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Kaplan Biochem and Genetics > The TCA Cycle and Oxidative Phosphorylation (Biochem) > Flashcards

The TCA Cycle and Oxidative Phosphorylation (Biochem) Flashcards

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1
Q

Can The TCA cycle occur in anaerobic conditions?

A

NO. Although O2 is not directly required in the TCA cycle, the pathway won’t occur anaerobically, because NADH and FADH2 will accumulate if O2 is not available for the ETC

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2
Q

How many ATP does 1 NADH yield?

A
  • 3 ATP/1NADH
  • NADH donates 3 H+
  • each NADH donates 2e- to the ETC
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3
Q

Primary Function of the TCA cycle

A
  • oxidation of Acetyl CoA to 2CO2
  • Substrates: Acetyl CoA + 3NAD + FAD + GDP + Pi
  • produces: 2 CO2 + 3 NADH + FADH2 + GTP
  • *The ONLY fate of Acetyl CoA in this pathway is its oxidation to CO2.
  • therefore, the CAC does not represent a pathway by which there can be net synthesis of glucose from Acetyl CoA
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4
Q

Isocitrate dehydrogenase, the major control enzyme of the TCA cycle is:

  • inhibited by ____ and
  • activated by ___
  • creates
A

Isocitrate dehydrogenase, the major control enzyme of the TCA cycle is:

  • inhibited by NADH and ATP and
  • activated by ADP and calcium
  • converts isocitrate to alpha-ketoglutarate
  • gives off CO2
  • Requires NAD to be reduced to NADH (this NADH goes on to create 3 ATP in the ETC)
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5
Q

alpha ketoglutarate dehydrogenase

  • what does it do?
  • What does it require?
A
  • converts alpha-ketoglutarate to succinyl Co-A
  • gives off CO2
  • Requires NAD to be reduced to NADH (this NADH goes on to create 3 ATP in the ETC)
  • alpha ketoglutarate dehydrogenase is similar to the pyruvate dehydrogenase complex. It requires: TLCFN
  • thiamine (Vit B1)
  • lipoid acid
  • CoA (from panthenate aka Vit B5)
  • FAD (from riboflavin aka Vit B2)
  • NAD (from niacin aka Vit B3) (may also be synthesized from tryptophan)
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6
Q

Succinyl-CoA synthetase (succinate thiokinase) catalyzes

A
  • Succinyl Co-A to Succinate
  • converts GDP + Pi to GTP!
  • a substrate-level phosphorylation of GDP and GTP
  • (this is our 3rd example of substrate-level phosphorylation; 2 were in glycolysis)
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7
Q

Succinate dehydrogenase is:

  • catalyzes what reaction
  • located on the
  • it also functions as
A
  • converts succinate to fumarate
  • requires FAD that it reduces to FADH2
  • this FADH2 goes on to create 2 ATP in the ETC
  • Think (F)AD required to create (F)umarate
  • it is located on the inner mitochondrial membrane
  • where it also functions as Complex II of the ETC
  • Fumarate is also a product of the urea cycle
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8
Q

How many ATP does 1 FADH2 yield?

A
  • 2 ATP per 1 FADH2
  • each FADH2 donates 2 H+
  • each FADH2 donates 2 e- to the ETC
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9
Q

Citrate (intermediate of the CAC) may leave the mitochondria via the _____ to ____

A

Citrate (intermediate of the CAC) may leave the mitochondria via the

  • citrate shuttle
  • to deliver acetyl CoA into the cytoplasm for FA synthesis
  • FA synthesis occurs in the cytoplasm of the liver
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10
Q

Succinyl CoA is a high-energy intermediate of the CAC that can be used for

A
  • heme synthesis and

- to activate ketone bodies in extra hepatic tissues

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11
Q

Malate (intermediate of the CAC) can leave the mitochondria via the ____ for ____

A

Malate (intermediate of the CAC) can leave the mitochondria via the malate shuttle for gluconeogenesis

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12
Q

1 Acetyl CoA can yield how many ATP?

A

1 Acetyl CoA –> 2CO2 + 12 ATP

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13
Q

Which CAC intermediate is also a product of the urea cycle?

A

Fumarate

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14
Q

How many ATP are made per NADH?

A
  • there are 3H+ per NADH, that can be converted into 3 ATP

- therefore, with NADH there is a ratio of 1 ATP/H+

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15
Q

How many ATP are made per FADH2?

A
  • there are 2H+ per FADH2, that can be converted into 2 ATP

- therefore, with NADH there is a ratio of 1 ATP/H+

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16
Q

What is Complex I of the ETC and what does it do?

A
  • NADH is oxidized by NADH dehydrogenase (Complex 1)

- Complex 1 accepts electrons from NADH

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17
Q

In the ETC, the electrons are passed along ga series of protein and lipid carriers. Their order is:

A
  1. NADH dehydrogenase (Complex 1) accepts e- from NADH
  2. Coenzyme Q (a lipid)
  3. cytochrome b/c1 (an Fe/heme protein) aka Complex III
  4. cytochrome c (an Fe/heme protein)
  5. cytochrome a/a3 transfers electrons to O2 (a Cu/heme protein) aka cytochrome oxidase, aka Complex IV
  • the Fe acts as an e- receptor: Fe3+ –> Fe2+
  • the Cu acts as an e- receptor: Cu+ –> Cu
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18
Q
  • Which components of the inner mitochondrial membrane in the ETC reoxidize their FADH2?
  • and where do they pass their electrons?
A
  • Succinate dehydrogenase and the alpha-glycerol phosphate shuttle enzymes reoxidize their FADH2
  • and they pass their electrons directly to CoQ (a lipid)
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19
Q

What is another name for Complex III of the ETC?

A
  • cytochrome b/c1
  • (an Fe/heme protein)
  • the Fe acts as an e- receptor: Fe3+ –> Fe2+
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20
Q

What is another name for Complex IV of the ETC?

A
  • cytochrome a/a3 aka cytochrome oxidase
  • (a Cu/heme protein)
  • the Cu acts as an e- receptor: Cu+ –> Cu
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21
Q

How does ATP synthesis by oxidative phosphorylation work?

A
  • the ATP synthase complex has the structure: F0F1, and spans the inner mitochondrial membrane
  • As protons flow into the mitochondria through the F0 component, their energy is used by the F1 component (ATP synthase) to phosphorylate ADP using Pi
  • 1 NADH yields 3 ATP
  • 1 FADH2 yields 2 ATP
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22
Q

Where does the TCA cycle occur?

A

mitochondria

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23
Q

Citrate synthase condenses

A

the incoming acetyl group with oxaloacetate to form citrate

24
Q

Proteins and drugs that uncouple ETC ____ rate of ETC and ____ efficiency

A
  • Proteins and drugs that uncouple ETC increase the rate of ETC but decrease its efficiency.
  • When the ETC is uncoupled it still generates heat, but doesn’t make any ATP
  • this increases the [ADP] which stimulates an increase in the rate of ETC, but it’s not going to fix the problem
25
Q

What is the controlled step of the CAC?

A
  • isocitrate dehydrogenase
  • it is inhibited by NADH
  • causing the CAC to stop when the ETC stops in the anaerobic cell
26
Q

Where do the ETC and Oxidative Phosphorylation occur in prokaryotes?

A
  • on the cell membrane (bc they don’t have mitochondria)
27
Q
  1. what are the consequences of inhibiting the ETC?

2. What inhibits the ETC?

A
  1. ATP synthesis decreases, ETC decreases,
    - O2 consumption decreases,
    - increased intracellular NADH/NAD and FADH2/FAD ratios
  2. Inhibited by:
    - cyanide (complex IV, cytochrome oxidase)
    - Barbiturates and rotenone (complex I, NADH dehydrogenase)
    - doxorubicin (CoQ)
    - antimycin (Complex III)
    - Oligomycin (F0 component of F0F1 ATP synthase)
    - carbon monoxide (complex IV, cytochrome oxidase)
28
Q
  1. Uncouplers of the ETC

2. consequences of uncoupling the ETC

A
  1. Uncouplers:
    - 2,4 DNP
    - Aspirin in high doses (i.e. doses used to treat RA)
    - uncoupling proteins (ie thermogenin aka UCP, natural uncoupling protein. Found in Brown Fat. Allows energy loss as heat to maintain a basal temperature around the kidneys, neck, breastplate and scapulae in newborns)
  2. Uncouplers decrease the proton gradient causing:
    - ATP synthesis decreases, ETC increases, O2 consumption increases
    - uncouplers destroy the proton gradient
    - produce heat rather than ATP
    - increase oxidation of NADH
29
Q

A/E of Aspirin in doses used to treat RA

A
  • uncoupling of Oxidative Phosphorylation
  • increased O2 consumption
  • depletion of hepatic glycogen and
  • the pyretic effect of toxic doses of salicylate
  • depending on the degree of salicylate intoxication, the symptoms can vary from tinnitus to pronounced CNS and acid-base disturbances
30
Q

Tissue hypoxia and the ETC

A
  • hypoxia deprives the ETC of O2, decreasing the rate of ETC and ATP production
  • When ATP levels fall, glycolysis increases, and in the absence of O2, all produce lactate (lactic acidosis)
  • Anaerobic glycolysis is not able to meet the demand of most tissues for ATP–esp nerves and cardiac muscle
31
Q

Cyanide and the ETC

  • effect
  • Tx
A
  • Cyanide binds irreversibly to cytochrome a/a3 (aka complex IV, cytochrome oxidase)
  • preventing e- transfer to O2, and producing many of the same changes seen in tissue hypoxia
  • nitrites may be used as an antidote for cyanide poisoning if given rapidly.
  • they convert Hb to metHb, which binds cyanide in the blood BEFORE reaching the tissues
  • O2 is also given, if possible
32
Q

Sources of cyanide

A
  • burning polyurethane (foam stuffing in furniture and mattresses)
  • byproduct ot nitroprussied (released slowly; thiosulfate can be used to destroy the cyanide)
33
Q

Carbon Monoxide and the ETC

A
  • Carbon Monoxide binds to cytochrome a/a3 (aka complex IV, cytochrome oxidase) but not as tightly as cyanide
  • preventing e- transfer to O2, and producing many of the same changes seen in tissue hypoxia
  • it also binds to Hb, displacing O2
34
Q

Symptoms of Carbon Monoxide poisoning

A
  • headache
  • nausea
  • tachycardia
  • tachypnea
  • lips and cheeks turn a cheery-red color
  • respiratory depression and coma result in death if not treated by giving O2
35
Q

Sources of Carbon Monoxide

A
  • propane heaters and gas grills
  • vehicle exhaust
  • tobacco smoke
  • house fire
  • methylene chloride-based paint strippers
36
Q

Reactive Oxygen Species

A
  • Superoxide (O2-)
  • hydrogen peroxide (H202)
  • hydroxyl radical (OH.)
  • these react rapidly with lipids to cause peroxidation, with proteins, and with other substrates resulting in denaturation and PPT in tissues.
  • PMN create these to kill bacteria in phagolysosomes
  • small # of ROS are a normal byproduct of the ETC, and are normally destroyed by catalase
37
Q

Why is there an increased rate of ROS production with a reperfusion injury?

A
  • ATP levels will be low and NADH levels will be high in a tissue deprived of O2
  • when O2 is suddenly introduced, there is a burst of activity in the ETC, generating incompletely reduced ROS
38
Q

What is the body’s defense against ROS in highly aerobic tissues?

A
  • superoxide dismutase and catalase
39
Q

RBC and ROS

A
  1. in RBC, large # of superoxide are created by the spontaneous dissociation of O2 from Hb. These are:
    - methemoglobin and superoxide
  2. The enzymes required to detoxify the superoxide:
    - glutathione peroxidase
    - superoxide dismutase and catalase
    - Vitamin E in membranes
    - vitamin C in the cytoplasm
    - low levels of any of these enzymes results in hemolysis
    - ex) inadequate production of NADPH in G6PD leads to accumulation of destructive H2O2
40
Q

If O2 is limited, the rate of Oxidative phosphorylation ___ and the concentrations of NADH and FADH2 ____

A
  • If O2 is limited, the rate of Oxidative phosphorylation decreases and the concentrations of NADH and FADH2 increase
  • the accumulation of NADH inhibits the CAC
  • this is called “respiratory control”
41
Q

In the presence of adequate O2, the rate of oxidative phosphorylation is dependent on

A
  • the availability of ADP
  • The [ADP] and [ATP] are reciprocally related, an accumulation of ADP = a decrease in ATP and the amount of energy available in the cell
  • ADP accumulation signals the need for ATP synthesis
  • ADP allosterically activates isocitrate dehydrogenase, to increase the rate of the CAC and the production of NADH and FADH2
42
Q

Mutations in mitochondrial DNA affect

A
  • highly aerobic tissues (i.e. nerves, muscles)

- and the diseases exhibit maternal inheritance

43
Q

Key characteristics of most mitochondrial DNA (tDNA) diseases

A
  • lactic acidosis
  • massive proliferation of mitochondria in muscle, resulting in ragged red fibers
  • Ex) MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)
  • Ex) Leber Hereditary optic neropathy
  • Ex) Ragged red muscle fiber disease
44
Q

Succinate Dehydrogenase is part of the ETC and also part of what cycle?

A

the CAC

45
Q

FADH2 bypasses ____ and donates _____

A
  • FADH2 donates 2 e- and bypasses Complex I of the ETC
  • Complex II does not accept electrons and doesn’t transport a H+
  • Coenzyme Q (uniquinone) doesn’t pump H+ across the membrane
46
Q

What inhibits Complex I of the ETC?

A
  • Barbiturates (have a narrow TI)
  • Ex) phenobarbitol (antiseizure med)
  • Rotenone (an insecticide)
47
Q

the Glycerol 3P shuttle in the ETC is also involved in

A

Glycolysis

48
Q

how does cyanide inhibit the ETC?

A
  • it reduces Fe
  • binds to Fe3+ and shuts down the ETC
  • it inhibits at Complex IV, cytochrome oxidase
49
Q

what inhibits ATP synthase?

A

oligomycin

50
Q

What is 2,4 DNP?

A
  • it is an uncoupler of the ETC
  • it is a diet pill, but can be fatal bc it can cause a high fever
  • takes H+ back across the membrane where energy is lost as heat without ATP synthesis
  • uncouplers are proteins that allow H+ back into the inner Mito matrix, thus destroying the concentration gradient used to create ATP
51
Q

nitroprusside

A
  • used for emergency HTN
  • produces cyanide
  • antidote for cyanide toxicity: amyl nitrate
52
Q

What inhibits Complex IV of the ETC?

A

Cyanide

53
Q

What does oligomycin do?

A

Inhibits ATP synthase of the ETC

54
Q

What controls the rate of ATP synthesis via the ETC?

A

the [ADP]

- when there is high [ADP] , increased ATP synthesis

55
Q

What is the antidote for cyanide toxicity?

A

amyl nitrate

56
Q

What happens when citrate accumulates?

A
  • citrate is produced by citrate synthase from acetyl CoA and OAA in mito during CAC (but can exit mito via citrate shuttle)
  • when CAC slows, citrate accumulates –> enters cytosol
  • in cytosol acts as negative allosteric regulator of PFK-1 (thus prevents excess substrate from entering the cycle)
  • citrate is a + allosteric effector of cytosolic acetyl CoA carboxylase (rate-limiting and regulated enzyme of FA synthesis)
  • Acetyl CoA carboxylase: acetyl CoA + CO2 + biotin –> malonyl CoA ( = ABC enzyme; requires ATP, Biotin, CO2)
57
Q

Fructose 2,6 bisphosphatase

A
  • an activity of the bifunctional enzyme PFK-2
  • breaks down fructose-2,6 bisphosphate (synthesized by the kinase domain of PFK2) which is a potent allosteric activator of PFK1) and an inhibitor of fructose 1,6 bisphosphatase in gluconeogenesis
  • this results in the inhibition of glycolysis and activation of gluconeogenesis (opposite of function of fructose 2,6 bisphosphate)
  • regulated covalently
  • in liver: phosphorylation of PFK2 by PKA, activates the PHOSPHATASE activity (and inactivates the kinase)
  • in cardiac: phosphorylation by AMP kinase activates the phosphatase activity (and activates the kinase)

Kaplan Biochem and Genetics (21 decks)

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