Metabolism of Carbohydrates

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Metabolism of Carbohydrates
Sugar cane carries out photosynthesis, in which
sunlight drives the reduction of CO2 to
carbohydrates which are stored in the cane as
sucrose.
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Learning Objectives
Define monosaccharide, oligosaccharide, and
polysaccharide. Distinguish between aldose and
ketose. Define epimer. Define anomers, and
describe mutarotation. Identify the anomeric
carbon in a cyclic structure of a
carbohydrate. Identify whether glucose is either
a or b. Define reducing sugar, and identify the
reducing end of a monosaccharide or
disaccharide. Identify whether a given
disaccharide or trisaccharide is a reducing
sugar.
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Learning Objectives
Describe an O-glycosidic bond between
monosaccharides. Describe the structure of
glycogen. Define homopolysaccharide and
heteropolysaccharide. Define anabolism and
catabolism. Describe the connection between
catabolism and anabolism, and identify adenosine
triphosphate (ATP) as the universal energy
carrier. Define and/or describe glycolysis and
the pentose phosphate pathway. Define hexose and
pentose. Describe the two phases of glycolysis.
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Learning Objectives
Identify the major fate of glucose in animal
cells. Describe the reactions catalyzed by
hexokinase, glucokinase, phosphofructokinase-1,
and pyruvate kinase. Distinguish between
substrate-level and respiration linked
phosphorylation. Define mutase and
isomerase. Identify the net energy yield of
glycolysis, and the production of two pyruvate (3
carbon compound) from one glucose (6 carbon
compound), Describe channeling of substrates
between enzymes.
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Learning Objectives
Describe the aerobic and anaerobic fates of
pyruvate in mammalian tissues. Describe the
reaction catalyzed by lactate dehydrogenase
(LDH), and its function in the anaerobic cycling
of NADH to NAD. Describe the Cori cycle in
mammalian organisms. Define fermentation,
aerobic, anaerobic, and hypoxia. Describe the
reactions catalyzed by glycogen phosphorylase and
the debranching enzyme.
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Learning Objectives
Write out the glycolytic pathway (no structures)
including cofactors and/or coenzymes, and clearly
indicating either the reversibility or
irreversibility of each reaction under normal in
vivo conditions.
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Carbohydrates are the most abundant type of
biological compound on earth (cellulose in plants
is a polymer of glucose units). In humans,
carbohydrates constitute about 1 of the body (by
weight).
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aldehyde group
monosaccharides simple sugars that are either
aldehydes or ketones with two or more hydroxyl
groups the most abundant monosaccharide in
nature is the six carbon sugar D-glucose, also
referred to as dextrose.
aldose
ketone group
ketose
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epimers two sugars that differ in the
configuration around one carbon atom.
Fisher projection formulas
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Monosaccharides have cyclic structures
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Formation of the two cyclic forms of D-glucose
The interconversion of the a and b anomers is
called mutarotation.
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anomers isomeric forms of monosaccharides that
differ only in the configuration about the
hemiacetal or hemiketal carbon.
anomeric carbon the hemiacetal or carbonyl carbon
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Haworth perspective formulas
The edges nearest the reader are in bold lines.
Hydroxyl groups below the ring are on the right
side in Fisher projections.
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Two possible chair forms
ax axial
eq equitorial
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Monosaccharides are reducing agents
reducing sugars sugars capable of reducing
ferric or cupric ion
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O-glycosidic bond
An O-glycosidic bond is formed when a hydroxyl
group from one sugar reacts with the anomeric
carbon of another sugar.
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When an anomeric carbon participates in a
glycosidic bond, it cannot be oxidized by ferric
or cupric ion. The sugar containing that anomeric
carbon cannot exist in linear form and can no
longer act as a reducing sugar.
reducing end the end of a chain with a free
anomeric carbon
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Disaccharide a carbohydrate consisting of two
covalently joined monosaccharide units or
residues.
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Oligosaccharides short chains of several
monosaccharides joined by glycosidic bonds.
In cells, most oligosaccharides having three or
more units do not occur as free entities, but are
bonded to lipids or proteins. These molecules
are called glycoconjugates.
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Polysaccharide (or glycan) a linear or branched
polymer of monosaccharide units linked by
glycosidic bonds.
A short section of amylose, one of the
polysaccharides in starch. This is a linear
polymer with a1 4 glycosidic bonds.
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Glycogen granules in a hepatocyte. These
granules form in the cytosol, and are much
smaller than starch granules in plants.
Glycogen granules
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Glycogen is the main storage polysaccharide of
animal cells.
a1 4 linked subunits of glucose with a1 6
branches
a1 6 linkage
non-reducing ends
a1 4 linkage
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homopolysaccharides contain a single type of
monomer heteropolysaccharides contain two or
more different monomers
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Glycolysis is an almost universal central pathway
of glucose catabolism, the pathway with the
largest flux of carbon in most cells.
catabolism the phase of intermediary metabolism
concerned with the energy-yielding degradation of
nutrient molecules.
anabolism intermediary metabolism involving the
energy-requiring biosynthesis of cell components
from smaller precursor molecules.
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.
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Stored nutrients
Complex biomolecules
The overall network of enzyme-catalyzed pathways
constitutes cellular metabolism.
Ingested foods
Mechanical work
Osmotic work
ATP (adenosine triphosphate) is the major
connecting link, the shared intermediate, between
the catabolic and anabolic components of this
network.
Catabolic reaction pathways
ADP
Anabolic reaction pathways
ATP
ATP is the universal carrier of metabolic energy.
CO2
NH3
H2O
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In most animal tissues, the major fate of glucose
is breakdown via glycolysis to pyruvate with the
production of ATP.
D-glucose is the major fuel of most organisms.
It is ingested in the diet, and is relatively
rich in potential energy. By storing glucose as
a high molecular weight polymer (glycogen), a
cell can stockpile large quantities of hexose
units while maintaining relatively low cellular
concentrations of glucose.
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Definitions
glycolysis the catabolic pathway by which a
molecule of glucose (a hexose) is broken down
into two molecules of the three-carbon compound,
pyruvate.
pentose phosphate pathway a pathway that serves
to interconvert hexoses and pentoses and is a
source of reducing equilvalents and pentoses for
biosynthetic purposes.
hexose a simple sugar with a backbone containing
six carbons.
pentose a simple sugar with a backbone
containing five carbons.
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Overview The Two Phases of Glycolysis
The breakdown of the six-carbon glucose into two
molecules of three-carbon pyruvate occurs in 10
steps.
The first five steps in glycolysis are called the
preparatory phase glucose is phosphorylated by
ATP and cleaved into two triose (3 carbon)
phosphates.
In the second, or ATP-generating phase, a triose
phosphate is oxidized by NAD and phosphorylated
using inorganic phosphate. The next series of
reactions rearrange the phosphates into high
energy bonds so that ATP can be produced from ADP.
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Glucose
Preparatory Phase
First priming reaction
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Glucose-6-phosphate
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Fructose-6-phosphate
Second priming reaction
3
Fructose-1,6-bisphosphate
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Glyceraldehyde-3-phosphate

Dihydroxyacetone phosphate
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Glyceraldehyde-3-phosphate

Dihydroxyacetone phosphate
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Glyceraldehyde-3-phosphate (2)
At the end of the preparatory phase one 6-carbon
glucose molecule has been converted into 2
three-carbon triose phosphates, and two molecules
of ATP have been used in phosphorylation steps.
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Glyceraldehyde-3-phosphate (2)
ATP-generating phase
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1,3-Bisphosphoglycerate (2)
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3-Phosphoglycerate (2)
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2-Phosphoglycerate (2)
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Phosphoenolpyruvate (2)
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Pyruvate (2)
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1 Phosphorylation of glucose
Glucose is activated for subsequent reactions by
its phosphorylation at C-6 to yield
glucose-6-phosphate with ATP as the phosphoryl
donor. This reaction, catalyzed by hexokinase,
is irreversible under intracellular conditions.
(Reaction requires Mg2). Hepatocytes (liver)
contain a form of hexokinase called hexokinase D
or glucokinase which differs in kinetic and
regulatory properties.
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2 Conversion of glucose-6-phosphate to
fructose-6-phosphate
Phosphoglucose isomerase catalyzes this
reversible reaction which requires Mg2.
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3 Phosphorylation of fructose-6-phosphate to
fructose-1,6-bisphosphate
In the second of two priming reactions,
phosphofuctokinase-1 (PFK-1) catalyzes the
transfer of a phosphoryl group from ATP to the
C-1 of fructose-6-phosphate. This step is a major
point of regulation of glycolysis. The activity
of PFK-1 is increased when the supply of ATP is
low (when ADP and AMP are at high levels). The
enzyme is inhibited when ATP levels are high and
the cell has other fuels like fatty acids.
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4 Cleavage of fructose-1,6-bisphosphate
Fructose-1,6-bisphosphate is cleaved by the
enzyme aldolase to yield two different triose
phosphates. During glycolysis, the reaction
products ( two triose phosphates) are removed
quickly by the next two steps, pulling the
reaction in the forward direction.
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5 Interconversion of the triose phosphates
Only glyceraldehyde-3-phosphate can be directly
degraded by the subsequent steps of glycolysis.
Dihydroxyacetone phosphate is converted to this
triose by triose phosphate isomerase. This
reaction completes the preparatory phase of
glycolysis.
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6 Oxidation of glyceraldehyde-3- phosphate to
1,3-bisphosphoglycerate
This is the first of two energy-conserving
reactions that eventually lead to the formation
of ATP. The aldehyde group (at C-1) of
glyceraldehyde-3-phosphate is dehydrogenated to a
carboxylic acid anhydride with phosphoric acid.
This anhydride, called an acyl phosphate, has a
very high standard free energy. This conserves
most of the energy liberated during oxidation of
glyceraldehyde-3-phosphate.
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Reaction mechanism of glyceraldehyde-3-phosphate
dehydrogenase
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Glyceraldehyde-3-phosphate dehydrogenase is
inhibited by iodoacetate.
Iodoacetate is a potent inhibitor of this enzyme
because it forms a covalent derivative of the
catalytically critical cysteine residue rendering
the enzyme inactive.
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7 Phosphoryl transfer from 1,3-bisphosphoglycer
ate to ADP
This reaction transfers the high-energy
phosphoryl group from 1,3-bisphosphoglycerate to
ADP to form ATP and 3-phosphoglycerate. Steps 6
and 7 together constitute an energy-coupling
process in which 1,3-bisphosphoglycerate is the
common intermediate. substrate channeling is
involved in these two reaction steps
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The outcome of these coupled reactions is that
the energy released upon oxidation of an aldehyde
to a carboxylic acid is conserved by the coupled
formation of ATP from ADP and Pi. The formation
of ATP by phosphoryl group transfer from a
substrate (such as 1,3-bisphosphoglycerate) is
referred to as substrate-level phosphorylation. S
ubstrate-level phosphorylation involves soluble
enzymes and chemical intermediates. Respiration-li
nked phosphorylation involves membrane-bound
enzymes and transmembrane gradients of protons.
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8 Conversion of 3-phosphoglycerate to
2-phosphoglycerate
The enzyme phosphoglycerate mutase catalyzes a
reversible shift of the phosphoryl group between
C-3 and C-2 of glycerate Mg2 is essential for
this reaction.
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Mechanism of the phosphoglycerate mutase reaction
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The general name mutase is given to enzymes that
catalyze the transfer of a functional group from
one position to another in the same
molecule. Mutases are subclasses of isomerases,
enzymes that interconvert stereoisomers or
structural or postional isomers.
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9 Dehydration of 2-phosphoglycerate to
phosphoenolpyruvate
Enolase catalyzes the reversible removal of water
(dehydration) from 2-phosphoglycerate to produce
the very high-energy phosphate compound
phosphoenolpyruvate (PEP).
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10 Transfer of the phosphoryl group from
phosphoenolpyruvate to ADP
In this substrate-level phosphorylation, the
product pyruvate first appears in its enol form,
and then tautomerizes rapidly and
non-enzymatically to its keto form. Pyruvate
kinase is an important site of regulation.
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The overall equation for glycolysis
glucose 2NAD 2ADP 2Pi
2 pyruvate 2NADH 4H 2ATP 2H2O
The net energy yield of glycolysis
2 ATP and 2 NADH per molecule of glucose
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Definition
Substrate-level phosphorylation phosphorylation
of ADP (or some other nucleoside diphosphate)
coupled to the dehydrogenation of an organic
substrate independent of the electron-transfer
chain (and respiration-linked phosphorylation).
adenosine triphosphate (ATP)
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Nicotinamide adenine dinucleotide (NAD)
Nicotinamide
Adenine
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Channeling of substrate between two enzymes in
the glycolytic pathway reactions 6 and 7
Glyceraldehyde-3-phosphate
A stable, functional complex of the two enzymes
creates a channel to pass substrate from one
enzyme to the next.
The intermediate, 1,3-bis phosphoglycerate, is
never released to the solvent
3-Phosphoglycerate
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Three possible fates of pyruvate formed in
glycolysis
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Pyruvate is an important junction in carbohydrate
metabolism.
glucose 2NAD 2ADP 2Pi
2 pyruvate 2NADH 4H 2ATP 2H2O
Under aerobic conditions, pyruvate is further
oxidized via the tricarboxylic acid cycle (TCA
Cycle), and NADH is oxidized back to NAD by the
electron transport chain where the terminal
electron acceptor is molecular oxygen. This route
supplies more ATP and NAD for continued
glycolytic processing of glucose. Without NAD
glycolysis will stop.
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Under hypoxic conditions (limited oxygen) such as
in very active skeletal muscle, NADH cannot be
regenerated by the electron transport chain.
Under these conditions, NAD is regenerated from
NADH by the reduction of pyruvate to lactate.
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Glucose
Anaerobic regeneration of NAD to allow the
indefinite glycolytic oxidation of glucose and
the production of ATP
2 NAD
2 NADH
2 Pyruvate
2 Lactate
lactate dehydrogenase (LDH)
Lactate is transported to the liver where it is
converted to glucose during the recovery from
strenuous muscular activity.
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The Cori Cycle
glycogen
Muscle ATP produced by glycolysis and fermented
to lactate under anaerobic conditions
glucose
lactate
ATP
The cycle of reactions that includes glucose
conversion to lactate in muscle and lactate
conversion to glucose in liver is called the Cori
cycle.
Blood lactate
Blood glucose
Liver ATP used in synthesis of glucose
(gluconeogenesis) during recovery from strenuous
muscle activity.
lactate
glucose
ATP
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The Pasteur Effect
In his studies of yeast fermentation of glucose,
Louis Pasteur discovered that the rate and total
amount of glucose consumption were many times
greater under anaerobic than aerobic
conditions. The ATP yield under anaerobic
conditions is much less than under aerobic
conditions where glucose is completely oxidized
to CO2 and H2O. Therefore, under anaerobic
conditions, more glucose must be utilized to
produce the same amount of ATP.
The flux of glucose through the glycolytic
pathway is regulated to achieve constant ATP
levels.
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Glucose catabolism is deranged in cancerous
tissues
Glucose uptake and glycolysis proceed about ten
times faster in most solid tumors than in
noncancerous tissues. Tumor cells commonly
experience hypoxia (limited oxygen supply)
because they lack (at least initially) an
extensive capillary network to supply oxygen.
Cancer cells not close to a capillary depend upon
anaerobic glycolysis for much of their ATP
production.
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Definitions
fermentation the general term for the anaerobic
degradation of glucose or other organic compounds
to obtain energy energy is conserved as ATP.
anaerobic occurring in the absence of air or
oxygen.
aerobic requiring or occurring in the presence
of air or oxygen.
hypoxia the metabolic condition in which the
supply or oxygen is severely limited, such as
vigorously contracting skeletal muscle.
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Feeder Pathways for Glycolysis
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Glycogen granules in a hepatocyte. These
granules form in the cytosol, and are much
smaller than starch granules in plants.
Glycogen granules
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Glycogen is the main storage polysaccharide of
animal cells.
a1 4 linked subunits of glucose with a1 6
branches
a1 6 linkage
non-reducing ends
a1 4 linkage
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Non-reducing end
Pi
Glycogen phosphorylase
Glucose-1-phosphate molecules
transferase activity of debranching enzyme
a1 6 glucosidase activity of debranching enzyme
Glucose
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Conversion of glucose-1-phosphate for entry into
glycolysis
Glucose-1-phosphate
Glucose-6-phosphate
phosphoglucomutase