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Medical Biochemistry -1b > Citric Acid Cycle and Oxidative Phosphorylation > Flashcards

Citric Acid Cycle and Oxidative Phosphorylation Flashcards

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USMLE® Step 1 flashcards
0
Q

What are c.a.c’s anabolic functions? catabolic functions?

A

It can catabolize Acetyl-CoA to yield CO2. During catabolism, it can generate high-energy compounds (such as GTP, ATP) and reduced cofactors such as FADH and NADH.

It can be anabolic by yielding various intermediates such as citrate, alpha-ketoglutarate, succinyl CoA, oxaloacetate, etc. that are used to synthesize other compounds (such as glucose, amino acids, fatty acids, heme and other cell constituents).

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1
Q

Why is the citric acid cycle (c.a.c) said to be amphibolic?

A

It possesses both catabolic and anabolic functions

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2
Q

What are other names for the citric acid cycle?

A
  1. Tricarboxylic Acid (TCA) cycle

2. Krebs Cycle

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3
Q

What is the fuel for the c.a.c? From what metabolites is it derived?

A

Acetyl CoA is the fuel for the c.a.c.

Acetyl CoA is synthesized from pyruvate, NAD+ and CoASH via pyruvate dehydrogenase. Also, Acetyl CoA is derived from fatty acids, amino acids, and glucose.

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4
Q

What four intermediates of the cycle are important for synthesis of other cell constituents, and what are those contsituents?

A

Citrate: made via citrate synthase and provides carbons for fatty acid synthesis and gluconeogenesis. It also inhibits the rate-limiting enzyme, phosphofructokinase-I in glycolysis

alpha-ketogluterate: made by isocitrate dehydrogenase it is generated into glutamate (in one step by transamination)

Succinyl CoA : made by alpha ketoglutarate dehydrogenase. Provides heme synthesis.

Oxaloacetate: made by malate dehydrogenase. Gives rise to glucose synthesis and aspartate (by one step transamination)

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5
Q

Where in the cell does the citric acid cycle occur?

A

In the mitochondrion

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6
Q

Where in the cell does oxidative phosphorylation occur?

A

mitochondria inner membrane

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7
Q

How many molecules of reduced cofactors are produced by the oxidation of one molecule of acetyl CoA by the C.a.c?

A

3 moles of NADH
1 mole of FADH2
1 mole of GTP

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8
Q

What are the fates of Pyruvate?

A
  • reduction to lactate (via lactate dehydrogenase)
  • carboxylation to oxaloacetate (via pyruvate carboxylase)
  • transamination to alanine (via aminotransferase)
  • oxidation to acetyl CoA (via pyruvate dehydrogenase)
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9
Q

What is the order of the intermediates of the TCA cycle?

A

citrate -> isocitrate -> succinyl CoA -> Succinate -> Fumarate -> Malate -> Oxaloacetate

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10
Q

Why is the TCA cycle strictly aerobic?

A

because the regeneration (reoxidation of reduced cofactors (e.g. NADH and FADH2) ultimately depend on molecular oxygen (via the electron transport chain)

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11
Q

During oxidative-phosphorylation, what is oxygen excreted as?

A

Water

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12
Q

What is succinate good for outside the TCA cycle?

A

Made by succinate CoA synthase, succinate controls vascular proliferation and it’s receptors are found on RETINAL GANGLION cells. When stimulated, succinate can lead to vascular proliferation and blindness.

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13
Q

What enzymes catalyze the formation of NADH in the TCA cycle?

A

Step 3: isocitrate —> alpha-ketoglutarate (via isocitrate dehydrogenase)

Step 4: alpha-ketoglutarate —> succinyl CoA (via alpha-ketogluarate dehyrdrogenase

Step 8: malate —> oxaloacetate (via malate dehyrdrogenase)

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14
Q

What step of the TCA cycle is GTP produced?

A

Step 5: From succinyl CoA —> succinate (via succinate thiokinase)

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15
Q

At what step(s) in the TCA cycle is FADH2 produced?

A

Step 6: Succinate —> fumarate (via succinate dehyrdrogenase)

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16
Q

How many ATP’s are generated through oxy/phos during the oxidation of NADH? FADH2? WHy are these numbers approximate?

A

1 NADH –> ~3 ATP
1 FADH2 –> ~2 ATP

Numbers are approximate because the reduced electron carriers outside the mitochondrial matrix require a shuttle system to move across the inner mitochondrial membrane, which requires energy.

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17
Q

What other “high-energy” compound is created directly in the TCA cycle? (besides FADH2 and NADH)

A

GTP

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18
Q

Why is pyruvate carboxylase an important enzyme? What is its allosteric effector?

A

○ Pyruvate carboxylase provides OAA (oxaloacetate) to keep the TCA cycle going when intermediates are being removed for synthesis (anaplerotic function)
○ positive allosteric effector of pyruvate carboxylase - acetyl CoA

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19
Q

Why is pyruvate dehydrogenase an important enzyme?

A

Pyruvate dehydrogenase - links glycolysis to the TCA cycle by converting pyruvate to acetyl coA.

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20
Q

What is pyruvate dehydrogenase inhibited by? stimulated by?

A

Stimulated by:
Directly: NAD+
Indirect: Ca2+ and high insulin

Inhibited by:
Direct: Acetyl CoA and NADH
Indirect: low insulin

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21
Q

Pyruvate dehydrogenase and alpha-ketoglutamate are similar enzymes. How do they differ?

A

Pyruvate dehydrogenase is controlled by phosphorylation/dephosphorylation, and alpha-ketoglutarate dehydrogenase is NOT.

22
Q

Insulin stimulates the activity of pyruvate dehyrdogrenase by…?

A

activating pyruvate dehydrogenase (Pdh) phosphatase.

23
Q

What are controls of the Citric Acid Cycle?

A
  • availability of acetyl CoA ([acetylCoA])
  • availability of Oxygen ([O2])
  • redox potential = proportion of NAD+/NADH
  • “the energy charge” = ATP/(ADP+AMP)
24
Q

The oxidation of one mole of glucose via glycolysis and the c.a.c. produces how many moles of ATP (if you count the GTP’s as ATP’s).

A

~30 moles of ATP/GTP

25
Q

What types of diseases or dysfunctions are succinate dehyrdogenase and fumarate hydratase linked to?

A

mitochondrial dysfunction and cancer

27
Q

What is TCA dysfunction a postulated cause of? What is the biochemical basis?

A

Human diseases and tumor formation due to accumulation of succinate and fumarate. This is caused by mutations in fumarate hydratase and succinate dehydrogenase. The accumulation of succinate and fumarate inhibit the hydroxylation of proline on hypoxia-inducible factors (HIF’s), which leads to cell proliferation and angiogensis.

The HIF’s inactivate prolyl hydroxylase, thus causing the transcriptional activation of genes that support tumor growth, neovascularization, invasion and metastasis.

28
Q

What is the role of the proton gradient in ox/phos? How is it generated?

A

The roles of the proton gradient include:
■ ATP generation
■ cell motility
■ proton-driven uptake of:
● calcium
● nickel & other metals
● DNA: genetic transformation in bacteria

29
Q

Does proton pumping cause the mitochondrial MATRIX to become more basic (alkaline) or acidic?

A

basic/alkaline

30
Q

Across which complexes (# and name) in the ox/phos are protons pumped across?

A

● Complex I (NADH/CoQ reductase)
● Complex III (CoQ/cytochrome c reductase)
● Complex IV (cytochrome oxidase)

31
Q

Across which complexes (# and name) in the ox/phos are protons NOT pumped across?

A

protons are NOT pumped across Complex II (Succinate dehydrogenase/CoQ reductase)

32
Q

During ox/phos what drives proton flow into the mitochondrial membrane?

A

ATP Synthesis

33
Q

What enzyme of the TCA cycle is also a member of the electron transport system? What does it do?

A

succinate dehydrogenase (in complex II) passes electrons from FADH to Coenzyme Q

34
Q

Ox/phos is totally dependent upon the impermeability of the inner mitochondrial membrane to

A

protons

35
Q

During the oxidative part of ox/phos, what happens?

A

electrons are transferred from NADH to Complex I

36
Q

What are the two characteristics of an uncoupler of ox/phos? How does an uncoupler work?

A

■ lipophilic - soluble in membranes
■ weak acids - readily protonated/deprotonated, depending on pH

Uncouplers work by facilitating the passage of protons across the inner mitochondrial membrane ANYWHERE else other than the ATP synthase

37
Q

What are the consequences of uncoupling ox/phos?

A

■ decreased ATP synthesis
■ increased HEAT (thermogenesis)
■ increased oxidation rate, (i.e. electron transport, fuel metabolism, O2-consumption)

38
Q

What are characteristics of Brown adipose tissue (BAT)

A

■ contains many mitochondria
■ forms fat globules
■ contains thermogenin (UCP-1, or Uncoupling protein -1)
■ helps generate heat during “non-shivering thermogenesis”, like in a newborns who cannot shiver
■ produce heat without much ATP synthesis

39
Q

What are biological roles of UCP’s?

A

■ thermogenesis
■ Antioxidant: minimize formation of reactive oxygen species (ROS)
■ increases insulin secretion/action

40
Q

Where within the cell does ox/phos occur?

A

○ within and across the inner mitochondrial membrane

○ the inner mitochondrial membrane has much more protein than other membranes in the cell.

41
Q

What is P50, and how does it change with a right shift? (Don’t forget about Hb).

A

○ pO2 at which half of hemoglobin’s binding sites are occupied

42
Q

What is dinitrophenol (DNP)? What can it act as?

A

Dinitrophenol is a highly lipid soluble weak acid that can act as an uncoupler of ox/phos

43
Q

Which of the enzymes of the c.a.c. have been identified as tumor supressors?

A

Recoupling (antagonists) of UCP2 can possibly suppress tumors.

44
Q

What are the two transductive events of Oxidative Phosphorylation

A

Oxidation (Redox potential energy: (NADh+FADH2)»Groton gradient leads to…

Phosphorylation: proton gradient&raquo_space; Chemical Energy (ATP)

45
Q

What is the formula for the Electronmotive Potential? What is the criterion for spontaneity in a redox reaction?

A

∆G’o = - n F ∆E’o

The criterion for spontaneity in a redox reaction is a
positive ∆E’o.

46
Q

Mutations in what genes mtDNA have led to Leber Hereditary Optic Atrophy?

A

mutations in genes for Complex I, III, and IV polypeptides.

47
Q

What are three mitochondrial diseases involving vision? What is one main symptom?

A

Alper’s Disease - blindness
LHON (leber Hereditary Opti cNeuropathy): blindness in young men
MELAS (Mitochondrial Encephalomyopathy Lacid Acidosis and Strokelike Episodes): stroke-like episodes with focused neurological deficits

48
Q

What is the progression of the oxidation reduction potential E_0(V) in oxidative phosphorylation?

A

N(ADH)egative to pO2sitive

49
Q

What can form superoxides in ox/phos and what can it damage in the TCA cycle?

A

superoxides are formed from an accumulation of H+ buildup in the intermembrane space. This causes the Complexes I and III to be highly reduced, which causes Oxygen to bind and form superoxides. Supeoxides can damage aconitase from the TCA cycle.

50
Q

What enzyme of the citric acid cycle is also a member of the electron transport system?

A

succinate dehydrogenase ( Complex II )

51
Q

Insulin stimulates the activity of pyruvate dehydrogenase by?

A

activating pyruvate dehydrogenase phosphatase (which, removes a phosphate to convert pyruvate dh to it’s active form)

52
Q

What are two direct inhibitors of Pyruvate dh? What is their mechanism?

A

Acetyl CoA and NADH directly inhibit pyruvate dehydrogenase (which converts pyruvate to acetyl CoA) by activating pyruvate dh kinase, which adds a phosphate to pyruvate dh, making it inactive.

53
Q

Acetyl CoA is a positive allosteric effector for

A

pyruvate dh kinase [glycolysis]

pyruvate decarboxylase [gluconeogenesis]

54
Q

When enzyme has been found to be defective in patients born of consanguineous mating and suffering from severe mental and physical retardation?

A

fumarate hydratase

Medical Biochemistry -1b (6 decks)

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