by PDH complex.
89
What reaction does succinyl-CoA synthetase catalyze, and what type of phosphorylation does it involve?
Converts succinyl-CoA → succinate, coupled to substrate-level phosphorylation of ADP or GDP.
90
How is α-KGDH regulated, and how does its regulation differ from PDH?
It is inhibited by succinyl-CoA, NADH, ATP, GTP. Unlike PDH, it is not regulated by covalent phosphorylation.
91
Outline the steps of this reaction mechanism.
CoASH displaced → forms succinyl phosphate. Phosphate forms a covalent intermediate with a histidine residue. Phosphate is transferred to ADP or GDP → forms ATP or GTP.
92
What determines whether ATP or GTP is produced?
tissue-specific isoforms of the enzyme: one favors ADP, the other GDP. Both may be present in varying amounts.
93
What is the net ΔG° of the succinyl-CoA synthetase reaction, and why is it reversible?
Net ΔG° ≈ –3.8 kJ/mol. Though the phosphorylation step is endergonic (+32.2 kJ/mol), it is driven by the highly exergonic thioester hydrolysis (–36 kJ/mol).
94
What enzyme allows GTP to be converted to ATP, and why is this important?
Nucleoside diphosphate kinase catalyzes: GTP + ADP ⇌ GDP + ATP, allowing GTP energy to contribute to ATP pools
95
What makes succinate dehydrogenase unique among citric acid cycle enzymes?
It is the only CAC enzyme embedded in the inner mitochondrial membrane, and it is also part of Complex II of the ETC.
96
What cofactor does succinate dehydrogenase use, and why?
FAD, which is tightly bound and can accept electrons from carbon–carbon single bonds, due to its more positive reduction potential.
97
Describe the mechanism of succinate oxidation.
A general base removes a proton from C2. A hydride is transferred from C3 to FAD, forming FADH₂ and fumarate.
98
ShdA: Succinate binding, FAD site. ShdB: Contains 3 iron–sulfur clusters to shuttle electrons. ShdC/D: Anchor the enzyme in the membrane.
99
How is succinate dehydrogenase regulated?
Activated by: high succinate, ADP, and Pi. Inhibited by: OAA and malonate (a competitive inhibitor used by Krebs to study the cycle).
100
Which enzyme catalyzes the hydration of fumarate, and what is the ΔG° of this reaction?
Fumarase (a lyase) catalyzes this reaction. ΔG° = –3.8 kJ/mol, indicating it is exergonic and reversible.
101
What is the stereochemical outcome of fumarase activity?
Fumarase catalyzes a stereospecific hydration yielding L-malate only (not D-malate or meso forms).
102
Describe the mechanism of fumarase.
A general base deprotonates water. The resulting OH⁻ attacks the C=C double bond of fumarate → forms an OH at C-2, carbanion at C-3. A general acid protonates the carbanion → yields L-malate.
103
What type of enzyme is fumarase, and what does this tell you about its reaction type?
Fumarase is a lyase, meaning it catalyzes addition/removal reactions involving double bonds (here: hydration across a double bond).
104
Which enzyme catalyzes the oxidation of L-malate, and what are the products?
Malate dehydrogenase catalyzes the reaction: L-malate + NAD⁺ → OAA + NADH + H⁺
105
What is the ΔG° of the malate dehydrogenase reaction, and how is it driven forward in vivo?
ΔG° = +29 kJ/mol (highly endergonic). The reaction proceeds forward in vivo because oxaloacetate is continuously consumed by citrate synthase in the next cycle turn.
106
Outline the mechanism of malate oxidation.
histidine residue abstracts a hydrogen from the C-2 hydroxyl group of L-malate. A hydride is transferred from C-2 to NAD⁺ → forming NADH. A carbonyl forms at C-2, yielding oxaloacetate.
107
Where are the two isoforms of malate dehydrogenase located, and what are their functions?
Mitochondrial isoform: participates in citric acid cycle. Cytoplasmic isoform: involved in the malate–aspartate shuttle for transferring reducing equivalents (NADH) into mitochondria.
108
n each turn of the citric acid cycle, how many carbon atoms are lost as CO₂, and from where are they derived?
Two CO₂ molecules are released per turn, but they are derived from the oxaloacetate that initially reacts with acetyl-CoA—not from the newly added acetyl group.
109
When do the carbon atoms from the newly entered acetyl-CoA actually get released as CO₂?
These carbon atoms are not released until at least the second turn of the cycle. They become part of succinate, a symmetric molecule, and are indistinguishable afterward.
110
What structural feature of succinate leads to carbon scrambling and delayed CO₂ release from acetyl-CoA?
Succinate’s symmetry means the two carbons from acetyl-CoA are evenly distributed and indistinguishable, making it impossible to selectively release them in the same turn.
111
Why is it important that OAA is regenerated at the end of the cycle?
OAA is necessary to condense with a new acetyl-CoA in the first step of the next cycle turn, allowing the cycle to continue perpetually.
112
What does "amphibolic" mean, and how is the citric acid cycle amphibolic?
Amphibolic means functioning in both catabolic and anabolic roles.
113
Catabolic
Oxidation of acetyl-CoA to CO₂ and generation of energy (NADH, FADH₂, GTP).
113
Anabolic:
Provides intermediates for biosynthesis (e.g., OAA for gluconeogenesis and amino acids, citrate for fatty acids, succinyl-CoA for heme).
113
Which intermediate is a precursor for glutamate, glutamine, proline, and arginine?
α-Ketoglutarate is the precursor for these amino acids via transamination reactions.
114
Which citric acid cycle intermediate is used in gluconeogenesis and amino acid biosynthesis?
Oxaloacetate (OAA) is a precursor for gluconeogenesis and the synthesis of aspartate, lysine, threonine, isoleucine, and methionine.
115
What intermediate is needed for heme biosynthesis?
Succinyl-CoA is required for porphyrin/heme biosynthesis
116
How does citrate contribute to cytoplasmic biosynthesis?
Excess citrate exits mitochondria and is cleaved by citrate lyase into acetyl-CoA (used for fatty acid/steroid synthesis) and OAA (used for malate and pyruvate cycling/NADPH generation).
117
What is the role of anaplerotic reactions?
They replenish citric acid cycle intermediates drained by biosynthetic (anabolic) processes to maintain energy generation.
118
What is the most important anaplerotic enzyme and its regulation?
Pyruvate carboxylase, which converts pyruvate to OAA, is activated by acetyl-CoA, indicating low OAA availability.
119
Name two other anaplerotic sources of cycle intermediates.
Succinyl-CoA synthesis from certain fatty acids (odd-chain). Transamination of glutamate to α-ketoglutarate and aspartate to OAA.
120
Which three enzymes of the citric acid cycle are regulated and why?
citrate synthase, Isocitrate dehydrogenase, α-Ketoglutarate dehydrogenase These catalyze irreversible steps with large –ΔG°, representing key metabolic branch points.
121
How are these key enzymes regulated?
By substrate availability, Product inhibition, Feedback inhibition (e.g., NADH, ATP), Activation by Ca²⁺ in mitochondria (especially during muscle contraction)
122
What happens to citrate when exported to the cytoplasm?
Citrate lyase cleaves it into acetyl-CoA + OAA (ATP-dependent). OAA → malate (via cytoplasmic malate dehydrogenase). Malate → pyruvate + CO₂ + NADPH (via malic enzyme). Acetyl-CoA → used for fatty acid and cholesterol biosynthesis.
123
What is the purpose of NADPH generated by malic enzyme?
NADPH is used for biosynthetic reactions in the cytoplasm, especially fatty acid synthesis.
124
What happens to the pyruvate formed in the cytoplasm?
It reenters mitochondria and is converted into either oxaloacetate (via pyruvate carboxylase) or acetyl-CoA (via PDH complex).
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What other route can cytoplasmic malate take besides conversion to pyruvate?
It can be transported back into the mitochondria and reoxidized to OAA by mitochondrial malate dehydrogenase.
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How is isocitrate dehydrogenase regulated?
It is activated by ADP and NAD⁺ (indicators of low energy) and inhibited by ATP and NAD(P)H (indicators of high energy).
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Why is isocitrate dehydrogenase tightly regulated?
Because the citrate ↔ isocitrate reaction is reversible and favors citrate accumulation. Isocitrate is rapidly removed by the next step, so regulating this enzyme controls citrate export for biosynthesis.
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Why can only citrate (not isocitrate) be exported out of mitochondria?
Only citrate has a specific transporter in the inner mitochondrial membrane, enabling its role in biosynthesis and regulation in the cytoplasm.
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What happens to citrate in the cytoplasm?
Citrate lyase cleaves it into acetyl-CoA (for fatty acid/lipid synthesis) and OAA. OAA → malate → either back to mitochondria or → pyruvate via malic enzyme, producing NADPH.
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What are the three key cytoplasmic roles of citrate?
precursor of acetyl-CoA for lipid synthesis. Allosteric activator of acetyl-CoA carboxylase (FA synthesis). Inhibitor of PFK-1, thus suppressing glycolysis.
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How is α-ketoglutarate dehydrogenase regulated?
nhibited by: NADH, succinyl-CoA (its product). Activated by: AMP and Ca²⁺. It ensures α-ketoglutarate stays in the cycle when energy is needed, or is diverted for biosynthesis when energy is high.
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What determines whether α-ketoglutarate is retained or used for biosynthesis?
The NADH/NAD⁺ ratio and energy charge (AMP/ATP levels): Low NADH or high AMP = retain in cycle. High NADH = divert to biosynthesis.
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How does Ca²⁺ signaling regulate the citric acid cycle?
Increased matrix Ca²⁺ (from cytoplasmic signaling) stimulates: PDHC via PDP activation, Isocitrate dehydrogenase, α-Ketoglutarate dehydrogenase → Result: ↑ ATP production to meet cellular energy demand.
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How do PDHC and pyruvate carboxylase balance biosynthesis vs energy production?
PDHC converts pyruvate to acetyl-CoA for energy production. Pyruvate carboxylase converts pyruvate to OAA to replenish TCA intermediates (anaplerotic). Acetyl-CoA activates pyruvate carboxylase and inhibits PDHC, helping rebalance OAA when it's low.
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Why do defects in citric acid cycle enzymes often affect the brain?
Because the brain has high ATP demands, mutations in TCA cycle enzymes cause encephalopathy with symptoms like cognitive deficits, seizures, and tremors.
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Which enzyme mutations are linked to human encephalopathies?
Mutations in genes encoding: α-ketoglutarate dehydrogenase, Succinate dehydrogenase (subunit A), Fumarase, Succinyl-CoA synthetase.
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How do mutations in TCA enzymes relate to cancer?
SDH and fumarase mutations → pheochromocytoma and renal cell cancer. These mutations disrupt metabolism, promoting aberrant cell signaling and growth.
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What is the glyoxylate cycle and where does it occur?
A modified citric acid cycle in glyoxysomes (plants/fungi), cytoplasm (bacteria), enabling net conversion of 2-carbon units (acetate/acetyl-CoA) into 4-carbon compounds for biosynthesis (e.g., glucose).
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What key decarboxylation steps are bypassed in the glyoxylate cycle?
The CO₂-releasing steps of the citric acid cycle are bypassed, allowing net carbon retention for gluconeogenesis.
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What are the two unique enzymes of the glyoxylate cycle?
Isocitrate lyase → splits isocitrate into succinate and glyoxylate. Malate synthase → condenses glyoxylate + acetyl-CoA to form malate.
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What is the net product of the glyoxylate cycle from two acetyl-CoA molecules?
One succinate (used for glucose synthesis) and one oxaloacetate (reused in the cycle).
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Why can’t animals convert fatty acids to glucose?
Animals lack isocitrate lyase and malate synthase, so they cannot bypass the decarboxylation steps and therefore cannot net-synthesize glucose from acetyl-CoA (fatty acids).
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biochem2 (3 decks)

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