Metabolism of Carbohydrate

By: Endalamaw Tesfa

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Learning Objective
At the end of this session students will be able to:

Define what is carbohydrate

Explain the importance of carbohydrates
List the types of carbohydrates
Describe the chemistry of carbohydrates
Explain how polysaccharides are synthesized
Explore digestion, absorption, transportation, and
utilization of carbohydrates by the tissues
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Learning Objective cont

Identify the steps and enzymes of glycolysis

Explain the biochemical importance of PPP

Describe the steps and the products of TCA cycle
Explain the biochemical roles of gluconeogenesis
Describe glycogen metabolism & glycogen storage
disease

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Contents
I.

Chemistry of Carbohydrate

II. Classifications of Carbohydrate

III. Digestion and absorption of Carbohydrates
IV. Glycolysis
V. Hexose monophosphate shunt
VI. TCA cycle
VII.Gluconeogenesis
VIII. Glycogenesis
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I. Chemistry of Carbohydrates (CHOs)

Definitions of CHO
Carbohydrates are organic compounds containing C, H
and O2 with the general formula CnH2nOn
H and O2 are present in 1:2 ratio like that in water
They may be regarded as hydrates of C with one
molecule of H2O for each C atom, i.e., Cn(H2O)n.
By definition, CHOs are polyhydroxy aldehydes or
ketones or substances that yield such compounds on
hydrolysis
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Importance of CHOs
It is the major source of energy and form major part
of the staple (basic) diet across the world.
Plants synthesize billions of tons of CHOs every year

by photosynthesis.
CHOs play a major structural and protective role for
the bacteria, plants, crustaceae and animals.
They constitute an important part of free nucleotides,
DNA, RNA and coenzymes.
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CHOs constitute the most important domains in

protein- and lipid-carbohydrate complexes
Participate in the cell-cell interaction and recognition.
They also form the constituents of synovial and
vitreous fluids.
They supply carbon for the synthesis of cell
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II. Classification of CHOs

Based on the number of sugar units and the size of the
molecule, CHO could be grouped into three types:
1. Monosaccharides (simple sugars):
They are simplest form of sugars, which cannot be
further hydrolyzed.
They represent the building units and hydrolytic end
products of the more complex CHOs.
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2. Oligosaccharides:
These are the conjugates of CHOs where 2-10
monosaccharide units are linked to each other.

3. Polysaccharides:
These are higher polymers of CHOs and contain more
than 10 monosaccharide units per molecule.

Polysaccharides divided into two groups

homopolysaccharides
Hetropolysaccharides
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Monosaccharides
Monosaccharides vary from trioses to heptoses.
Can be aldose or ketose
All monosaccharides contain at least one chiral carbon
Optically active (except the biose glycolaldehyde).
CHOs exist in either of D or L, configuration as
determined by the orientation of the OH group around the
subterminal asymmetric carbon.
The D-conformation has the -OH on the right side,
whereas,
has the -OH on the left side.
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Important Monosaccharides
D-glyceraldehyde and dihydroxyacetone
They are aldo- and keto-trioses, respectively, that are
intermediary compounds in CHO and lipid metabolism.
D-Ribose
It is the most important pentose
Component of RNA, DNA, ATP, GTP etc. and a
number of coenzymes.
It is a reducing aldo-sugar synthesized in the body
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glucose.

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Glucose (or dextrose)

It is the grape and blood sugar.
Glucose is the building unit and end product of
hydrolysis of starch, dextrin, glycogen, sucrose, maltose
and lactose.
It is the major body sugar
All monosaccharides ingested may be converted into
glucose in the body and all can be synthesized from it.

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Mannose
It is a subunit in glycoproteins and neuraminic acid.
It is obtained by hydrolysis of the plant mannosans
and gums.

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Galactose
It is a reducing aldo-sugar and a subunit of the milk
sugar, lactose.
It is also a constituent of the structure of glycoproteins,
glycolipids and mucopolysaccharides
It is non-fermentable.
It gives insoluble galactic acid (mucic acid) on
oxidation with concentrated nitric acid.
Inborn errors of its metabolism causes galactosemia.
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It is due to congenital deficiency of the enzyme

galactosyl-1-phosphate uridyltransferase,
It results accumulation of galactose 1-phosphate in the
tissue
Galactosemia manifested as nutritional failure,

hepatosplenomegaly with cirrhosis, cataracts, mental

retardation, galactosuria, aminoaciduria, and albuminuria,
which regress or disappear if galactose is removed from
the diet.
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Fructose
It is the sweetest and reducing keto-sugar.
It is the main sugar in bee's honey and fruits.
It is obtained from inulin and sucrose hydrolysis.
Like glucose, it gives needle-like osazone crystals.
It is called the semen sugar, since it is present is
seminal fluid and is the source of energy for the
spermatozoa.

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It is fermentable and gives cherry red color with

Seliwanoff's reagent.
The four- and five-carbon ketoses are designated by
inserting ul into the name of a corresponding aldose,
E.g. D-ribulose is the ketopentose corresponding to the

aldopentose D-ribose.
The ketohexoses are named otherwise:
E.g. fructose and sorbose.
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Structure of Monosaccharides
OH HO

H
CHO
H
HO

OH
H

H
HO

OH
H

OH

OH

OH

Open chain form

CH2OH
HO

O
H

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HO
HO

OH

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OH
O

OH

OH H

OH

D-Glucose

CH2OH
OH

6
H

Open chain form

OH

Haworth's pyranose cyclic form

Fischer's hemiacetal cyclic form
(Glucopyranose; - and -anomers)
(- and -anomers)

OH

D-Fructose

D-Glucose

CH2OH

6 CH2OH
H

CH2OH

D-Glucose

Pyran

H
C

CH2OH

Furan

CH2OH O

H
OH

5
O

CH2OH

D-Fructose

OH

OH
OH

CH2OH

1CH2OH OH

D-Fructose

Haworth's furanose cyclic form

Fischer's hemiacetal cyclic form
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(Fructofuranose; - and -anomers)
(- and -anomers)

The aldo- and keto- monosaccharides with 5 and 6

carbons are:
A. Weak aldehydes or ketones;
B. Have - and -anomeric forms that can form - and
-methyl glycosides;

C. Show mutarotation; and

D. Give cyclic compounds on reaction with acids.

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The aldehyde or ketone group spontaneously reacts

with OH groups on the 4th or the 5th downstream carbon
to form an intramolecular hemiacetal or hemiketal ring
structure, respectively.
The resulting five- and six-membered ring structures

called furan and pyran, respectively.

Therefore, the sugars in such forms are termed
furanoses and pyranoses, respectively.
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There are two geometric structures, known as

Fischers and Haworths projection formulas.

In Haworths projections, all H and OH groups

located on the left side of open chain are written
upwards and all H and OH groups located on the right
side are written downwards.
The radical of the molecule is written upwards in Dsugar and inside the ring downwards in L-sugar.

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Some, such as glucose, are more stable as 6-membered

rings, whereas, others are more stable as 5-membered
rings, such as fructose.
In forming the ring, a new stereocenter is created at the
carbon which the ether linkage is created.

If the OH group is "down" relative to the ring, then it is

called the -isomer.
If the OH group is up it is called the -isomer.
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In glucose, the - isomer is predominant than the

isomer at a ratio of 64:36.
There are two competing effects that determine whether
a monosaccharide will attain - or -conformation.
A group that is equatorial will be more stable; because
it is less crowded,
whereas, a group that is axial will be more stable
because it hydrogen bonds with the ether linkage
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Isomerism in Carbohydrates
Stereoisomerism:
The total number of possible stereoisomers of a
compound is given by the Vont Hoffs rule
Possible stereoisomers = i.e., "2n",
n is the number of asymmetric carbon atoms.
Stereoisomers can be of four types:

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1. Anomers

3. Epimers

2. Enantiomers

4. Geometric isomers

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1. Anomers (- and -):

These are isomers that differ in distribution of H and

OH groups around the asymmetric anomeric carbon

atom after cyclization of the molecule,
e.g., - and -glucopyranose.

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2. Enantiomers (D- and L-isomers):

These isomers differ in distribution of H and OH

groups around the sub-terminal asymmetric carbon

atoms.
D-form has the OH group to the right, but L-form is on
the left.
D- and L-forms appear as mirror images of each other.
Metabolically, these two forms are massively different.
D-sugars are metabolizable, the L-sugars are not.
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CHO
H

OH
CH2OH

D-Glyceraldehyde

CHO
HO

H
CH2OH

L-Glyceraldehyde

Racemic mixture is a solution containing equal

concentration of D- and L-forms of a compound;
the mixture is optically inactive.

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3. Epimers:
These are isomers that differ in distribution of H and
OH groups around a single asymmetric carbon atom,
other than the anomeric and sub-terminal carbons.

Ribose is a C3-epimer of xylose, and glucose is a C2epimer of mannose and C4-epimer of galactose.
This difference confers massive metabolic variation
among the epimers.

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4.Geometric isomers:
These are isomers that differ in distribution of atoms or
groups around the axis of a double bond in space,
e.g., cis-form of a compound that has groups on the
same side of the double bond and trans-form that has the
groups on opposite sides of the double bond.
Examples are cis-fumaric acid in which the two
carboxylic groups are present on one side and transfumaric acid in which these groups are present on the
opposite
sides of the C=C bond.
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Optical Activity:
It is the ability, conferred by the asymmetric carbon to
the sugar in solution, to rotate the plane of the plane-

polarized light either to the right when the sugar is

dextrorotatory (d or +), such as glucose, galactose and
starch; or to the left when the sugar is levorotatory (l or ),
such as fructose & invert sugar.
HOOC C H
HOOC C H
Cis- Malic
HOOC C H
H C COOH Trans- Fumaric
acid
Malate (cis-isomer) Fumarate (trans-isomer)acid
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Chemical Properties of Monosaccharides

A) Susceptibility to Oxidation (sugar acids)
I. Oxidation of CHOs with mild oxidizing reagents or
specific dehydrogenases
II. The terminal -CH2OH group is oxidized into an
uronic acid
III. Both of the aldehyde and the terminal -CH2OH groups

are oxidized into a saccharic acid catalyzed by a strong

oxidizing reagent, such as concentrated nitric acid.
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CHO
H

COOH

OH

CH2OH

D-Glyceraldehyde

OH
CH2OH
O

COOH

H3C C NH

H
HO

OH
H

H
HO

OH
H

OH

OH

OH

OH

D-Glucose

CH2OH

D-Gluconic acid

H
O

H
HO

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OH

OH

H
H

OH
H

COOH

H
OH

COOH

CHOH

N-acetyl-neuraminic acid;
a sugar acid, a deoxy sugar,
CH2OH
and, a sugaramine
L-Ascorbic acid (vitamin C)

CHOH
CH2OH

OH
OH

CH2OH

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D-Glyceric acid

CHO

CH2OH

OH

-D-Glucose

OH

OH

OH

OH

OH

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B) Susceptibility to Reduction (sugar alcohols)

Glyceraldehyde is reduced into glycerol during
carbohydrate and lipid metabolism.
Glycerol is a major lipid alcohol and is the base for
pharmaceutical preparations and the explosive
trinitroglycerine.

Ribose is reduced to ribitol, a component of the

vitamin B2.
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Glucose Reduced Into Sorbitol :

A base in several pharmaceutical preparations an
intermediate in conversion of glucose into fructose in
the seminal vesicles for sperm nutrition.
Sorbitol is an abnormal product from the
hyperglycemia associated with diabetes mellitus and
its intracellular accumulation causes cellular damage

(Cataract).
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 Mannose gives rise to Mannitol is injected

intravenously to reduce intracranial hypertension in cases

of meningitis, cerebral hemorrhage or thrombosis

Has been used for the assessment of kidney function.
Fructose is reduced into both Sorbitol & Mannitol
Galactose is reduced to Galactitol or Dulcitol.
Inositol is a hexahydric cyclic sugar alcohol containing
6 -OH groups.

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Reducing Properties of Monosaccharides

Monosaccharides and disaccharides with free aldehyde
or ketone group can reduce the cupric salts, bismuth,
silver and picric acid.
The reduction of cupric to cuprous state in alkaline
medium forms the basis of Fehlings, Benedicts and
Barfoeds tests for reducing sugars.
The routine diagnostic detection of glucose in urine of
diabetes mellitus patients by Benedicts test.
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Sugaramines
Sugars that have an amino group in place of an -OH group on C2.
Monosaccharide amines are very important structural components
in glycolipids, glycoproteins & mucopolysaccharides.
They further derivatized by N-acetylation & sulfation
Glucosamine is derived from chitin, the exoskeleton of insects.
It also exists in the N-acetyl glucosamine or sulfated glucosamine

forms particularly in mucopolysaccharides.

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Galactosamine is the major sugar derivative in the cartilage

and bone mucopolysaccharide chondroitin sulfate, glycolipids
& may be acetylated or sulfated.
Mannosamine is an active component of the structure of
some antibiotics, e.g., erythromycin.
N-acetyl neuraminic acid (NANA) is one form of sialic acid
that is classified as a sugar acid (has -COOH at C1), a deoxy
sugar (has -H at C3) and as a sugaramine (has -NH2 at C5).

It is a component of glycoproteins and glycolipids, e.g.,

gangliosides. It is synthesized from N-acetyl-mannosamine.
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Sugaramines

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OLIGOSACCHARIDES
Disaccharides
Disaccharides contain two monosaccharides joined
together by O-glycosidic linkage.
The most common glycosidic linkage is between C1 of
one and C4 of the other (14) monosaccharide.
Other glycosidic linkages include; 16, 13, 12,
11 and 23
The linkage can be - or - depending upon the type of

the anomeric
carbon participating in the linkage.
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Reducing Disaccharides
Maltose (malt sugar):
Maltose consists of an -glucose unit connected to a
glucose unit through -1,4-glucosidic linkage
It is produced by partial acid or enzymatic (amylase)
hydrolysis of dietary starch and glycogen.
It is hydrolyzed into two glucose molecules by HCl or
by the intestine maltase enzyme

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Isomaltose
It is similar to maltose except that the two glucose
residues are -1,6-glucosidic linked.
It is produced during digestion of branch point of the
starch amylopectin by amylase.
It is hydrolysable into two glucose molecules by the
intestinal sucrase-isomaltase enzyme complex that also
hydrolyzes sucrose, and maltose

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Glucosidic linkage of maltose and isomaltose

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Lactose (milk sugar):

It is formed of -galactose and glucose molecule linked

by -1,4-glycosidic linkage.
It is hydrolyzed by HCl or by intestine enzyme, lactase,
into galactose and glucose

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Cellobiose:
It is composed of a -glucose unit linked to a glucose
molecule by -1,4-glucosidic linkage.
It is produced by partial acid hydrolysis of cellulose.
It is non-fermentable, non-digestible because humans
lack an enzyme
CH2OH
O

4
OH

H
OH

OH

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1
H

-D-Glucose

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CH2OH
O

H
O

4 H
OH

OH

OH

1
H

-D-Glucose
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Non-reducing Disaccharides
Sucrose:
It is the major cane and beet sugar, commonly named as
table sugar
It is formed of -glucose linked to -fructose by -1,2-glycosidic linkage
It is a fermentable but non-reducing sugar
It is dextrorotatory, but when hydrolyzed by the
intestinal sucrase enzyme or by HCl
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The produced fructose and glucose mixture is

levorotatory because of the strong levorotation of fructose.

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Trehalose:
It is composed of one a-D-glucopyranosyl unit
connected to an -D-glucopyranoside linked by -1,1glucosidic linkage.
It is a component of a highly toxic lipid extracted from
Mycobacterium tuberculosis.
It is a non-reducing sugar with good quality sweet taste.
The sugar is known as a stabilizer of proteins and a
protector of the plant and animal tissues from damage by
dehydration
and freezing.
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Because of these beneficial characteristics, trehalose is

used in processed foods and medicinal and cosmetic
preparations.
It is hydrolyzed by the intestinal trehalase into two glucose molecules
CH2OH

O
H
OH

H
OH

1
O

OH

H
OCH3
HOH2C

H
OH

O
H

OH

Structure of Trehalose
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POLYSACCHARIDES
They are high molecular weight polymers of
monosaccharides and are the major form of CHOs
occurring in nature.
They are classified into two categories such as:
Homopolysaccharides,
Heteropolysaccharides

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Starch:
It is the major storage and nutritional form of plant
CHOs in cereals.
The starch granules are composed of two types of
polysachharides
Amylose and amylopectin.
Amylose - The core of the granule is composed of the
unbranched helical chains of amylose glucosan molecule
composed of -glucose units linked through -1,4Endalamaw T linkages.
glucosidic

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Amylopectin
The outer shell is made up of the amylopectin branched
chain glucosan molecules composed of -glucose units
linked through -1,4-glucosidic linkages in straight chains
and through -1,6-glucosidic linkages at the branch points
Amylopectin is insoluble in water and gives red color
with iodine solution.
The chain branching points of amylopectin recur
periodically every 20-30 glucose units.
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Glycogen:
Glycogen is the major storage form of CHOs in most
animal cells, particularly in muscles and liver.
It is a branched chain glucosan formed by -glucose
units linked through -1,4 and -1,6-glucosidic linkages
resembling amylopectin but its branching points recur
periodically every 8-10 glucose units with more frequent.
CH 2OH

CH 2OH
O

H
H
OH

OH

H
O

OH
CH 2OH
H
OH

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H
OH

OH

CH 2OH
O

H
OH

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OH

H
O

O
H
OH
H

H
OH

H
O

glycogen

H
1
O
6 CH 2
5
H
OH
3
H

CH 2OH
O
H
2
OH

H
1

4
O

CH 2OH
O

H
OH
H

H
O
OH

O
H
OH

H
OH

OH
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This makes glycogen molecule more compact and

highly branched than amylopectin and a globular
particle form that has a diameter of 21 nm.
Within each particle, the branching along one initial
chain is repeated 12 times from the core glycogenin
protein primer
Glycogen is acid hydrolysable into a mixture of dextrins and maltose when heated in the presence of dilute
HCl or enzymatically by amylase.
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Glycogen
gives deep-red color with iodine solution

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Cellulose:
It is the major structural plant polysaccharide occurring in
nature.
It forms the skeleton of plant cells and vessels, and, is the
major component of plant fibers, such as linen, cotton and
paper.
It is composed of -glucose units linked by -1,4glucosidic linkage.
It is indigestible in human, it offers very important benefits
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as dietary

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This help lowering blood cholesterol.

Its fermentation by large intestinal bacteria gives
volatile FAs (particularly butyric acid) that are strong
anticancer agents against colorectal cancer.
These large intestinal bacteria also synthesize some
water-soluble vitamins
CH2OH
H

O
H
OH

H 1

OH

O
H

H
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OH
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6CH OH
2
5
O

4 OH
3

H 1
2

OH

O
H
OH

CH2OH

CH2OH

CH2OH
H

O
H
OH

OH

O
H
OH

OH

OH

H
H

OH

cellulose
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Inulin
Is a polysaccharide of fructose (and hence a fructosan)
found in tubers and roots of dahlias, artichokes, and
dandelions.
It is readily soluble in water and is used to determine
the glomerular filtration rate.

Dextrins
Are intermediates in the hydrolysis of starch.
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Chitin:
It is a homopolysaccharide that forms the exoskeleton of
insects and crustaceans and is composed of -N-acetylglucosamine units joined by -1,4-glucosidic linkage.

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Hetropolysaccharide
Proteoglycans
are glycoconjugates in which a core protein is attached
covalently to one or more large glycans, such as heparan
sulfate, chondroitin sulfate, or keratan sulfate
The glycan is the greater portion (by mass) of the
molecule
It is the major components of connective tissue such as
cartilage
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It provide the ground or packing substance of connective

tissues
Bound to the outside of the plasma membrane by a
transmembrane peptide or a covalently attached lipid,
proteoglycans provide points of adhesion, recognition, and
information transfer between cells, or between the cell and
the extracellular matrix

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Lipopolysaccharides
It is a carbohydrate-lipid conjugates where the
oligosaccharide is attached to the lipid moiety through a
hexosamine residue or an alcohol, e.g., sphingosine.
Are the dominant surface feature of the outer membrane
of gram-negative bacteria such as E. coli and Salmonella.
These molecules are prime targets of the antibodies
produced by the vertebrate immune system in response to
bacterial infection and are therefore important
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determinants
of the serotype of bacterial strains

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Glycosaminoglycans (mucopolysaccharides)
Are complex carbohydrates characterized by their
content of amino sugars and uronic acids.
When these chains attached non-covalently to a protein
molecule, the result is a proteoglycan.
Mucopolysaccharides classified into two major types;
1. the sulfate-free e.g. hyaluronic acid, and
2. sulfate containing e.g. chondroitin, heparin,
heparan, dermatan and keratan sulfates.
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III. Digestion of Carbohydrates

Depend on the digestibility CHOs divided into three
groups.
1. Ready-to-absorb carbohydrates:

E.g. monosaccharides
2. Digestible carbohydrates: oligosaccharides and
polysaccharides.
3. Non-digestible carbohydrates: E.g. cellulose,
pentosans, hemicellulose, lignin, gums and pectins.
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Digestion of carbohydrates
The principal sites of dietary CHO digestion are the
mouth and intestinal lumen.
The enzyme needed for degradation of most dietary
CHOs are primary
disaccharidases and endoglycosidase- used for the
breaking oligosaccharides and polysaccharides
Hydrolysis of glycosidic bond catalyzed by a family of
glycosidase that degrades CHOs into their reducing sugar
components
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Carbohydrate digestion in the mouth:

Saliva contains Salivary amylase (ptyalin),
produced by the salivary glands.
The enzyme has a pH optima of 6.6 - 6.8 and is
activated by chloride ions.
The -glycosidase enzyme is specific for
hydrolysis of -1,4 glucosidic linkage into maltose
and dextrins.

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Carbohydrate digestion in the stomach:

Salivary amylase continues to act on starch,
glycogen or dextrins for 2 - 3 minutes only and
becomes ineffective as soon as the food reaches the
stomach because of the extreme acidic pH of 1- 2
There is no carbohydrate splitting enzyme in the
stomach but HCl hydrolyses the disaccharides
particularly sucrose into glucose and fructose

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CHO digestion in the small Intestine:

A. The pancreatic amylase :
This is an -glycosidase also known as amylopsin
and is very similar to ptyalin in its action.
It has an optimum pH 7.1 and is also activated by
chloride ion
It acts exactly as salivary amylase
It digest cooked and uncooked starch, glycogen and

starch dextrins which escaped digestion by HCl or

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salivary
amylase in the mouth
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B. Intestinal mucosal brush border enzymes:

The final digestion of carbohydrates occurs in the small
intestine by the action of the hydrolases secreted from the
intestinal mucosal cells.

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Intestinal amylase:
This enzyme is an exo-polysaccharidase.
It hydrolyses the terminal glucose residues of the
oligo- and polysaccharides by acting on the -1,4
glucosidic bonds.
Lactase (-galactosidase with a pH optima of 5.4
6.0) hydrolyzes lactose into glucose and galactose.
Lactose Glucose + Galactose

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Maltase (-glucosidase) which hydrolyses maltose into

2 glucose units.
It can also digest -1,4 linked oligosaccharides,
Maltose Glucose + Glucose
-Dextrinase (Isomaltase) (oligo 1-6 glucosidase)
which hydrolyzes isomaltose into two glucose units.
Isomaltose Glucose + Glucose

71

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Sucrase (invertase) which converts sucrose into

glucose and fructose

Sucrose Glucose + Fructose

Trehalase for hydrolysis of trehalose into two glucose
units by acting on -1,1 glucosidic bond.
Trehalose Glucose + Glucose

72

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73

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Absorption of Carbohydrates
Carbohydrates absorbed mainly in jejunum.
The rate of absorption decreases down the intestine i.e.
proximal jejunum absorbs much more effectively than the
distal portion.
Very small amount is absorbed in the stomach or large
intestine
Monosaccharide's are absorbed through the mucosal cells into
the blood stream and are delivered to the liver by the portal
vein chiefly in the form of hexoses and as pentose sugars.
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All monosaccharides are not absorbed at the same rate

The rates of absorption of the monosaccharides with

reference to that of glucose are given in the following table

75

Monosaccharide
Galactose
Glucose
Fructose
Mannose
Xylose
EndalamawArabinose
T

Absorption rate
110
100
43
19
15
9
6/18/2014

Active absorption/ reabsorption:

The active transport of CHOs involves the sodium-

dependent glucose co-transporters, e.g., SGLT1

The glucose transporter is a mobile carrier protein
molecule presents in the apical (lumenal) cell membrane
of intestine and kidney.
It absorbs glucose and galactose against their
concentration gradient and is coupled with Na+-K+
ATPase.
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77

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Facilitated absorption and transport

The sodium- and energy-independent transport of
monosaccharides down their concentration gradient is
called facilitated diffusion.
At least five facilitative diffusion glucose transporters,
GLUT 1-5, are involved in the bidirectional transmembrane absorption and transport of monosaccharides.
GLUT are transmembrane proteins with 12 membranespanning domains and work as gate pores.
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Cellular Glucose Transporters

Type

Glucose
Affinity
GLUT-1 Low

GLUT-2 Very low

Tissue distribution

Control/Role

Wide

Constitutive, is the cell surface

receptor for the human T cell
leukemia virus (HTLV)
Increases glucose level in -Cells
to stimulate insulin secretion
High affinity glucose transporter

Kidney, intestine,
liver, -Cells
GLUT-3 High
Intestine, neurons,
placenta
GLUT-4 Very high Skeletal and cardiac
muscles, adipose
tissue, brain
GLUT-5 Very low
Testes, brain,
for Glucose intestine, kidney,
muscle and adipose
Endalamaw T
tissue
79

Insulin-responsive (rate limiting

step)
Fructose transporter, very low
affinity glucose transporter
6/18/2014

Disorders of CHO Digestion and Absorption

Lactose Intolerance
Lactose intolerance is a maldigestion/malabsorption
syndrome due to the inability to digest and/or absorb
dietary lactose
The patient experiences abdominal bloating, nausea,
abdominal cramps, diarrhea and flatulence upon ingesting
such food sources
This could be due to the inherited or age-dependent
Endalamaw T
decline
of enzyme expression

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Fructose Intolerance
Most of the cases of fructose intolerance involve
severely ill infants with recurrent hypoglycemia and
vomiting, occurring at the time of weaning when
fructose or sucrose is added to the diet and result in
marked malnutrition.
Hepatomegaly may be present and a test dose of
fructose often precipitates hypoglycemic shock.
The biochemical defect in the metabolism of fructose,
81

Endalamaw TAldolase B enzyme is deficient.

wherein,

6/18/2014

IV. Glycolysis
It is an oxidation of glucose to give pyruvate or lactate
It takes place in the cytoplasm of all tissue cells, but it is

importance in:
1. Tissues with no mitochondria: mature RBCs, cornea & lens
2. Tissues with few mitochondria: Testis, leucocytes, medulla
of the kidney, retina, skin and GIT
3. Tissues undergo frequent oxygen lack: skeletal muscles
especially during exercise.
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glucose

Glycolysis

ATP
Hexokinase

ADP
glucose-6-phosphate

Phosphoglucose Isomerase
fructose-6-phosphate
ATP
Phosphofructokinase
ADP
fructose-1,6-bisphosphate
Aldolase

83

glyceraldehyde-3-phosphate + dihydroxyacetone-phosphate
Triosephosphate
Isomerase
Glycolysis continued
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glyceraldehyde-3-phosphate
NAD+ + Pi
Glyceraldehyde-3-phosphate
Dehydrogenase
NADH + H+

Glycolysis
continued

1,3-bisphosphoglycerate
ADP
Phosphoglycerate Kinase
ATP
3-phosphoglycerate
Phosphoglycerate Mutase
2-phosphoglycerate
Enolase
H2O
phosphoenolpyruvate
ADP
Pyruvate Kinase
ATP
pyruvate

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1. Activation of Glucose
Circulating blood glucose metabolically inert unless it is activated
to glucose-6-phosphate (Glu-6-P) inside the cells.
Once phosphorylated, glucose is trapped inside the cells because
cell membrane is impermeable to it.
The activation takes place with the help of tissue-specific

isoenzymes of hexokinase that arose through gene duplication

(including glucokinase that is hexokinase IV isoenzyme)

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2. Isomerization of Glu-6- P to Fru-6-P:

It is done by phosphohexose isomerase that is an aldo-ketoisomerase.
Only the -anomer of Glu-6-P is isomerized into Fru-6-P
It is a freely reversible reaction.

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3. Activation of Fru-6- P to Fru-1,6-diP:

The reaction is catalyzed by phosphofructokinase-1
(PFK-1), using ATP and Mg2+ ions.
This is the most important, rate-limiting and irreversible
reaction of glycolysis.
The enzyme PFK-1 is activated by accumulation of
Fru-2,6-diP, which is produced by the bifunctional
phosphofructokinase-2 (PFK-2).

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The bifunctional enzyme carries out two enzyme

activities, viz.; the synthesis and hydrolysis of Fru-2,6-diP,
and is regulated by the availability of Glu-6-P.
When Gl-6-P concentration is high, its kinase activity is
stimulated and it phosphorylates Fru-6-P to Fru-2,6-DiP.
When Glu-6-P is low, it works as an Fru-2,6-diP
phosphatase to produce Fru-6-P.
PFK-1 has tissue-specific isoenzymes with regulatory
properties that match the differential role of glycolysis in
88

Endalamaw T tissues.
different

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4. Cleavage of Fru -1,6-Diphosphate:

The six-carbon Fru-1,6-DiP is split into two triose
phosphates by aldolase (aldehyde-alcohol - aldol cleavage and condensation).
The fructose phosphates exist in the cell mainly in the
furanose form, but they react with phosphohexose
isomerase, phospho-fructokinase and aldolase in the openchain form.

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This reaction is freely reversible.

The enzyme, Aldolase, exists as a number of tissuespecific isoenzymes, all of which contain four subunits.
Aldolase A occurs in most tissues and acts on Fru-1,6DiP.
Aldolase B occurs in liver and kidney and acts on
fructose-1- phosphate and Fru-1,6-DiP.
It uses a lysine residue at the active site to bind the
substrate and mutations there inactivate the enzyme.
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Interconversion of the two triose phosphates: It takes place

by phosphotriose isomerase enzyme in a reversible reaction.
The equilibrium is in favor of glyceraldehyde-3-phosphate
formation, leading to production of two molecules of
glyceraldehyde-3-phosphate, because of the preferential
continuous utilization by subsequent glycolytic reactions.

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6. Oxidation of Glyceraldehyde-3-P into

1,3-Diphosphoglycerate:
The oxidation of glyceraldehyde-3-phosphate is catalyzed by
glyceraldehyde-3-phosphate dehydrogenase, an SH-containing
enzyme, in the presence of NAD+ as a coenzyme and inorganic
phosphate (Pi).
The enzyme is formed of four identical polypeptides, i.e.,
homotetramer.
Each polypeptide has 4 cysteine -SH groups.

One of these -SH groups is found at active site of the enzyme.

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The aldehyde group of the substrate binds to the active

site of the enzyme -SH and forms a thiohemiacetal that is
oxidized to a high-energy thiol ester.
The two hydrogen atoms (from -SH and -CHO)
removed in this oxidation are transferred to the enzymebound NAD+ to give rise to NADH.H+ and an enzymebound phosphoglyceric acid.
Phosphorolysis (hydrolysis by adding phosphate)
liberates the free enzyme with reconstituted - SH group.
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The -COOH group takes up an inorganic phosphate (Pi)

to form a high energy bond as free 1,3-diphosphoglycerate.
The reaction is peculiar in that it raises the potential of a
free Pi into a bound high-energy phosphate.

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7. Conversion of 1,3-diphosphoglycerate
into 3-phosphoglycerate:
This reaction involves harvesting of the high-energy phosphate at
C1 to generate an ATP from an ADP because the energy of the acylphosphate bond is high enough (~13 kcal/mole) to make the reaction

energetically favorable.
The reaction is an example of substrate level phosphorylation, i.e.,
production of ATP from ADP utilizing high-energy bond in a
substrate directly without the involvement of electron transport
chain.
It is one of the very rare reactions that utilize ATP and yet are
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Endalamaw T

reversible under normal cell conditions.

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8. Conversion of 3-phophoglycerate into

2-phosphoglycerate:
The phosphate I rearranged so as to create a high
energy phosphate out of it through moving it from C3 to
C2 catalyzed by phosphoglycerate mutase.
The 2,3-Bi-phosphoglycerate is an intermediate and/or
cofactor in this reaction.

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9. Conversion of 2-phosphoglycerate into PEP:

Subsequent removal of water enolase enzyme in
presence of Mg2+ or Mn2+ redistributes energy within
the molecule to form PEP.
The redistribution of energy results in conversion of
the phosphoester linkage into a high-energy phosphate
bond at C2.

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10. Conversion of PEP into pyruvate:

The reaction is catalyzed by pyruvate kinase.
The enol-pyruvate formed is highly unstable and
spontaneously tautomerizes into pyruvate.
It is irreversible and energetically favorable because PEP
is at a higher energy level than pyruvate through releasing
~14 kcal/mole.
This is the example of second substrate level
phosphorylation in glycolytic pathway.
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It utilizes the high-energy bond at C2 of PEP to convert an ADP

into an ATP.
To this point, the overall net reaction of the glycolytic pathway is
irreversible without the expenditure of energy because it has an
overall negative G0' of approximately 22 kcal.
The overall reaction is as follows;

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Bioenergetics of glycolysis:
Under anaerobic conditions:
ATP invested in the activation phase
One ATP in the activation of glucose to Glu-6-P.
One ATP in the activation of F-6-P to F-1,6-DiP.
Total ATP invested = 2 ATP
ATP Gained:
2 ATP by substrate level phosphorylation from 1,3diphosphoglycerate.
100

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2 ATP from substrate level phosphorylation from PEP.

Net ATP gained = 4 ATP gained - 2 ATP lost = 2 ATP
for glucose into lactate.
During rapid contraction, muscle cells require a very
fast supply of energy in the form of ATP.
The extra demand of ATP is met by glycolysis because
substrate level phosphorylation is 100-times faster than
oxidative phosphorylation
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Under aerobic conditions:

Total ATP invested in the activation phase = 2 ATP, as
under anaerobic conditions.
Total ATP gained = 8
A. 4 ATP (obtained by substrate level phosphorylation)
B. 2 NADH.H+ (produced from oxidation of
glyceraldehyde-3-phosphate);

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1 NADH.H+ can give rise to either two or three ATP

through respiratory chain depending upon which shuttle
system is used for its transfer across the mitochondrial
membrane;

Therefore, 2X3 ATP = 6 ATP.

Net ATP gained : 6ATP+2 ATP = 8 ATP

103

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Fates of pyruvate
1. Entry into the citric acid/ TCA cycle.
Glycolysis releases relatively little of the energy present
in a glucose molecule;
much more is released by the subsequent operation of
the TCA cycle and oxidative phosphorylation
Following this route under aerobic conditions, pyruvate
is converted to acetyl CoA by the enzyme pyruvate
dehydrogenase and the acetyl CoA then enters the TCA
cycle.
Endalamaw T

104

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105

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2. Conversion to FAs or ketone bodies.

When the cellular energy level is high (ATP in excess),
the rate of the TCA cycle decreases and acetyl CoA begins
to accumulate.
Under these conditions, acetyl CoA can be used for FA
synthesis or the synthesis of Ketone bodies.

106

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3. Conversion to lactate.
The NAD+ used during glycolysis (in the formation of
1,3-bisphosphoglycerate by glyceraldehyde 3-phosphate
dehydrogenase; must be regenerated if glycolysis is to
continue.
Under aerobic conditions, NAD+ is regenerated by the
re-oxidation of NADH via the electron transport chain.

107

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 When oxygen is limiting, as in muscle during vigorous

contraction, the reoxidation of NADH to NAD+ by the electron

transport chain becomes insufficient to maintain glycolysis
Under these conditions, NAD+ is regenerated instead by
conversion of the pyruvate to lactate by lactate dehydrogenase:

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Fate of Lactate
When sufficient oxygen becomes available once more,
NAD+ levels rise through operation of the electron
transport chain.
The lactate dehydrogenase reaction then reverses to
regenerate pyruvate that is converted by pyruvate
dehydrogenase to acetyl CoA which can enter the TCA
cycle

109

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 Lactate dehydrogenase in mammals oxidize NADH to

NAD+ hence produced ATP under anaerobic
conditions.
Lactate produced in contracting skeletal muscle is
transported in the bloodstream
Then to the liver where it is converted back to glucose
and can return once again via the bloodstream to the
skeletal muscle to be metabolized to yield energy
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4. Conversion to ethanol.
In yeast and some other microorganisms under anaerobic
conditions,
The NAD+ required for the continuation of glycolysis is
regenerated by a process called alcoholic fermentation.
The pyruvate is converted to acetaldehyde (by pyruvate
decarboxylase) and then to ethanol (by alcohol dehydrogenase),

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Regulation of Glycolsis
1. Phosphofructokinase (PFK)
The most important control step of glycolysis is the
irreversible reaction catalyzed by PFK
The enzyme is regulated in several ways
1.ATP/AMP-----PFK is allosterically inhibited by ATP
but this inhibition is reversed by AMP

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2.Citrate.
PFK is also inhibited by citrate, the first product of the

TCA cycle

3.Fructose 2,6-bisphosphate (F-2,6-BP)

F-2,6-BP is synthesized from F- 6- P by an enzyme
called phospho-fructokinase 2 (PFK2), a different enzyme
from PFK.
F-2,6-BP is hydrolyzed back to F- 6- P by fructose
bisphosphatase 2 (FBPase2).
113

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 F- 6- P stimulates the synthesis of F-2,6-BP and inhibits

its hydrolysis
F-2,6-BP in turn strongly activates PFK and hence
stimulates glycolysis
The overall effect is that when F- 6- P levels are high,

PFK (and hence glycolysis) is stimulated

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115

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 When blood glucose levels fall, the hormone glucagon

is released into the bloodstream.

This triggers a cAMP cascade that leads to

phosphorylation of the PFK2/FBPase2 polypeptide at a
single serine residue.
This activates FBPase2 and inhibits PFK2, lowering
the level of F-2,6-BP and hence decreasing the rate of
glycolysis.

116

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When blood glucose levels rise; the phosphate group is

removed from the PFK2/FBPase2 polypeptide by a
phosphatase,
This leads to inhibiting FBPase2 and activating PFK2,
raising the level of F-2,6-BP and hence increasing the

rate of glycolysis

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Hexokinase

Hexokinase catalyzed the phosphorlation of glucose is

the first irreversible step of glycolysis.
Accumulation of glucose-6-phosphate and F-6-P
allosterically inhibit hexokinase.

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Comparison b/n Glucokinase and Hexokinase:

Glucokinase

Hexokinase

1. Site

Liver only

All tissue cells

2. Affinity to glucose

Low affinity (high km) i.e. it

acts only in the presence of
high blood glucose
concentration.

High affinity (low km) i.e. it acts

even in the presence of low blood
glucose concentration.

3. Substrate

Glucose only

Glucose, galactose and fructose

4. Effect of insulin

Induces synthesis of
glucokinase.

No effect

5. Effect of glucose-6-p No effect

Allosterically inhibits hexokinase

6. Function

It phosphorylates glucose inside

the body cells. This makes
glucose concentration more in
blood than inside the cells. This
leads to continuous supply of
glucose for the tissues even in the
presence of low blood glucose
concentration.
6/18/2014

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Endalamaw T

Acts in liver after meals.

It removes glucose coming in
portal circulation, converting
it into glucose -6-phosphate.

Pyruvate kinase
Pyruvate kinase catalyzes the third irreversible step in
glycolysis.
It is activated by fructose 1,6-bisphosphate, AMP/ADP
ATP and the amino acid alanine allosterically inhibit
the enzyme so that glycolysis slows when supplies of ATP
and biosynthetic precursors (indicated by the levels of
Ala) are already sufficiently high.

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In similar to that of PFK , when the blood glucose

concentration is low, glucagon is released and stimulates

phosphorylation of the enzyme via a cAMP cascade

This covalent modification inhibits the enzyme so that
glycolysis slows down in times of low blood glucose
levels.

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Hormonal Regulation:
The speed of glycolysis is determined by the ratio of
insulin: glucagon
Insulin stimulates synthesis of Glucokinase, PFK and
Pyruvate kinase, so it stimulates glycolysis.
It also induces glucose transporters to provide cells
with glucose for glycolysis
Glucagon and adrenaline are inhibitory at the PFK-1
and Pyruvate Kinase levels
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Differences between aerobic and anaerobic glycolysis:

Aerobic

Anaerobic

1. End product

Pyruvate

Lactate

2 .Energy

6 or 8 ATP

2 ATP

3. Regeneration

Through respiration

Through Lactate

of NAD+

chain in mitochondria

4. Availability to Available and 2

123

formation
Not available as

TCA cycle in Pyruvate can oxidize

lactate is

mitochondria

cytoplasmic

Endalamaw T

to give 30 ATP

substrate

6/18/2014

E. Oxidation of extramitochondrial NADH+H+:

1. Cytoplasmic NADH+H+ cannot penetrate
mitochondrial membrane, however, it can be used to
produce energy (4 or 6 ATP) by respiratory chain
phosphorylation in the mitochondria
2. This can be done by using special carriers for
hydrogen of NADH+H+
These carriers are either dihydroxyacetone phosphate
(Glycerophosphate shuttle) or oxaloacetate (aspartate
124

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T
malate

6/18/2014

Metabolic Importance of Glycolysis:

1. Energy production:
a) anaerobic glycolysis gives 2 ATP.
b) aerobic glycolysis gives 6/ 8 ATP.

2. Oxygenation of tissues:
Through formation of 2,3 bisphosphoglycerate, which
decreases the affinity of Hemoglobin to O2

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3. Provides Important Intermediates:

A. Dihydroxyacetone phosphate: can give glycerol-3
phosphate, which is used for synthesis of TAGs and
phospholipids (lipogenesis)
B. 3- Phosphoglycerate: which can be used for synthesis
of AA serine
C. Pyruvate: which can be used in synthesis of AA
alanine
4. Aerobic glycolysis provides the mitochondria with
126

pyruvate,
which gives acetyl CoA Krebs' cycle 6/18/2014
Endalamaw T

Interconnection with PPP provides pentoses

Reversal of glycolysis in gluconeogenesis is an
important source of glucose
It is the main pathway of metabolism of fructose from
the diet
A small number of genetic diseases occur due to
deficiency in activity of enzymes of glycolysis; these are
manifested mainly as hemolytic anemias
Used to develop cancer therapy
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Reversibility of glycolysis (Gluconeogenesis):

1. Reversible reaction means that the same enzyme can catalyzes the
reaction in both directions.
2. all reactions of glycolysis -except 3- are reversible.

3. The 3 irreversible reactions (those catalyzed by kinase enzymes)

can be reversed by using other enzymes.
Glucose-6-p

Glucose

F1, 6 Bisphosphate

Fructose-6-p

Pyruvate

Phosphoenol pyruvate

4. During fasting, glycolysis is reversed for synthesis of glucose

from non-carbohydrate sources e.g. lactate.

This mechanism is called gluconeogenesis.

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V. Hexose Monophosphate Shunt (HMP)

(Pentose Phosphate Pathway)
HMP is an alternative pathway for glucose oxidation that
neither produces ATP nor utilizes it
It produces NADPH.H+ , ribose-5-phosphate, and is the
pathway for metabolism of dietary pentoses and
interconversion of sugars required for the synthesis of
complex heteropolysaccharides
It is considered as a shunt (by-pass) from the main
stream
of glycolysis.
Endalamaw T

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Site of HMP Shunt:

HMS operates in the cytosol of highly proliferating
tissues & that are in active FA & steroid synthesis, like;
liver, adipose tissues, lactating mammary gland, RBCs,
adrenal cortex, thyroid and testis
HMP is not active in non-lactating mammary glands and
the skeletal muscles
HMP has two phases of reaction - Irreversible
oxidative phase &, Reversible non-oxidative phase
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131

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Irreversible Oxidative Phase HMP:

The oxidative phase of HMP consists of oxidation &
decarboxylation of glucose-6-phosphate to yield ribulose5-phosphate.
The oxidative phase generates NADPH
All the four reactions in this phase are irreversible.
Glucose-6-phosphate is converted into 6phosphogluconolactone catalyzed by Glu-6- PDH in
presence of NADP and Mg2+ or Ca2+
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The glucose molecule is oxidized at carbon C1 to a

carboxylic residue, which enters into a ring (lactone)
structure with carbon C5.
The reaction can be inhibited by certain drugs, such as
sulfonamides and antimalarial drugs.
6-Phosphogluconolactone is hydrolyzed into 6phosphogluconate catalyzed by 6-phosphogluconolactone
hydrolase that opens up the ring structure and generates
the carboxylic group at carbon C1.
133

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6-Phosphogluconic acid is dehydrogenated into 3-keto-6phosphogluconate catalyzed by 6-phosphogluconate

dehydrogenase.
It requires NADP+ as a coenzyme & is the second
oxidation step.
O

OH

C
H

OH

HO

H
H

OH

Glucose-6-phosphate dehydrogenase
O O

H2 C

2+
2+
Ca
Mg
NADPH.H+
NADP+

P OH
OH

-D-Glucose-6-phosphate
Endalamaw T

134

COOH

OH

HO

H
H

OH

Hydrolase
O O

H2 C

P OH
OH

6-Phospho-gluconolactone

H2 O

OH

HO

H
H

OH
OH
H2 C

O
P OH
OH

6-Phospho-gluconate
6/18/2014

Subsequently the 3-Keto-6-phosphogluconate is

spontaneously decarboxylated into ribulose-5-phosphate
Therefore, the whole process is oxidative
decarboxylation
COOH
H

OH

HO

H
H

OH
OH
H2 C

COOH

6-Phospho-gluconate dehydrogenase
O

2+
2+
Ca
Mg
NADPH.H+
NADP+

P OH
OH

6-Phospho-gluconate
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Endalamaw T

OH
O

H
H

Spontaneous

OH
OH
H2 C

CH2OH
O

O
P OH
OH

CO2

OH

OH
H2C

O
P OH
OH

Ribulose-5-phosphate

3-Keto-6-phospho-gluconate
6/18/2014

Reversible Non-Oxidative Phase HMP:

Reversible phase of HMP shunt converts ribulose-5phospate into ribose-5-phosphate and glycolytic
intermediates.
In this phase, major sugars, glyceraldehydes to the
sedoheptulose can be generated.
Most of these interconversions take place with the help
transketolase & transaldolase enzymes.

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Generation of Ribose:
When there is cellular demand for pentoses, ribulose- 5phosphate is isomerized into its aldose isomer - ribose-5phosphate - by ribulose-5-phosphate isomerase.
Xylulose-5-phosphate is a regulator of glycolysis
It activates protein phosphatase 2A that directly
activates PFK- 2 and indirectly activates pyruvate kinase
through induction of its gene expression.

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CH2OH
H

O
OH

OH
H2C

Phosp
O
P

Ph o sp
OH

h o- p

om e r
s
i
e
s
o
en t

a se

CHO
OH

OH

OH

H2C

OH

OH

Ribose-5-phosphate
CH2OH

ho-pe

n t o se

epime

OH

Ribulose-5-phosphate

r as e

HO

H
H2C

OH

OH

OH

Xylulose-5-phosphate

Utilization of pentose sugars:

After the body needs of NADPH.H+ and ribose have been fulfilled,

the unused xylulose is converted into other sugars and the two
glycolytic intermediates; fructose-6-phosphate and glyceraldehyde3-phosphate
Endalamaw T that rejoin glycolysis.

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Interconversion of carbohydrates:
The non-oxidative phase of HMP shunt provides a
system of exchange of carbon atoms such that most of the
sugars are interconvertable into each other.
The exchange of 2-carbon moiety by transketolase and
3-carbon moiety by transaldolase between different sugarphosphates can generate the sugars from 3-carbon
(glyceraldehydes-3-P) to 7-carbon (sedohelptulose-7-P).

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All the reactions of these interconversion are reversible

and hence the non-oxidative phase has no beginning or end

Ribulose-5-phosphate ( 5 carbons) Transketolase Glyceraldehyde-3-phosphate ( 3 carbons)

+
+
Xylulose-5-phosphate (5 carbons)
Sedoheptulose-7-phosphate (7 carbons)
Glyceraldehyde-3-phosphate ( 3 carbons) Transaldolase Erythrose-4-phosphate ( 4 carbons)
+
+
Sedoheptulose-7-phosphate (7 carbons)
Fructose-6-phosphate (6 carbons)
Erythrose-4-phosphate ( 4 carbons) Transketolase Glyceraldehyde-3-phosphate ( 3 carbons)
+
+
Xylulose-5-phosphate (5 carbons)
Fructose-6-phosphate (6 carbons)
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Transketolase enzyme
Requiring TPP & Mg2+, transfers 2-carbon unit from
xylulose-5- P onto ribose-5- P in a reversible reaction to
produce a ketose heptulose (sedoheptulose-7- P) & an
aldotriose; glyceraldehyde-3- P.
TPP is the intermediate carrier of the 2-carbon unit.
CH2OH
C
CH2OH

CHO

O
HO
H

H
H2C

OH

P
OH

Xylulose-5-phosphate
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141

OH

OH

H
H

OH

H
H

OH

OH

H2 C

OH

OH

H2C

OH

HO

Ribose-5-phosphate

Transketolase
TPP; Mg2+

CHO

OH

H
H2 C

OH

OH

Sedoheptulose-7phosphate

OH

P
OH

OH

Glyceraldehyde-3phosphate
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Transaldolase Enzyme
Reversibly transfers a 3-carbon moiety (active
dihydroxyacetone, carbons 1-3) from the ketose
Sedoheptulose-7- P onto the Glyceraldehyde-3- P to
produce Erythrose-4- P & Fru-6- P
CH2OH
C
HO

CH2OH

O
CHO

H
H

OH
OH

OH

H2 C

CHO
H
OH

OH

H2 C

OH

P
OH

Sedoheptulose-7- + Glyceraldehyde-3phosphate
phosphate
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OH

OH

H2 C

OH

Transaldolase

HO

OH

H
H
OH

H2 C

OH
OH

P
OH

OH

Erythrose-4-phosphate + Fructose-6-phosphate
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Transketolase
Transfers two carbon fragments from Xylulose-5- P
molecule onto Erythrose-4- P in presence of TPP & Mg2+
giving Fru-6- P & Glyceraldehyde-3- P
Both of which rejoin glycolysis
CH2OH
O

CH2OH
O
HO

OH
H2C

CHO

O P OH
OH

OH

OH
H2C

CHO
O

O P OH
OH

Xylulose-5-phosphate + Erythrose-4-phosphate
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OH
H2C

O P OH

HO
H

H
OH

OH
H2C

O P OH

OH
OH
Transketolase Glyceraldehyde-3+ Fructose-6-phosphate
TPP; Mg2+
phosphate
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Metabolic Importance of NADPH

The produced NADPH is utilized for the following
metabolic and synthetic pathways:
Synthesis, elongation, and desaturation of FAs
Synthesis of cholesterol and other steroids
Synthesis of sphingosine and cerebrosides
Synthesis of non-essential AAs, e.g., glutamate and
tyrosine from phenylalanine
Regeneration of reduced glutathione
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Metabolic hydroxylation of endogenous metabolites and

xenobiotics with Cyt-P450
In the reversible UDP-glucose dehydrogenase reaction
Coenzyme for methemoglobin reductase
NADPH oxidase to produce O2- in phagocytic cells
Reversible production of NADH.H+ by
NADPH.H+/NAD transhydrogenase that could be used
for energy production
Synthesis of fructose from glucose
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Conversion of ribonucleotides to deoxyribonucleotides

by ribonucleotide reductase
Synthesis of neurotransmitters

Pentoses could be used in:

Synthesis of NAs (ribose in RNA & deoxyribose in
DNA).
Synthesis of coenzymes, e.g., NAD, FAD, CoASH, &
other free nucleotide coenzymes, e.g., ATP, GTP, etc.
Synthesis of mucopolysaccharides.
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G6PD DEFICIENCY
G6PD catalyzes NADP reduction into NADPH.
NADPH protects cells from oxidative damage by

regenerating reduced glutathione (GSH).

Erythrocytes do not generate NADPH in any other
way, they are more susceptible than other cells to
destruction from oxidative stress.
NADPH.H+ reduces the oxidized glutathione by
glutathione reductase, a flavoprotein enzyme containing
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FAD.

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Deficiency of G6PD and/or 6PGD reduces NADPH.H+

production and oxidized glutathione (GSSG) accumulates.

Peroxides as strong oxidants and the more damaging

free radicals generated from them are not scavenged.
They oxidize hemoglobin of red cells into
methemoglobin that polymerizes and some will protrude
from the cell membrane as Heinz bodies.
Oxidants also peroxidize lipid of RBCs membranes.

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149

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VI. The Citric Acid Cycle (TCA cycle)

It is a series of reactions in mitochondria that oxidize as
acetyl-CoA and reduce coenzymes that upon reoxidation
are linked to the formation of ATP

It is the final common pathway for the aerobic oxidation

of CHO, lipid, and protein because glucose, FAs, and
most AAs are metabolized to acetyl-CoA or intermediates
of the cycle

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It also has a central role in gluconeogenesis, lipogenesis,

and interconversion of AAs
Many of these processes occur in most tissues, but the
liver is the only tissue in which all occur to a significant
extent
The repercussions are therefore profound when, for
example, large numbers of hepatic cells are damaged as in
acute hepatitis or replaced by connective tissue

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Overview of TCA cycle

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Pyruvate Dehydrogenase Complex

(PDH) is a large enzyme complex in
the mitochondrion consisting of 3
different types of enzyme subunits.
1. Pyruvate dehydrogenase (E1),
2. Dihydrolipoyl transacetylase (E2)
3. Dihydrolipoyl dehydrogenase (E3)
It is the enzyme that connects the
glycolytic pathway to the TCA cycle
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Four coenzymes are required

1. Thiamine or vitamin B1 - thiamine
pyrophosphate (TPP)
2. Pantothenic acid - coenzyme A (CoASH)
3. Riboflavin FADH 2
4. Niacin - NADH

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Regulation of TCA Cycle

The TCA cycle is regulated at multiple points
However, in general it is safe to say that it is inhibited by
ATP and NADH
The inhibition by NADH keeps it tightly regulated by
oxygen supply, since NADH is converted to NAD+ by
oxidative phosphorylation
The inhibition by ATP keeps the TCA cycle in balance
with energy supply
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When ATP is high, the TCA cycle is inhibited and

precursors to the TCA cycle (pyruvate, acetyl CoA and

AAs) are diverted into other pathways

Acetyl CoA, citrate, and succinyl CoA are the end
products of individual steps in the TCA cycle and their
accumulation inhibits the step involved in their
production
Results in inhibition of the cycle as a whole

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Finally, Ca++ stimulates the TCA cycle at several

points
This is important because electrical stimulation of the
muscle causes an increase in intracellular Ca ++ levels
Thus, during exercise the TCA cycle will be
maximally stimulated in muscle
The regulation of the TCA cycle is summarized below

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Regulation of the TCA Cycle

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Relationship B/n TCA Cycle and Other

Metabolic Pathways

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Cellular Respiration

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Oxidative Phosphorylation
Def. A process that links oxidation of reduced Coenzymes
to phosphorylation of ADP
Components of oxidative Phosphorylation
Electron Transport system
Electrochemical gradient
ATP synthesis
ETS

Def. A set of complexes of inner Mitochondrial membrane

that transfers e-s from Reduced Coenzymes to O2
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The Electron Transport Chain

A. The electrons released in glycolysis and transported
into the mitochondria by shuttle mechanisms and those
derived from the TCA cycle are transferred to O2 and
combined with protons to form H2O
1. The electron transport chain is located in the inner
mitochondrial membrane.

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163

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a. The ETC is organized into four complexes, each of

which is composed of several integral membrane proteins
and coenzymes capable of reversible oxidation-reduction.
b. Each complex can accept electrons and then transfer
them to other complexes through mediation of mobile
carriers, ubiquinone (coenzyme Q) and cytochrome c.
c. Electrons carried by NADH are transferred to complex I.
d. Succinyl dehydrogenase of the TCA cycle is complex II
with its FAD coenzyme, residing on the inner surface of the
innerEndalamaw
mitochondrial
membrane.
T

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2. Electrons from both complex I and complex II are

transferred to ubiquinone, a lipophilic compound residing
in the membrane.
3. Ubiquinone delivers electrons to complex III, which
transfers them to complex IV via cytochrome c.
4. Complex IV with its important cytochrome a + a3
catalyzes the formation of water from the electrons,
protons, and O2

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Mitchell's Chemiosmotic Theory

1. Protons are translocated from the matrix into inter
membrane space as e-s move from reduced coenzymes to
O2
2. The consequence of the aforementioned vectorial
movement is generation of electrochemical gradient
3. Electrochemical gradient is converted to energy
content of ATP

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Overview of Chemiosmotic Theory

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Energy Capture During Electron Transport

A. As electrons pass through complexes I, III, and IV (but
not complex II), protons are transported across the inner
mitochondrial membrane from the matrix to the
intermembrane space, creating a pH gradient that
represents a form of stored energy
B. The pH gradient is used to drive ATP synthesis by the
movement of protons back to the matrix through a
transmembrane protein complex, or ATP synthase.
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1. This mechanism was first described as the

chemiosmotic theory of ATP generation, or the
Mitchell hypothesis.
2. As protons pass through a channel in the ATP
synthase complex, ADP and Pi are joined to form ATP
C. ATP synthesized in the mitochondria is translocated
to the cytoplasm by a cotransporter that simultaneously
brings ADP into the mitochondria.

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Energy Yield & Regulation of OP

A. Most ATP yield of glucose metabolism occur via
oxidative phosphorylation
B. The calculated ATP yield is somewhat variable because
glycolytic electrons transferred by the glycerol phosphate
shuttle bypass complex I of the electron transport chain.
Oxidative phosphorylation is regulated by ratio of ATP/
ADP.
The higher this ratio the more OP gets inhibited
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VII. GLUCONEOGENESIS
Pathways that responsible for converting noncarbohydrate precursors to glucose or glycogen
In mammals occurs in liver and kidney
Fasting requires all the glucose to be synthesized from
these non-carbohydrate precursors.
Most precursors must enter the Krebs cycle at some

point to be converted to Oxaloacetate.

OAA is the starting material for gluconeogenesis
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Gluconeogenesis cont
Gluconeogenesis meets the needs of the body for
glucose when carbohydrate is not available from the diet
or from glycogenolysis

Major Substrate for Gluconeogenesis:

1. Lactic acid from muscle, erythrocyte
2. Glycerol from TG hydrolysis
3.Glucogenic amino acid
4. Propionic acid
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A supply of glucose is necessary especially for nervous

system and erythrocytes.

Key Enzymes for Gluconeogenesis:

1. Pyruvate carboxylase
2. Phosphoenol pyruvate karboxykinase
3. Fructose 1,6-biphosphatase

4. Glucose-6-phosphatase

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174

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Tissues involve in Gluconeogenesis

Liver The major organ contributing to blood glucose. Liver
has the capacity to convert three carbon precursors into glucose.
Kidney Cortex - Kidney medulla consumes most of glucose
produced by the kidney cortex.
Brain, Skeletal muscle and other Extrahepatic Tissues
Gluconeogenesis is limited due to deficiency of G-6-Ptase.
Glucose from these tissues does not contribute to blood

glucose.
Heart and Smooth muscles and Adipocytes limited due to
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deficiency
of Fru-1,6-diphosphatase.

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Conversion of Pyruvate to PEP

Pyruvate kinase is by-passed by two enzymes:
i) pyruvate carboxylase, and,
ii) PEP carboxykinase.
1. The mitochondrial enzyme pyruvate carboxylase
changes Pyruvate into OAA by carboxylation
reaction in the presence of biotin & activated CO2

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PEP Carboxykinase
Converts OAA into PEP utilizing GTP as phosphate
donor and releasing H2O and CO2 again.
In human, the main enzyme form locates to cytoplasm
and is hormonally and metabolically regulated

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The irreversible PFK-1 and Gluco-/Hexokinase reactions

requires the usage of two enzymes; the Fru-1,6- BPtase and

Glu-6-Ptase.

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Gluconeogenesis From Glycerol

Glycerol absorbed from diet or derived from lipolysis of
fat is activated by glycerol kinase into glyerol-3- P in
liver, kidney, lactating mammary gland, heart & intestine

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Gluconeogenesis From Propionic Acid

Propionic acid is derived from methionine, isoleucine,
-oxidation of odd number FAs, cholesterol conversion
into bile acids, and, fermentation of fibers in large intestine
and rumen of herbivorous animals.
Propionic acid is the major source of blood glucose
synthesized by gluconeogenesis in such animals.

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181

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Gluconeogenesis From Lactate & Pyruvate

Cori's cycle is conversion of glucose to lactate in
muscle & conversion of lactate to glucose in liver
Cori's Cycle is not limited to the anaerobic oxidation of
glucose in active muscles, but also encompasses the
tissues like RBCs and adipocytes.
Lactate and/or pyruvate diffuse into blood stream from
these tissues to reach the liver and the kidney where
transformation takes place into glucose by
gluconeogenesis.
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THE CORI & GLUCOSE- ALANINE CYCLE

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VIII. GLYCOGEN METABOLISM

Storing carbohydrates in the form of glycogen is essential due to
the following advantages:
Dietary intake of glucose and glucose precursors is sporadic.
Storage of glucose in the form of fat is not suitable because:
1. Fat cannot be mobilized as rapidly in muscles as
glycogen.
2. Fat cannot be used as a source of energy in the absence of
oxygen as glucose, which can be oxidized anaerobically to

lactate.
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3. Unlike glycogen, fat cannot be transformed directly to

glucose by any pathway in human body to guarantee blood

glucose levels for tissues critically requiring glucose, e.g.,

RBCs and brain.
Glucose cannot be stored as such within the cells
because it is osmotically active and at equivalent amounts
to glycogen,
It will induce osmotic lysis of the cell due to the uptake
of considerable amounts of water.
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RELATIVE TISSUE CONTENT OF GLYCOGEN

Tissue

Normal tissue
mass

Glycogen stores

Liver

1800 g

75 - 180 g

Skeletal muscles

35 kg

100 - 300 g

Extra-cellular
glucose

10 liter

10 g

Total

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185 - 490 g

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Synthesis of Glycogen (Glycogenesis)

Glycogenesis takes place in the cytoplasm of almost all
tissues of the body
The turnover of glycogen in liver and skeletal muscles
is rapid and significant
Muscle glycogen serves as emergency store for its own
usage during exercise,
While the liver glycogen serves to maintain blood
glucose level during fasting
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Synthesis of glycogen from Glucose is carried out by the

enzyme Glycogen Synthase.
The activation of glucose to be used for glycogen synthesis
is carried out by the enzyme UDP-glucose

pyrophosphorylase.
The enzyme exchanges the phosphate on C-1 of glucose-1phosphate for UDP (Uridine diphosphate).
The energy of the phospho glycosyl bond of UDP glucose
is utilized by glycogen Synthase to catalyze the incorporation
of glucose in to Glycogen.
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UDP is subsequently released from the enzyme.

The -1,6 branches in glucose are produced by amylo-

(1,4-1,6) transglycosylase, also termed as branching

enzyme.
This enzyme transfers a terminal fragment of 6 to 7
glucose residues to an internal glucose residue at the C-6
hydroxyl position.

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Glycogen synthase can only extend the already existing

glycogen, por-glycogen or glycogenin primer molecule by

adding glucose units at its non-reducing C4 end.

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Glycogen Catabolism (Glycogenolysis)

Glycogen Phosphorylase catalyzes phosphorolytic
cleavage of the (14) glycosidic linkages of glycogen,
releasing glucose-1-phosphate
-1,4 glycosidic link is cleaved by phosphorylysis with
retention of energy potential in the phosphate ester of
glucose-1-phosphate.
It stops at fourth glucose from -1,6 branch point
It is activated by phosphorylation, regulated by
glucagon
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Debranching Enzyme
Transferase enzyme transfers 3 glucose residues from
a 4-residue limit branch to the end of another branch,
diminishing the limit branch to a single glucose residue
The (16) glucosidase moiety of the debranching
enzyme then catalyzes hydrolysis of the (16)
linkage, yielding free glucose.
This is a minor fraction of glucose released from
glycogen.
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193

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Free glucose is released for

every ~10 glucose-1-phosphate

residues.
Liver glycogen is never
hydrolyzed to zero content,
although it goes from 300
M/g to 42 M/g within 24
hrs, liver remains having a
minimum amount of glycogen
(16 M/g after 64 hrs).
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The major product of glycogen breakdown is glucose-1phosphate, from Phosphorylase activity

Phosphoglucomutase catalyzes the reversible reaction:
glucose-1-phosphate glucose-6-phosphate
Enzyme-Ser-OPO32

CH2OPO32

CH2OH
H

O
H
OH

OH
H

H
OPO32

OH

glucose-1-phosphate
195

Enzyme-Ser-OPO32

Enzyme-Ser-OH

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O
H
OH

OH
H

OH

CH2OPO32
H
OPO32

O
H
OH

H
OH

OH
H

OH

glucose-6-phosphate
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Glycogen Storage Diseases(GSDs)

First reported by van Craveld(1928) & von
Gierke(1929)
Till now, about 11 major types of GSDs have been
documented along with their subtypes.
GSDs are a group of inherited disorders characterized
by deposition of an abnormal type/ quantity of glycogen
in the tissues.
It is due to deficiency of enzymes that involve in
196

glycogen
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Glycogen Storage Diseases

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Type 0
It is due to the deficiency of liver glycogen synthase
It leads to fasting hypoglycemia, ketosis and early
death

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GSD-I (Von Girkes Disease)

Deficiency of G-6-phosphatase in liver/intestinal
mucosa
Chromosome: 17q 21, mostly GA or G C
mutations
Incidence 1: 200,000 people
The liver and kidney are involved, and hypoglycemia
is a major problem
Management: Frequent meals high in corn-starch;
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nocturnal
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GSD-II (Pompe Disease)

It is a fatal disorder characterized by deficiency of
lysosomal -1,4- and -1,6-glycosidase (acid maltase),
which act on glycogen to hydrolyze it.
Frequency: 1: 40,000
It is an Autosomal recessive inheritance multiple
mutations on Chromosome17q acid maltase gene
Symptoms(Infantile onset): cardiomegaly, enlarged
tongue, muscle weakness, death in 1st year of life
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Symptoms(Adult onset):
Skeletal muscle dysfunction, limb-girdle dystrophy,
hepatomegaly, respiratory insufficiency, nocturnal

ventilatory insufficiency, urinary incontinence in old age

Diagnosis: CK, enzyme assay in cultured fibroblasts
Management: High protein, low CHO diet
New finding: Recombinant human -1,4 glucosidase
infused IV in 3 infants twice weekly showed
improvements & children lived more than 1 year
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GSD-III (Forbes Disease, Cori Disease,

Limit Dextrinosis)
Deficiency of Glycogen debranching enzyme which
has 2 activities: Amylo-1,6 glucosidase and oligo 1,4-1,4gluconotransferase
Structure of stored glycogen is abnormal with short &
missing outer chains
Frequency: 1: 100,000
Chromosome: 1 p 21
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Symptoms: Hepatomegaly, hypoglycemia, muscle

weakness, wasting, ventricular hypertrophy, myopathy
Diagnosis: CK, AST, ALT, LDH, ALP; enzyme assay
in leucocytes or liver/muscle biopsy samples; liver
ultrasound
Most patients survive with progressive muscular
weakness

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GSD IV (ANDERSEN DISEASE)

The biochemical defect was identified to be the
deficiency of the alpha-1,4-glucan branching enzyme
also known as Glycogen Branching Enzyme (GBE1)
Clinical feature:
Failure to thrive, hepatosplenomegaly, and liver
cirrhosis.
There is progression to portal hypertension, ascites, and
liver failure, leading to death by age 5 years
Chromosome:
3p12
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GSD V (McArdle Disease)

It is caused by mutation in the gene encoding muscle
glycogen phosphorylase on Chromosome: 11q13
Transient myoglobinuria may occur after exercise but
this may precipitate acute renal failure
Patients may report muscle weakness, myalgia, and lack
of endurance since childhood or adolescence.
Later in adult life, there is persistent and progressive
muscle weakness and atrophy with fatty replacement.
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GSD VI (Hers Disease)

It is a benign disorder caused by the partial or total lack of
liver glycogen phosphorylase activity.
It is inherited autosomal recessive traits on Chromosome:
14q21-q22.
Patients inability to utilize liver glycogen for maintenance of
blood glucose results in moderate hypoglycemia, which may
then trigger oxidation of FAs causing ketosis.

hypoglycemia, mild ketosis, growth retardation, and

prominent Hepatomegaly.
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GSD VII (Tarui Disease)

It is due to Muscle PFK Deficiency
Marked weakness and stiffness invariably appeared in
muscle groups subjected to vigorous or prolonged exertion
PFK activity was entirely absent in muscle and about 50%
in erythrocytes
Decreased production of 2,3-DPG was held responsible
for the paradoxic erythrocytosis
The defect on chromosome 12
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GSD VIII
Deficiency of liver phosphorylase b kinase
The clinical symptoms include hepatomegaly, growth
retardation, elevation of AST, ALT, hypercholesterolemia,
hypertriglyceridemia, and fasting hyperketosis

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Thanks!!

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