Ch 14 Exam 3 Flashcards
What are the major pathways of glucose utilization?
What is glycolysis?
glycolysis = process by which a molecule of glucose is degraded in a series of enzyme-catalyzed reactions to yield two molecules of the three-carbon compound pyruvate
some free energy is conserved as ATP and NADH
The glycolytic breakdown of glucose is the sole source of metabolic energy in some mammalian tissues and cell types (erythrocytes, renal medulla, brain, and sperm, for example).
What are three noteworthy chemical transformations of glycolysis?
three noteworthy chemical transformations:
1. degradation of the carbon skeleton of glucose to yield pyruvate
2. phosphorylation of ADP to ATP by compounds with high phosphoryl group transfer potential, formed during glycolysis: substrate level phosphorylation
3. transfer of a hydride ion to NAD+, forming NADH
Whats an overview of glycolysis?
in the preparatory phase:
ATP is consumed
∆G of the intermediates increases
hexose carbon chains are converted to glyceraldehyde 3-phosphate
What is the payoff phase of glycolysis?
the payoff phase yields:
energy conserved as 2 ATP and 2 NADH
2 pyruvate
The chemistry of the glycoysis?
What is the importance of phosphorylated intermediates?
all nine intermediates are phosphorylated
functions of the phosphoryl groups:
prevent glycolytic intermediates from leaving the cell
serve as essential components in the enzymatic conservation of metabolic energy
lower the activation energy and increase the specificity of the enzymatic reactions
How does phosphorylation of glucose happen?
hexokinase activates glucose by phosphorylating at C-6 to yield glucose 6-phosphate
ATP serves as the phosphoryl donor
hexokinase requires Mg2+ for its activity
irreversible under intracellular conditions
What is hexokinase?
humans encode 4 hexokinases (I to IV) that catalyze the same reaction
isozymes = two or more enzymes that catalyze the same reaction but are encoded by different genes
(Hexokinase is Present in Nearly All Organisms)
How does Conversion of Glucose 6-Phosphate to Fructose 6-Phosphate happen?
phosphohexose isomerase (phosphoglucose isomerase) catalyzes the reversible isomerization of glucose 6-phosphate to fructose 6-phosphate
mechanism involves an enediol intermediate
reaction readily proceeds in either direction
What is The Phosphohexose Isomerase Reaction?
How does Phosphorylation of Fructose 6-Phosphate to Fructose 1,6-Bisphosphate happen? Why is this important?
phosphofructokinase-1 (PFK-1) catalyzes the transfer of a phosphoryl group from ATP to fructose 6-phosphate to yield fructose 1,6-bisphosphate
essentially irreversible under cellular conditions
the first “committed” step in the glycolytic pathway
(Compounds that contain two phosphate or phosphoryl groups attached at different positions in the molecule are named bisphosphates (or bisphospho compounds); for example, fructose 1,6-bisphosphate and 1,3-bisphosphoglycerate. Compounds with two phosphates linked together as a pyrophosphoryl group are named diphosphates; for example, adenosine diphosphate (ADP).)
How is Phosphofructokinase-1 allostericly regulated?
activity increases when:
ATP supply is depleted
ADP and AMP accumulate
fructose 2,6-bisphosphate is a potent allosteric activator: PFK2
ribulose 5-phosphate indirectly activates
How is fructose 1,6-Bisphosphate cleaved?
fructose 1,6-bisphosphate aldolase (aldolase) catalyzes a reverse aldol condensation and cleaves fructose 1,6-bisphosphate to yield glyceraldehyde 3-phosphate and dihydroxyacetone phosphate
reversible because reactant concentrations are low in the cell
What are the classes of an aldolase reaction?
Class I = found in animals and plants
Class II = found in fungi and bacteria
do not form the Schiff base intermediate
What is the interconversion of the triose phosphates?
triose phosphate isomerase converts dihydroxyacetone phosphate to glyceraldehyde 3-phosphate
reversible
final step of the preparatory phase of glycolysis
What is the Fate of the Glucose Carbons in the Formation of Glyceraldehyde 3-Phosphate?
after step 5 of glycolysis, the carbon atoms derived from C-1, C-2, and C-3 of the starting glucose are chemically indistinguishable from C-6, C-5, and C-4, respectively
What does the payoff phase a glycolysis provide?
in the payoff phase of glycolysis:
each of the two molecules of glyceraldehyde 3-phosphate undergoes oxidation at C-1
some energy from the oxidation reaction is conserved in the form of one NADH and two ATP per triose phosphate oxidized
The Payoff Phase of Glycolysis Yields ATP and NADH
How is Glyceraldehyde 3-Phosphate oxidated to 1,3-Bisphosphoglycerate?
glyceraldehyde 3-phosphate dehydrogenase catalyzes the oxidation of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate
energy-conserving reaction
How is the first step of the payoff phase energy-conserving?
formation of the acyl phosphate group at C-1 of 1,3-bisphosphoglycerate conserves the free energy of oxidation
acyl phosphates have a very high standard free energy of hydrolysis (∆G′° = −49.3 kJ/mol)
What is the Glyceraldehyde 3-Phosphate Dehydrogenase Reaction?
What is the Phosphoryl Transfer from 1,3-Bisphosphoglycerate to ADP?
phosphoglycerate kinase transfers the high-energy phosphoryl group from the carboxyl group of 1,3-bisphosphoglycerate to ADP, forming ATP and 3-phosphoglycerate
How do Steps 6 and 7 of Glycolysis Constitute an Energy-Coupling Process?
the sum of the two reactions is:
glyceraldehyde 3-phosphate + ADP + Pi + NAD+ ⇄ phosphoglycerate + ATP + NADH + H+ ∆G′° = −12.2 kJ/mol
substrate-level phosphorylation = the formation of ATP by phosphoryl group transfer from a substrate
different from respiration-linked phosphorylation
How does the Conversion of 3-Phosphoglycerate to 2-Phosphoglycerate take place?
phosphoglycerate mutase catalyzes a reversible shift of the phosphoryl group between C-2 and C-3 of glycerate
requires Mg2+
What is the phosphoglycerate mutase reaction?
How does Dehydration of 2-Phosphoglycerate to Phosphoenolpyruvate take place?
enolase promotes reversible removal of a molecule of water from 2-phosphoglycerate to yield phosphoenolpyruvate (PEP)
energy-conserving reaction
mechanism involves a Mg2+-stabilized enolic intermediate
How does Transfer of the Phosphoryl Group from Phosphoenolpyruvate to ADP take place?
pyruvate kinase catalyzes the transfer of the phosphoryl group from phosphoenolpyruvate to ADP, yielding pyruvate
requires K+ and either Mg2+ or Mn2+
What happens to pyruvate in its Enol form?
Pyruvate in its Enol Form Spontaneously Tautomerizes to its Keto Form
In this substrate-level phosphorylation reaction, the product pyruvate first appears in its enol form, then tautomerizes nonenzymatically to its keto form, which predominates at pH 7.
How is ATP and NADH formation coupled to glycolysis?
the overall equation for glycolysis is:
glucose + 2NAD+ + 2ADP + 2Pi ⟶ 2 pyruvate + 2NADH + 2H+ + 2ATP + 2H2O
the reduction of NAD+ proceeds by the enzymatic transfer of a hydride ion (:H−) from the aldehyde group of glyceraldehyde 3-phosphate to the nicotinamide ring of NAD+, yielding NADH
What is the standard free-energy change of glycolysis?
the conversion of glucose to pyruvate is exergonic:
glucose + 2NAD+ ⟶ 2 pyruvate + 2NADH + 2H+
∆G′°1 = −146 kJ/mol
the formation of ATP from ADP and Pi is endergonic:
2ADP + 2Pi ⟶ 2ATP + 2H2O
∆G′°2 = 2 x (30.5 kJ/mol) = 61.0 kJ/mol
the sum of the two processes gives the overall standard free-energy change of glycolysis, ∆G′°Sum:
∆G′°Sum = ∆G′°1 + ∆G′°2 = −146 kJ/mol + 61.0 kJ/mol
= −85 kJ/mol
under standard and cellular conditions, glycolysis is essentially irreversible
What is the energy remaining in pyruvate?
energy stored in pyruvate can be extracted by:
-aerobic processes:
oxidative reactions in the citric acid cycle
oxidative phosphorylation
-anaerobic processes
reduction to lactate
reduction to ethanol
pyruvate can provide the carbon skeleton for alanine synthesis or fatty acid synthesis
What is the Entry of Dietary Glycogen, Starch, Disaccharides, and Hexoses into the Preparatory Stage of Glycolysis?
What is glycogen phosphorylase?
glycogen phosphorylase = mobilizes glycogen stored in animal tissues and microorganisms by a phosphorolytic reaction to yield glucose 1-phosphate
(Endogenous Glycogen and Starch are Degraded by Phosphorolysis)
What is starch phosphoroylase?
Endogenous Glycogen and Starch are Degraded by Phosphorolysis
starch phosphorylase = mobilizes starch by a phosphorolytic reaction
What is phosphoglycomutase?
phosphoglycomutase = catalyzes the reversible reaction glucose 1-phosphate ⇄ glucose 6-phosphate
glucose 6-phosphate can continue through glycolysis or enter another pathway
What is mutase?
mutase = enzyme that catalyzes the transfer of a functional group from one position to another in the same molecule
subclass of isomerases (enzymes that interconvert stereoisomers or structural or positional isomers)
What is α-amylase?
Dietary Polysaccharides and Disaccharides
α-amylase = salivary and small intestine enzyme that hydrolyzes the internal (α1⟶4) glycosidic linkages of starch and glycogen, producing di- and trisaccharides
pancreatic α-amylase yields mainly maltose, maltotriose, and limit dextrins (fragments of amylopectin containing (α1⟶6) branch points, which are removed by limit dextrinases)
How are disaccharides hydrolyzed?
membrane-bound hydrolases in the intestinal brush border hydrolyze disaccharides:
monosaccharides pass through intestinal cells to the bloodstream, which transports them to the liver or other tissues
What is cellulase?
cellulase = attacks the (β1⟶4) glycosidic bonds of cellulose
absent in most animals
microorganisms produce cellulase
How is lactose digested?
lactase = converts lactose to glucose and galactose
present in infants but often absent in adults, producing lactose intolerance
lactase persistence phenotype = production of lactase into adulthood
lactose intolerance = inability to digest lactose due to the disappearance of lactase in adulthood
causes abdominal cramps and diarrhea
How does galactose metabolize and how can it cause disease?
galactose = product of lactose hydrolysis
important component in the infant diet
galactokinase = uses ATP to phosphorylate galactose at C-1
Galactose to Glucose 1-Phosphate: conversion proceeds through UDP-galactose and UDP-glucose intermediates
What is galactosemia?
galactosemia diseases = caused by a genetic defect in enzymes of this pathway
treatment involves carefully controlling dietary galactose
How is fructose involved in glycolysis?
fructose and mannose can be phosphorylated and funneled into glycolysis
hexokinase = phosphorylates fructose in the small intestine
Fructokinase = phosphorylates fructose in the liver
How do the Products of Fructose 1-Phosphate Hydrolysis Enter Glycolysis as Glyceraldehyde 3-Phosphate?
fructose 1-phosphate aldolase = cleaves fructose 1-phosphate to glyceraldehyde and dihydroxyacetone phosphate
triose phosphate isomerase = converts dihydroxyacetone phosphate to glyceraldehyde 3-phosphate
triose kinase = uses ATP to phosphorylate glyceraldehyde to glyceraldehyde 3-phosphate
Review
How does Mannose enter glycolysis?
hexokinase = phosphorylates mannose at C-6
phosphohexose isomerase = converts mannose 6-phosphate to fructose 6-phosphate
What are the three catabolic fates of pyruvate?
NADH must be recycled to regenerate NAD+
under aerobic conditions, pyruvate is oxidized to acetyl-CoA
under anaerobic conditions or low oxygen condition (hypoxia), pyruvate is reduced to lactate or ethanol
Why is pyruvate the Terminal Electron Acceptor in Lactic Acid Fermentation?
organisms can regenerate NAD+ by transferring electrons from NADH to pyruvate, forming lactate
lactate dehydrogenase = catalyzes the reduction of pyruvate to lactate
How does Reduction of Pyruvate to Lactate Regenerate NAD+?
glycolysis converts 2NAD+ to 2NADH
reduction of pyruvate to lactate regenerates 2NAD+
there is no net change in NAD+ or NADH
What is the reduced product in ethanol fermenation?
Ethanol is the Reduced Product in Ethanol Fermentation
yeast and other microorganisms regenerate NAD+ by reducing pyruvate to ethanol and CO2
the overall equation is:
glucose + 2ADP + 2Pi ⟶ 2 ethanol + 2CO2 + 2ATP + 2H2O
What is pyruvate decarboxylase?
pyruvate decarboxylase = catalyzes the irreversible decarboxylation of pyruvate to acetaldehyde
requires Mg2+ and the coenzyme thiamine pyrophosphate
What is thiamine pyrophosphate (TPP)?
thiamine pyrophosphate = coenzyme derived from vitamin B1
the thiazolium ring plays an important role in the cleavage of bonds adjacent to a carbonyl group
What is gluconeogenesis?
gluconeogenesis = pathway that converts pyruvate and related three- and four-carbon compounds to glucose
occurs in all animals, plants, fungi, and microorganisms
mainly occurs in the liver in mammals
In mammals, gluconeogenesis takes place mainly in the liver, and to a lesser extent in the renal cortex and in the epithelial cells that line the small intestine.
What steps do glucogenesis and glycolysis share?
gluconeogenesis and glycolysis are not identical pathways running in opposite directions
3 glycolysis reactions are essentially irreversible in vivo and cannot be used in gluconeogenesis
must be bypassed with exergonic reactions
What is the free energy change of glycolytic reactions?
the essentially irreversible glycolytic reactions are characterized by a large negative ∆G
Whats the role of biotin in the pyruvate carboxylase reaction?
Pyruvate carboxylase is the first regulatory enzyme in the gluconeogenic pathway, requiring acetyl-CoA as a positive effector.
Acetyl-CoA is produced by fatty acid oxidation, and its accumulation signals the availability of fatty acids as fuel.
What is malate dehydrogenase?
the mitochondrial membrane does not have an oxaloacetate transporter
malate dehydrogenase = mitochondrial enzyme that uses NADH to reduce oxaloacetate to malate
reaction is readily reversible under physiological conditions
oxaloacetate + NADH + H+ ⇄ L-malate + NAD+
What is Phosphoenolpyruvate Carboxykinase?
phosphoenolpyruvate carboxykinase = converts oxaloacetate to PEP
requires Mg2+ and GTP
reversible under intracellular conditions
oxaloacetate + GTP ⇄ PEP + CO2 + GDP
What are some alternative Paths from Pyruvate to Phosphoenolpyruvate?
when lactate is the glucogenic precursor, a second bypass predominates
oxaloacetate is directly converted to PEP in the mitochondrion by a mitochondrial isozyme of PEP carboxykinase
(The conversion of lactate to pyruvate in the cytosol of hepatocytes yields NADH, and the export of reducing equivalents (as malate) from mitochondria is therefore unnecessary.)
What are sequential reactions in gluconeogenesis?
What can plants and microorganisms do that mammals can not?
Mammals Cannot Convert Fatty Acids to Glucose; Plants and Microorganisms Can
animals lack the enzymatic machinery to convert acetyl-CoA from fatty acids to pyruvate.
plants and microorganisms have the glyoxylate pathway, which allows them to make glucose from fatty acids
(Conversion of stored fatty acids to sucrose in germinating seeds through the glyoxylate cycle. This pathway begins in specialized peroxisomes called glyoxysomes. The citrate synthase, aconitase, and malate dehydrogenase of the glyoxylate cycle are isozymes of the citric acid cycle enzymes; isocitrate lyase and malate synthase are unique to the glyoxylate cycle. Notice that two acetyl groups enter the cycle and four carbons leave as succinate. Succinate is exported to mitochondria, where it is converted to oxaloacetate by enzymes of the citric acid cycle. Oxaloacetate enters the cytosol and serves as the starting material for gluconeogenesis and for synthesis of sucrose, the transport form of carbon in plants.)
What is Glyceroneogenesis?
glyceroneogenesis = conversion of pyruvate to dihydroxyacetone phosphate via the early reactions of gluconeogenesis, followed by reduction to glycerol 3-phosphate
carried out in adipocytes
What are the Kinetic Properties of Hexokinase IV and Hexokinase I?
hexokinase IV (glucokinase) in the liver has kinetic properties related to its role in maintaining glucose homeostasis
Km is higher than the usual glucose concentration
How is Hexokinase IV regulated by Sequestration in the Nucleus?
the regulatory protein anchors hexokinase IV inside the nucleus, where it is segregated from the other glycolytic enzymes
fructose 6-phosphate is an allosteric effector
glucose causes dissociation of the regulatory protein
(Hexokinase IV is subject to inhibition by the reversible binding of a regulatory protein specific to liver.
The binding is much tighter in the presence of the allosteric effector fructose 6-phosphate.
Glucose competes with fructose 6-phosphate for binding and causes dissociation of the regulatory protein from the hexokinase, relieving the inhibition.)
How is FBPase-1 is Allosterically Inhibited by AMP?
high [AMP], which corresponds to low ATP, inhibits FBPase
slows glucose synthesis
high [ATP] slows glycolysis and speeds gluconeogenesis
How is Glycolysis and Gluconeogenesis regulated by Fructose 2,6-Bisphosphate?
What is the Regulation of Fructose 2,6-Bisphosphate Level?
phosphofructokinase-2 (PFK-2) = catalyzes the formation of fructose 2,6-bisphosphate
fructose 2,6-bisphosphatase (FBPase-2) = catalyzes the breakdown of fructose 2,6-bisphosphate
PFK-2 and FBPase-2 are two separate enzymatic activities of a single, bifunctional protein.
How is Xylulose 5-Phosphate a Key Regulator of Carbohydrate and Fat Metabolism?
xylulose 5-phosphate = an intermediate of the pentose phosphate pathway that activates phosphoprotein phosphatase 2A
phosphoprotein phosphatase 2A = dephosphorylates the bifunctional PFK-2/FBPase-2 enzyme
causes an increase in [fructose 2,6-bisphosphate]
(The increased glycolysis boosts the production of acetyl-CoA, while the increased flow of hexose through the pentose phosphate pathway generates NADPH. Acetyl-CoA and NADPH are the starting materials for fatty acid synthesis, which increases dramatically in response to intake of a high-carbohydrate meal.)
How is the Glycolytic Enzyme Pyruvate Kinase is Allosterically Inhibited by ATP?
The liver isozyme (L form), but not the muscle isozyme (M form), is subject to regulation by phosphorylation
When is the Conversion of Pyruvate to Phosphoenolpyruvate is Stimulated When Fatty Acids are Available?
acetyl-CoA signals that further glucose oxidation is not needed
acetyl-CoA:
allosterically stimulates pyruvate carboxylase
allosterically inhibits pyruvate dehydrogenase
What is ChREBP (Carbohydrate Response Element Binding Protein)?
ChREBP (carbohydrate response element binding protein) = transcription factor expressed in liver, adipose tissue, and kidney
acts in the nucleus to regulate gene expression for genes coding for enzymes needed for carbohydrate and fat synthesis
What is the Pentose Phosphate Pathway?
pentose phosphate pathway (phosphogluconate pathway, hexose monophosphate pathway) = pathway that oxidizes glucose 6-phosphate, producing pentose phosphates and NADPH
What is lactonase?
Lactonase Hydrolyzes Lactone to 6-Phosphogluconate
lactonase = catalyzes the hydrolysis of lactone to the free acid 6-phosphogluconate
What is 6-Phosphogluconate Dehydrogenase?
6-phosphogluconate dehydrogenase = catalyzes the oxidation and decarboxylation of 6-phosphogluconate to form ribulose 5-phosphate and 2nd molecule of NADPH
What is phosphopentose isomerase?
phosphopentose isomerase = converts ribulose 5-phosphate to its aldose isomer, ribose 5-phosphate
in some tissues (those require NADPH and Ribose 5 phosphate both), the pentose phosphate pathway ends at this point.
(Phosphopentose Isomerase Generates Ribose 5-Phosphate)
What is the overall Equation for the Pentose Phosphate Pathway?
the overall equation for this pathway is:
glucose 6-phosphate + 2NADP+ + H2O ⟶ ribulose 5-phosphate + CO2 + 2NADPH + 2H+
What is ribulose 5-phosphate epimerase?
ribulose 5-phosphate epimerase = epimerizes ribulose 5-phosphate to xylulose 5-phosphate
(The Nonoxidative Phase Recycles Pentose Phosphates to Glucose 6-Phosphate)
What are Nonoxidative Reactions of the Pentose Phosphate Pathway?
the conversion of pentose phosphates to glucose 6-phosphate begins the oxidative cycle again
What is the Transaldolase Reaction?
transaldolase = catalyzes the condensation of a three-carbon fragment from sedoheptulose 7-phosphate and glyceraldehyde 3-phosphate, forming fructose 6-phosphate and the tetrose erythrose 4-phosphate
What is the Second Transketolase Reaction?
the second transketolase reaction forms fructose 6-phosphate and glyceraldehyde 3-phosphate from erythrose 4-phosphate and xylulose 5-phosphate
How are carbanion intermediates stabilized?
thiamine pyrophosphate (TPP) = stabilizes a two-carbon carbanion in the transketolase reaction
protonated Schiff base = stabilizes the carbanion in the transaldolase reaction
What are the Oxidative and Nonoxidative Reactions of the Pentose Phosphate Pathway?
the first and third steps of the oxidative pentose phosphate pathway are essentially irreversible in the cell
the nonoxidative reactions are readily reversible
What is the reductive pentose phosphate pathway?
reductive pentose phosphate pathway = converts hexose phosphates to pentose phosphates
central to the photosynthetic assimilation of CO2 by plants
essentially the reversal of the nonoxidative reactions of the pentose phosphate pathway
What is partitioned between Glycolysis and the Pentose Phosphate Pathway?
Glucose 6-Phosphate is Partitioned between Glycolysis and the Pentose Phosphate Pathway
the relative concentrations of NADP+ and NADPH determine whether glucose 6-phosphate enters glycolysis or the pentose phosphate pathway
What does G6PD Deficiency cause?
–Inherited as an X-linked trait, G6PD deficiency affects mostly males and is the most common disease-producing enzyme abnormality in humans.
–More than 400 million individuals are affected worldwide.
–This enzyme deficiency has the highest prevalence in persons whose ancestries come from the Middle East, tropical Africa and Asia, and parts of the Mediterranean.
–G6PD deficiency is actually a family of deficiencies caused by a number of different mutations in the G6PD gene. Only some of the resulting protein variants cause clinical symptoms.
