Carbohydrate Metabolism II Flashcards by J L

Overview of Glucose Metabolism: Glycolysis and Gluconeogenesis

Gluconeogenesis occurs mainly in the _____.

Synthesis of glucose from pyruvate utilizes many of the
same enzymes as _____.

Three Glycolysis reactions have such a large negative ΔG
that they are essentially _____:
 _____ (or Glucokinase)
 _____
 _____.
These steps must be _____ in gluconeogenesis.

liver
glycolysis
irreversible
hexokinase
phosphofructokinase
pyruvate kinase
bypassed

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1st Bypass Reaction: Formation of Phosphoenolpyruvate (PEP)
• PEP cannot be directly formed from pyruvate:
– Formed through a two-step process via _____.
– OAA is an intermediary of the _____.

oxaloacetate (OAA)

TCA cycle

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1st Bypass Reaction: Formation of Phosphoenolpyruvate (PEP)

• Step 1: Pyruvate is carboxylated by a _____ to form OAA:
– Pyruvate carboxylase is a biotin-dependent _____
enzyme.
– Requires the hydrolysis of one molecule of _____.

• Step 2: OAA is decarboxylated to form PEP by a
_____: – Requires the hydrolysis of one molecule of _____.
– PEPCK is located in the _____, in _____, or both. – It is widely distributed in tissues.

PEP - _____ molecule

pyruvate carboxylase
mitochondrial
ATP

phosphoenolpyruvate carboxykinase (PEPCK)
GTP
cytosol
mitochondria
high energy

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2nd Bypass Reaction: Formation of Fructose 6-phosphate

_____ hydrolyzes Pi from fructose 1,6-bisphosphate to form fructose 6-phosphate

– not a _____ of the _____ reaction
– ATP is not produced when the phosphate is removed; Pi is release by _____

Fructose 6-phosphate is converted to glucose 6-phosphate by the same isomerase used in glycolysis (_____)

fructose 1,6-bisphosphatase
reversal
phosphofructokinase-1 PFK1
hydrolysis
phosphoglucoisomerase

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3rd Bypass Reaction: Formation of Glucose
• Glucose 6-phosphatase hydrolyzes Pi from glucose 6- phosphate, and free _____ is released into the blood:
– Not a reversal of the _____ reaction.
– _____ is not produced when the phosphate is removed; Pi is released by _____

glucose
glucokinase
ATP
hydrolysis

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Glycolysis vs. Gluconeogenesis

Glycolysis accomplishes a negative ΔG while yielding reducing equivalents (2 _____) and 2 net _____.
• Gluconeogenesis requires the use of 4 _____ and 2 _____ to achieve its negative ΔG.

NADH
ATP
ATP
GTP

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Gluconeogenesis and Glycolysis: a Futile Cycle?
Glycolysis and Gluconeogenesis both achieve _____, therefore both are _____.
If both pathways were simultaneously active in a cell, it would constitute a _____ that would waste energy.

An apparent “futile cycle” is actually the site of a finely _____ mechanism.

negative deltaG
spontaneous
“futile cycle”
regulated

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Reciprocal Regulation of Gluconeogenesis and Glycolysis

To prevent the waste of a tuile cycle, glycolysis and gluconeogenesis are _____
reciprocal allosteric regulation by _____:
-Phosphofructokinase (glycolysis)
–_____ by ATP and _____ by AMP
-Fructose-1,6-bisphosphatase (gluconeogenesis):
–_____ by AMP
high cellular ATP/AMP:
-glucose is not _____ to make ATP
low ATP/AMP:
-the cell does not expend _____ in the synthesis of glucose

reciprocally regulated
adenine nucleotides
inhibited
stimulated
inhibited
degraded
energy

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first mechanism that regulates both enzymes involved in the negative free energy = _____

this is considered to be a _____ regulation

allosteric regulation by adenine nucleotides

“local”

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Reciprocal regulation of Gluconeogenesis and Glycolysis

• Systemic regulation in liver cells by the cAMP cascade:
• Makes glucose available for release to the bloodstream:
– Inhibition of _____.
– Stimulation of _____.
Triggered by low _____.
Mediated by _____.
_____ of enzymes and regulatory proteins by Protein Kinase A (cAMP-
–Dependent Protein Kinase): Pyruvate Kinase:
 Glycolysis enzyme that is _____ when phosphorylated.
– CREB (cAMP response element-binding protein):
 Activates transcription of the _____ gene, leading to increased _____.
– Phosphofructokinase 2 makes and degrades an allosteric regulator, _____.

glycolysis
gluconeogenesis
blood glucose
glucagon
phosphorylation
inhibited
PEP carboxykinase
gluconeogenesis
fructose-2,6-bisphosphate

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Reciprocal regulation of Gluconeogenesis and Glycolysis

Reciprocal regulation by fructose-2,6-bisphosphate (F2,6P):

 F2,6P stimulates _____.
 F2,6P allosterically _____ the Glycolysis enzyme PFK-1 (see CHO lecture 1, slide 47).
 F2,6P activates the transcription of the _____ gene, the liver variant of Hexokinase that phosphorylates Glc to G6P, the input to _____.
 F2,6P allosterically inhibits the gluconeogenesis enzyme _____.

glycolysis
activates
glucokinase
glycolysis
fructose-1,6-bisphosphatase

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Reciprocal regulation of Gluconeogenesis and Glycolysis

Summary of effects of the glucagon-cAMP cascade in the liver:
 Gluconeogenesis is _____.
 Glycolysis is _____.
 Glycogen breakdown is _____.
 Glycogen synthesis is _____.
 _____ is formed for release to the blood.

stimulated
inhibited
stimulated
inhibited
free glucose

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Physiological Significance of Gluconeogenesis

• Failure of gluconeogenesis:
– Usually _____.
– Hypoglycemia leads to _____ and coma.
– Glucose is also necessary to maintain TCA cycle intermediates for _____.

• Excessive gluconeogenesis:
– May lead to _____ in critically ill patients.
– Due (in part) to excess of the stress hormone _____.

• Energy cost:
– _____ on very low carbohydrate diets.
– The continual demand for glucose leads to gluconeogenesis from _____.
– ATP required for gluconeogenesis is provided by increased oxidation of _____.

fatal
brain dysfunction
fat metabolism

hyperglycemia
cortisol

weight loss
amino acids
fatty acids

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Part II: The Tricarboxylic Acid Cycle (TCA; Krebs Cycle; Citric Acid Cycle)

• _____ of proteins, fats, and carbohydrates.
• Two stages of cellular respiration.
– Stage 1: Oxidation of fuels.
— Stage 1a: oxidation to _____.
— Stage 1b: oxidation of acetyl groups to
_____ with energy release as reduced
electron carriers _____ and _____.

• Stage 2: ATP generation from electrons
carried by NADH and FADH2 to reduce _____ to _____.

catabolism
acetyl CoA
CO2
NADH
FADH2

O2
H2O

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Alternative Fates of Pyruvate and Regeneration of NAD+

A. Pyruvate is metabolized in the _____, and the reducing power of NADH is used to synthesize ATP in the _____.

B. Fermentation to lactate in vigorously contracting muscle, in erythrocytes, in some other cells, and in some microorganisms: _____ and _____ form lactate, regenerating _____.

C. In yeast and other microorganisms, pyruvate is converted to _____.

TCA (Krebs) cycle
mitochondria

NADH
pyruvate
NAD+

ethanol

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The TCA and oxidative phosphorylation take place in mitochondria

Glycolysis occurs in the _____

Formation of acetyl COA and the TCA cycle > both take place in the _____ (not associated with the membrane; _____ proteins)

cell

matrix of the mitochondria
soluble

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TCA cycle: Important points

• Function: to fully \_\_\_\_\_ derived from carbohydrates, fats and proteins to CO2.
• Carbon atoms delivered to the TCA cycle in the form of \_\_\_\_\_.
• This oxidation produces:
\_\_\_\_\_: 
• GTP
• NADH
• FADH2
\_\_\_\_\_ used for biosynthetic processes,
e.g. fatty acids, amino acids
• \_\_\_\_\_

The TCA is an _____ pathway in _____.
The cycle is regulated by the state of cellular energetics and _____.
TCA cycle intermediates must be _____ to continue the cycle for energy production, as well as to provide substrates for biosynthetic pathways.

oxidize carbon atoms
acetyl CoA
high-energy molecules
metabolic intermediates
CO2

aerobic energy-producing
mitochondria
O2 availability
maintained

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Formation of Acetyl-Coenzyme A from Pyruvate

Pyruvate:

- Transported into _____ by a transporter
-Decarboxylated to acetyle-CoA by the _____

Pyruvate dehydrogenase:

- multi-enzyme complex containing multiple copies of _____ enzymes
- several coenzymes:
– _____
– coenzyme A (pantothenic acid)
– _____
– thiamine pyrophosphate (thiamine)

The release of _____ provides a powerful driving force for the reaction.

mitochondria
pyruvate dehydrogenase complex

three
NAD+ (niacin)
lipoamide FAD (riboflavin)

CO2

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Coenzyme A has a _____; the vitamin _____ is bonded to the nt; linker region: _____ (in reduced form ends in a thiol group)

in blue is the acetyl part (binds to the _____ group); everything else remains the same (vitamin b5 and the nt.)

nucleotide portion
B5
beta-mercapto ethylamine
thiol

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Conversion of pyruvate to acetyl-CoA: a key branch point of metabolism

Product inhibition by Acetyl CoA and NADH: when these products _____, decarboxylation of pyruvate is _____

The reaction is sensitive to the energy charge:

- _____ by ATP, acetyl-CoA, NADH, fatty acids
- _____ by AMP, CoA, NAD+, Ca2+

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accumulate
blocked
inhibited
stimulated

Step 1: Condensation of Acetyl-CoA with oxaloacetate (OAA) to form _____

Mediated by the enzyme _____.
This reaction is inhibited by _____.
Citrate is used in synthesis of _____ and _____.

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citrate
citrate synthase
ATP
cholesterol
FA

Step 2: Citrate is isomerized to _____.

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isocitrate

Step 3: Oxidation and decarboxylation of isocitrate to form _____

_____ and _____ are produced.
The reaction is inhibited by _____ and stimulated by _____.
α-KG is a precursor for glutamate, glutamine, purines.

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alpha-ketoglutarate
NADH
CO2
ATP
ADP

Step 4: α-KG is converted to _____
• _____ and _____ are produced.
• Mediated by a dehydrogenase: _____.
• Succinyl-CoA and NADH _____ the reaction.
• Succinyl-CoA is a precursor of _____ and chlorophyll biosynthesis

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succinyl-CoA
NADH
CO2
alpha-KG dehydrogenase
inhibited
heme

Step 5: Conversion of succinyl-CoA to _____ • Mediated by the _____ enzyme. • GDP is phosphorylated to form _____. • _____ – direct transfer of Pi to GDP. Succinyl-CoA + Pi + GDP --> Succinate + _____ + CoA-SH

``` succinate succinate thiokinase GTP substrate level phosphorylation GTP ```

Step 6: Succinate is oxidized to form _____ • _____ is produced. • Mediated by the _____.

fumarate FADH2 succinate dehydrogenase

Step 7: fumarate is hydrated to form _____ Step 8: Malate is oxidized to regenerate _____; one more _____ is produced

malate OAA NADH

Regulation of the TCA cycle - In general, the pathway will be inhibited when _____ levels are high - Conversely, the pathway will be stimulated when _____ levels are low and _____ levels are high

ATP ATP AMP/ADP

Overall stoichiometry of the TCA cycle AcetylCoA + 3 NAD + + FAD + GDP + Pi + 2 H2O --> 2 CO2 + 3 NADH + 3 H + + FADH2 + GTP + CoA-SH * 2 _____ are formed for each Acetyl CoA used. * 1 _____ is produced by substrate-level phosphorylation. * 3 _____ and 1 _____ carry high-energy electrons which will enter the _____ to produce ATP.

``` CO2 GTP NADH FADH2 electron transport chain ```

TCA Cycle and Gluconeogenesis * Gluconeogenesis enzyme _____ (pyruvate + CO2 -> OAA): * Allosterically _____ by acetyl-CoA. • [OAA] tends to be _____ for the TCA cycle. • When gluconeogenesis is active in liver, OAA is diverted to form _____. • OAA depletion hinders acetyl-CoA _____ into the TCA cycle. • The increase in _____ activates Pyruvate Carboxylase to make OAA.

``` pyruvate carboxylase activated limiting glucose entry [acetyl-CoA] ```

Summary of the TCA Cycle • _____, energy-producing pathway in _____. • Produces 1 _____, plus 3 _____ and 1 _____ which provide electrons for electron transport chain. • Regulated by the state of _____ and O2 availability: --- the end products ATP and NADH are _____, and the substrates NAD+ and ADP are _____. * The production of acetyl-CoA is _____ allosterically by metabolites that signal a sufficiency of metabolic energy (ATP, acetyl-CoA, NADH, and fatty acids) and _____ by metabolites that indicate a reduced energy supply (AMP, NAD, CoA). * Cycle intermediates must be _____.

``` aerobic mitochondria GTP NADH FADH2 cellular energetics inhibitory stimulatory ``` inhibited stimulated maintained

Part III: Energetics and Oxidative Phosphorylation • Oxidative phosphorylation couples oxidation of _____ to _____. • Coupling through the production of a _____ across the _____ mitochondrial membrane. • The rate of oxidative phosphorylation is tightly controlled by the level of _____ and the availability of _____.

reduced coenzymes ATP formation proton gradient inner ADP oxygen

The oxidative phosphorylation system is located on the _____ of the mitochondrion • The electron transport chain, a series of enzymes, coenzymes and electron transport proteins, are embedded in the _____. • The apparatus is organized _____ to facilitate electron transfer and ATP synthesis. ``` TCA = _____ in matrix ETC = enzymes associated with the _____ (ATP synthase) ```

``` inner membrane membrane spatially soluble inner mitochondrial membrane ```

Electron Transport Chain: The Chemiosmotic Theory * Chemiosmotic theory: the energy of electron flow is conserved by the pumping of _____ across the membrane, producing an _____ gradient, the _____. * Electrons are transferred along the chain. * Electron transfer is coupled to transport of protons into the mitochondrial _____ space. * Proton gradient provides energy for _____.

``` protons electrochemical gradient proton-motive force intermembrane ATP synthesis ```

energy that is transmitted by the redox reactions (comes from the oxidation of those reduced nt's) everytime there is a _____ > transports H+ from _____ into intermembrane space everytime a _____ of e- goes through the entire chain (xfer of _____ H+) > chemiosmotic theory

redox rxn matrix pair 3

Electron movement through the electron transport chain Builds up a high concentration of H+ in _____. When electrons enter _____, they combine with oxygen to form water. _____ and _____ are involved with reducing the three complexes

intermembrane space cytochrome oxidase NADH FADH2

Electron movement through the electron transport chain • Redox potential scale: --- Electrons pass from carriers with a _____ reduction potential to those with a _____ (more positive) potential. • Free-energy scale: --- _____ in free energy as a pair of electrons moves through the chain. • The energy released as electrons flow through three of the complexes is sufficient to power the pumping of H+ ions across the membrane, establishing a _____.

lower higher reduction proton-motive force

Ubiquinone (Coenzyme Q10) accepts _____ electrons and _____ protons • Complete reduction of ubiquinone requires _____ electrons and _____ protons, and occurs in _____ steps.

``` two two two two two ```

Cytochrome oxidase accepts electrons from _____ and forms H2O • Additional site of coupling to proton pump. • _____ of O2 uptake in humans goes to this complex. • _____ and _____ binding to complex stops electron transport.

cytochrome c 90% cyanide azide

Transfer of protons to intermembrane space creates an electrochemical proton gradient • Proton pumping across the membrane: • Increases [H+] outside the membrane (pH gradient). • Creates a difference in _____ potential (+ outside, - inside) across the membrane. • Protons will follow the electrochemical gradient from _____ to the _____. • ATP synthase uses the energy of the _____ (proton-motive force) to produce ATP. There is both an electrical gradient created in addition to a _____ gradient

``` electrical outside inside electrochemical gradient concentration ```

Electrochemical proton gradient across inner mitochondrial membrane allows ATP synthase to generate ATP ATP synthase creates a _____ pathway across the membrane, allowing protons to flow down their electrochemical gradient.

hydrophilic

ATP synthase * The F0 portion: * _____: channel for H+ flow. * Stalk: _____, driven by the H+ gradient. * The F1 portion: _____. * ATP synthase is an energy-generating _____.

transmembrane proton carrier rotor ATP synthase molecular motor

ATP Synthase enzyme allows H+ to cross membrane; the F1 part of the enzyme turns _____ each time one H+ crosses the hydrophilic channel difference in gradient/charge/cxn > xformed into _____ energy, but physically turning F1 _____ require _____ H+ ions for a complete turn > only _____ can synthesize a molecule of ATP

``` 120 degrees mechanical 120 degrees 3 one complete turn ```

The ATP synthase reaction is _____ • If the electrochemical proton gradient drops, there will not be sufficient energy to drive ATP production. • ATP will by hydrolyzed and the concentration of protons inside and outside the membrane will reach _____.

reversible | equilibrium

Uncoupling agents insert into the _____ membrane, making it _____ to protons • Uncoupling agents: • Allow H+ to flow into matrix without passing through the _____. • Uncouples electron transport from _____. * A number of poisons are uncoupling agents (e.g. _____, once used as a weight-loss drug). * _____: 20% of energy is dissipated.

``` inner permeable ATP synthase ATP synthesis dinitrophenol basal H+ leak ```

Uncoupling Proteins and Thermogenesis • Naturally occurring proteins (uncoupling proteins) allow H+ to flow into matrix bypassing the _____. • The energy of the electrochemical gradient is dissipated as _____. • In response to cold, increased by _____ and _____ to generate heat. * Brown adipose tissue is specialized for this process of _____. * Tissues containing brown fat serve as _____.

``` ATP heat thyroid hormone epinephrine non-shivering themogenesis "biological heating pads" ```

Quantitation of Energy Yields Stoichiometry • The quantitative relationship between NADH oxidation, H+ pumping and ATP synthesis varies with conditions. • We will use the following: For each intramitochondrial: NADH ==> _____ ATP FADH2 ==> _____ ATP • The efficiency with which oxidation energy of carbohydrates is converted into ATP bond energy is often greater than _____. • This is considerably greater than the efficiency of _____ (e.g. internal combustion) _____ (10-20%).

2.5 1.5 40% thermal engines

Final ATP Yield per molecule of glucose: _____

30 ATP

Summary • Energy production is THE _____ biological process. • Aerobic organisms “burn” foodstuffs to produce _____ and _____ (NADH and FADH2). * Oxidative phosphorylation is the mechanism for _____ oxidation of reduced coenzymes to ATP formation. * Coupling is accomplished through the production of a _____ across the inner mitochondrial membrane. * The rate of oxidative phosphorylation is tightly controlled by the availability of _____ and _____.

essential ATP reduced pyridine nucleotides coupling proton gradient ADP oxygen

Carbohydrate Metabolism II Flashcards

(49 cards)