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BIOCHEM > chapter 16 > Flashcards

chapter 16 Flashcards

1
Q

Fates of Pyruvate

A

fermentation to ethanol in yeast

-pyruvate->acetyl-coA->citric acid cycle, under aerobic conditions

-fermentation to lactate in vigorously contracting muscle, in erythrocytes, in some other cells, and in some microorganisms

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2
Q

Respiration & Cellular Respiration

A

-Process in which cells consume O2 and produce CO2
-Provides more energy (ATP) from glucose than glycolysis
-Also captures energy stored in lipids and amino acids
-Evolutionary origin: developed about 2.5 billion years ago (later than glycolysis)
-Used by animals, plants, and many microorganisms

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3
Q

Cellular Respiration

A

Stage 1: Acetyl-CoA Production
Oxidation of fatty acids, glucose and some amino acids yields acetyl-CoA

Stage 2: Acetyl-CoA Oxidation
Acetyl groups are fed into the TCA cycle and oxidized CO2- the energy released is conserved in electron carriers NADH, FADH2 and GTP (mitochondrial matrix, except succinate dehydrogenase located in the inner membrane)

Stage 3: Oxidative Phosphorylation
NADH and FADH2 oxidized, H+ and e- transferred to O2, generates a lot of ATP (inner membrane)

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4
Q

Respiration: Stage 1


A

Acetyl-CoA Production

Converts pyruvate to acetyl-CoA, generates some ATP, NADH and FADH2 by using the enzyme pyruvate dehydrogenase complex

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5
Q

Conversion of Pyruvate to Acetyl-CoA

A

Net Reaction:
-Oxidative decarboxylation of pyruvate
-First carbons of glucose to be fully oxidized to CO2

Catalyzed by the pyruvate dehydrogenase complex
-Requires 5 coenzymes
-TPP, lipoyllysine, and FAD are prosthetic groups
-NAD+ and CoA-SH are co-substrates

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6
Q

Structure of Coenzyme A

A

Coenzymes are not a permanent part of the enzymes’ structure.
–They associate, fulfill a function, and dissociate

CoA-SH to emphasize the active SH group contains pantothenate. The SH group forms a thioester with the acyl group. Thioesters have a high acyl group transfer potential and can transfer the acyl group to a variety of acceptor molecules

The function of CoA is to accept and carry acetyl groups

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7
Q

Structure of Lipoyllysine

A

Prosthetic groups are strongly bound to the protein
–The lipoic acid is covalently linked to the enzyme via a lysine residue

Lipoyllysyl moiety of dihydrolipoyl transacetylase acts as a carrier of hydrogen and an acetyl group

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8
Q

Pyruvate Dehydrogenase Complex 
(PDC)
Advantages of multienzyme complexes:

A

PDC is a large (up to10 MDa) multienzyme complex
-pyruvate dehydrogenase (E1)
-dihydrolipoyl transacetylase (E2)
-dihydrolipoyl dehydrogenase (E3)

Advantages of multienzyme complexes:
-short distance between catalytic sites allows -channeling of substrates from one catalytic site to another
channeling minimizes side reactions
- regulation of activity of one subunit affects the entire complex

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9
Q

Overall Reaction of PDC

A

An example of substrate channelling- intermediates do not leave the complex; [S] of E2 high; the acetyl group is not lost to other reactions.

E1- TPP
E2-Lipolysine, CoA-SH
E3-FAD, NAD

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10
Q

Sequence of Events in 
Oxidative Decarboxylation of Pyruvate

A

Enzyme 1
Step 1: Decarboxylation of pyruvate to an aldehyde
Step 2: Oxidation of aldehyde to a carboxylic acid
-Electrons reduce lipoamide and form a thioester

Enzyme 2
Step 3: Formation of acetyl-CoA (product 1)

Enzyme 3
Step 4: Reoxidation of the lipoamide cofactor
Step 5: Regeneration of the oxidized FAD cofactor
Forming NADH (product 2)

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11
Q

Respiration: Stage 2


A

Acetyl-CoA oxidation (TCA Cycle)

Generates more NADH, FADH2, and one GTP

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12
Q

Sequence of Events in the Citric Acid Cycle

A

Step 1: C-C bond formation to make citrate
Step 2: Isomerization via dehydration/rehydration
Steps 3–4: Oxidative decarboxylations to give 2 NADH
Step 5: Substrate-level phosphorylation to give GTP
Step 6: Dehydrogenation to give reduced FADH2
Step 7: Hydration
Step 8: Dehydrogenation to give NADH

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13
Q

Step 1

A

Formation of Citrate

C-C Bond Formation by Condensation of Acetyl-CoA and Oxaloacetate
-32.2kj/mol
-citrate synthase

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14
Q

Citrate Synthase

A

-Condensation of acetyl-CoA and oxaloacetate
-The only reaction with C-C bond formation

Uses Acid/Base Catalysis
—Carbonyl of oxaloacetate is a good electrophile
—Methyl of acetyl-CoA is not a good nucleophile…
—…unless activated by deprotonation

-Rate-limiting step of CAC
-Activity largely depends on [oxaloacetate]
-Highly thermodynamically favorable/irreversible
–Regulated by substrate availability and product inhibition

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15
Q

Induced Fit in the Citrate Synthase

A

Conformational change occurs upon binding oxaloacetate
Avoids unnecessary hydrolysis of thioester in acetyl-CoA

Open conformation:
Free enzyme does not have a binding site for acetyl-CoA

Closed conformation:
Binding of OAA creates binding for acetyl-CoA
Reactive carbanion is protected

Closed form with bound oxaloacetate and a stable analog of acetyl-CoA (carboxymethyl-CoA)

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16
Q

Step 2

A

Formation of Isocitrate via cis-Aconitate

Isomerization by Dehydration/Rehydration

=13.3kJ/mol
aconitase

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17
Q

Aconitase

A

-Elimination of H2O from citrate gives a cis C=C bond
–Lyase
-Citrate, a tertiary alcohol, is a poor substrate for oxidation
-Isocitrate, a secondary alcohol, is a good substrate for oxidation
-Addition of H2O to cis-aconitate is stereospecific

-Thermodynamically unfavorable/reversible
–Product concentration kept low to pull forward

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18
Q

Iron-Sulfur Center in Aconitase

A

Water removal from citrate and subsequent addition to cis-aconitate are catalyzed by the iron-sulfur center: sensitive to oxidative stress.

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19
Q

Citrate: A Symmetrical Molecule That Reacts

A

Asymmetrically

The two carbons brought in by acetyl-CoA are not the ones lost as carbon dioxide

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20
Q

Aconitase is

A

stereospecific

Only R-isocitrate is produced by aconitase

Distinguished by three-point attachment to the active site

21
Q

Step 3

A

Oxidation of Isocitrate to α-Ketoglutarate and CO2

-Oxidative decarboxylation 2#
-Oxidative decarboxylation of isocitrate to make α-ketoglutarate
-isocitrate dehydrogenase

22
Q

Isocitrate Dehydrogenase

A

Oxidative decarboxylation
–Lose a carbon as CO2
–Generate NADH

Oxidation of the alcohol to a ketone
–Transfers a hydride to NAD

Cytosolic isozyme uses NADP+ as a cofactor

Highly thermodynamically favorable/irreversible
–Regulated by product inhibition and ATP

23
Q

Mechanisms of Isocitrate Dehydrogenase:
Metal Ion Catalysis (Decarboxylation)
Carbon lost as CO2 did

A

Carbon lost as CO2 did NOT come from acetyl-CoA.

24
Q

step 4

A

Oxidation of α-Ketoglutarate to Succinyl-CoA, CO2

-Final oxidative decarboxylation
-Energy of oxidation is conserved in formation of a thioester bond with succinyl-CoA

-33.5kJ/mol
-alpha ketoglutarate dehydrogenase complex

25
Q

α-Ketoglutarate Dehydrogenase
-Carbons not directly from glucose because carbons lost came from
-Succinyl-CoA is another higher-energy

A

Last oxidative decarboxylation
-Net full oxidation of all carbons of glucose
—After two turns of the cycle
—Carbons not directly from glucose because carbons lost came from oxaloacetate

-Succinyl-CoA is another higher-energy thioester bond
-Highly thermodynamically favorable/irreversible
—Regulated by product inhibition

26
Q

Origin of C-atoms in CO2

A

Both CO2 carbon atoms derived from oxaloacetate

27
Q

α-Ketoglutarate Dehydrogenase

A

Complex similar to pyruvate dehydrogenase
–Same coenzymes, identical mechanisms
–Active sites different to accommodate different-sized substrates

28
Q

Step 5

A

-2.9kJ/mol
Generation of GTP through Thioester:
Thioester bond of succinyl-CoA has a ΔG’º of -36kJ/mol and is used to drive the synthesis of a phosphoanyhdride bond in ATP or GTP with a net ΔG’º of -2.9 kJ/mol
-succinyl-CoA synthetase

29
Q

Succinyl-CoA Synthetase

A

-Substrate level phosphorylation
-Energy of thioester allows for incorporation of inorganic phosphate
-Goes through a phospho-enzyme intermediate
-Produces GTP, which can be converted to ATP
-Slightly thermodynamically favorable/reversible
–Product concentration kept low to pull forward

30
Q

Step 6

A

Oxidation of succinate to Fumarate
Oxidation of alkane to alkene
0kJ/mol
-succinate dehydrogenase

31
Q

Succinate Dehydrogenase
Bound to
Oxidation of the alkane to alkene requires

A

Bound to mitochondrial inner membrane
-Part of Complex II in the electron-transport chain
Oxidation of the alkane to alkene requires FAD
-Reduction potential of NAD is too low

FAD is covalently bound, unusual

Near equilibrium/reversible
-Product concentration kept low to pull forward

32
Q

Step 7

A

Hydration of Fumarate to Malate
-3.8kJ/mol
Hydration Across a Double Bond

33
Q

Fumarase

A

Stereospecific
-Addition of water is always trans and forms L-malate
-OH- adds to fumarate… then H+ adds to the carbanion
-Cannot distinguish between inner carbons, so either can gain –OH

Slightly thermodynamically favorable/reversible
-Product concentration kept low to pull reaction forward

34
Q

Step 8

A

Oxidation of Malate to Oxaloacetate
Oxidation of Alcohol to a Ketone
=29.7kJ/mol

35
Q

Malate Dehydrogenase
Regenerates oxaloacetate for
Oxaloacetate concentration kept

A

Final step of the cycle
Regenerates oxaloacetate for citrate synthase

Highly thermodynamically UNfavorable/reversible
-Oxaloacetate concentration kept VERY low by citrate synthase
—Pulls the reaction forward

36
Q

One Turn of the Citric Acid Cycle

A

Complete oxidation of glucose is about 2840 kJ/mol. Overall energy from cellular respiration is about 32 molecules of ATP at about 30.5kJ/mol and an overall conservation of about 34% of the maximum yield.

37
Q

Net Result of the Citric Acid Cycle

A

Acetyl-CoA + 3NAD+ + FAD + GDP + Pi + 2 H2O 
2CO2 + 3NADH + FADH2 + GTP + CoA + 3H+

Net oxidation of two carbons to CO2
-Equivalent to two carbons of acetyl-CoA
-but NOT the exact same carbons

-Energy captured by electron transfer to NADH and FADH2
-Generates 1 GTP, which can be converted to ATP
-Completion of cycle

38
Q

Respiration: Stage 3


A

Oxidative Phosphorylation
-Generates a lot of ATP

39
Q

CAC intermediates are amphibolic

A

The cycle provides energy and also provides intermediates that are used in biosynthesis
Anaplerotic reactions (red )

40
Q

Anaplerotic Reactions

A

-Intermediates in the citric acid cycle can be used in biosynthetic pathways (removed from cycle)
-Must replenish the intermediates in order for the cycle and central metabolic pathway to continue
-4-carbon intermediates are formed by carboxylation of 3-carbon precursors

41
Q

Regulation of the Citric Acid Cycle

A

Two levels of regulation

Outside the TCA Cycle
-Pyruvate dehydrogenase complex

Inside the TCA Cycle
-Citrate synthase
Isocitrate dehydrogenase
α-ketoglutarate dehydrogenase

42
Q

Regulation of the Citric Acid Cycle
Regulated at highly thermodynamically

A

Regulated at highly thermodynamically favorable and irreversible steps
-PDH, citrate synthase, IDH, and KDH

General regulatory mechanism
-Activated by substrate availability
-Inhibited by product accumulation
-Overall products of the pathway are NADH and ATP
—Affect all regulated enzymes in the cycle
—Inhibitors: NADH and ATP
—Activators: NAD+ and AMP

43
Q

Regulation of Pyruvate Dehydrogenase

A

Pyruvate dehydrogenase complex is regulated by two different mechanisms
–Allosteric regulation
–Regulation by covalent modification

Mainly by reversible phosphorylation of E1
–Phosphorylation: inactive
–Dephosphorylation: active

PDH kinase and PDH phosphorylase are part of mammalian PDH complex
-Kinase is activated by ATP
—High ATP  phosphorylated PDH  less acetyl-CoA
—Low ATP  kinase is less active and phosphorylase removes phosphate from PDH  more acetyl-CoA

44
Q

Additional Regulatory Mechanisms

Citrate synthase is also inhibited by

Regulation of isocitrate dehydrogenase controls

-Inhibition of IDH leads to
-Accumulated citrate leaves

A

Citrate synthase is also inhibited by succinyl-CoA
-α-ketoglutarate is an important branch point for amino acid metabolism
-Succinyl-CoA communicates flow at this branch point to the start of the cycle

Regulation of isocitrate dehydrogenase controls citrate levels
-Aconitase is reversible
-Inhibition of IDH leads to accumulation of isocitrate and reverses acconitase
-Accumulated citrate leaves mitochondria and inhibits phosphofructokinase in glycolysis

45
Q

Glyoxylate Cycle

A

-A variation of TCA cycle, an anabolic pathway, used for the net synthesis of glucose from lipids
-occurring in plants, certain invertebrates and some microorganisms (E coli, yeast)
-Not found in vertebrates that lack isocitrate lyase and malate synthase
-Isozymes are found where there are common enzymes between the citric acid cycle and glyoxylate cycle

46
Q

Glyoxylate Cycle Operates in

A

Glyoxysomes in Plants

Electron micrograph of a germinating cucumber seed, showing a glyoxysome, mitochondria, and surrounding lipid bodies.

47
Q

Compartmentation of Glyoxylate Cycle

A

-Overall reaction of glyoxylate cycle:
2Acetyl-CoA + NAD+ + 2H2O → succinate + 2CoA + NADH + H+
-Each turn of the cycle consumes two molecules of acetyl-CoA and produces one molecule of succinate
-Succinate can be used for biosynthesis

Plants can synthesize glucose from acetate but mammals can’t!

48
Q

Coordinated Regulation of Glyoxylate and TCA Cycles

A

Control point is isocitrate dehydrogenase. Phosphorylation of the enzyme which inactivates it so that glyoxylate cycle is engaged

BIOCHEM (13 decks)

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