METABOLISME KARBOHIDRAT

Meizly Andina

DEPARTEMEN BIOKIMIA
FAKULTAS KEDOKTERAN
UNIVERSITAS MUHAMMADIYAH SUMATERA UTARA
2015
 Overview
• the utilization of glucose as a source of energy
• formation of glucose from noncarbohydrate precursors
• storage of glucose in the form of glycogen for later use, and
release of glucose from glycogen for use by cells.
• Glucose is the major form in which carbohydrate absorbed from
the intestinal tract is presented to cells of the body.
• Glucose is the only fuel used to any significant extent by a few
specialized cells and the major fuel used by the brain
• Glucose metabolism is defective in two very common metabolic
diseases, obesity and diabetes, which contribute in development
of a number of major medical problems, including atherosclerosis,
hypertension, small vessel disease, kidney disease, and
blindness.

Thomas M. Devlin, Textbook of biochemistry: with clinical correlations

 Overview
Glycolysis
• a pathway used by all cells of the body to extract part of the chemical energy inherent in the glucose molecule.
• converts glucose to pyruvate
• produces ATP
• sets the stage for complete oxidation of glucose to CO2 and H2O.
Gluconeogenesis
• a function of the liver and kidneys (some of the same enzymes used in the glycolytic pathway, although the
reactions catalyzed are in the opposite direction).
• requires ATP

Glycogenesis
• glycogen synthesis
• Many cells store glycogen for the purpose of having glucose available for later use
• The liver is less selfish, storing glycogen not for its own use, but for maintenance of blood glucose levels that
ensure that other tissues, especially the brain, have an adequate supply of this important substrate.
Glycogenolysis
• Glycogen degradation
• Regulation of the synthesis and degradation of glycogen is a model for our understanding of how hormones
work and how other metabolic pathways may be regulated.

 contributes to our understanding of the diabetic condition, starvation, and how tissues of the body respond to
stress, severe trauma, and injury.

Thomas M. Devlin, Textbook of biochemistry: with clinical correlations

METABOLISME
 DIGESTION & ABSORPTION: CARBOHYDRATES
• The principal dietary carbohydrates are polysaccharides, disaccharides (lactose
(milk sugar) and sucrose (table sugar)), and monosaccharides (fructose and
glucose).
• In the mouth, starch is attacked by salivary α-amylase (optimal pH for this enzyme
is 6.7)  is inhibited by the acidic gastric juice when food enters the stomach.
• In the small intestine, both the salivary and the pancreatic α-amylase also act on
the ingested polysaccharides (end products of α-amylase digestion:
oligosaccharides: the disaccharide maltose; the trisaccharide maltotriose; and α-
limit dextrins, polymers of glucose)
• The oligosaccharidases  further digestion of the starch derivatives are located in
the brush border of small intestinal epithelial cells : Maltase and sucrase breaks
down maltotriose and maltose. Sucrase hydrolyzes sucrose  1 glucose + 1
fructose. Lactase hydrolyzes lactoseglucose and galactose, and trehalase
hydrolyzes trehalose  2 glucose molecules.
• Deficiency of one or more of the brush border oligosaccharidases may cause
diarrhea (↑number of osmotically active oligosaccharide molecules that remain in
the intestinal lumen, causing the volume of the intestinal contents ↑), bloating,
and flatulence (production of gas (CO2 and H2) from disaccharide residues in the
lower small intestine and colon after ingestion of sugar

Kim E. Barret, et al, Ganong’s Review of Medical Physiology

 ABSORPTION
• The sugar molecules pass from the mucosal cells to the blood in the
capillaries draining into the portal vein  Hepar converts them into
glucose  blood flow
• The transport of most hexoses is dependent on Na+ in the intestinal
lumen
– SGLT-1 is responsible for uptake of dietary glucose from the gut.
– SGLT 2, is responsible for glucose transport out of the renal tubules

Kim E. Barret, et al, Ganong’s Review of Medical Physiology

Robert K. Murray, Harper’s Illustrated Biochemistry
Thomas M. Devlin, Textbook of biochemistry: with clinical correlations
 MITOCHONDRIAL ENERGY METABOLISM
AND INSULIN SECRETION

MODY2
 Glycolysis Occurs in All Human Cells
• Adult human brain uses approximately 120 g of glucose each day in
order to meet its need for ATP.
• Red blood cells lack mitochondria and therefore are unable to
convert pyruvate to CO2 and H2O.
• The cornea, lens, and regions of the retina have a limited blood
supply and also lack mitochondria (because mitochondria would
absorb and scatter light) and depend on glycolysis as the major
mechanism for ATP production.
• Kidney medulla, testis, leukocytes, and white muscle fibers are
almost totally dependent on glycolysis as a source of ATP, because
these tissues have relatively few mitochondria.
• Tissues dependent primarily on glycolysis for ATP production
consume about 40 g of glucose per day in a normal adult

Thomas M. Devlin, Textbook of biochemistry: with clinical correlations

Overviews of the major ways in
which glucose is metabolized
within body cells

(a) Glucose transport into the cell by a

glucose transport protein (GLUT);
(b) glucose phosphorylation by hexokinase;
(c) the pentose phosphate pathway;
(d) glycolysis;
(e) lactic acid transport out of ther cell;
(f) pyruvate decarboxylation by pyruvate
dehydrogenase;
(g) TCA cycle;
(h) glycogenesis;
(i) glycogenolysis;
(j) lipogenesis;
(k) gluconeogenesis;
(l) hydrolysis of glucose 6phosphate and
release of glucose from the cell into
the blood;
(m) formation of glucuronides (drug and
bilirubin detoxification by
conjugation) by the glucuronic acid
pathway.

Thomas M. Devlin, Textbook of biochemistry: with clinical correlations

 GLIKOLISIS

• Glycolysis is a pathway by which a glucose molecule is oxidized to two

molecules of pyruvate, with energy conserved as ATP and NADH.
• In the cytosol of all cells

• Aerobic or anaerobic
• In aerobic glycolysis :
- glucose converted to two pyruvate
- sets the stage for pyruvate to acetyl CoA
• In anaerobic glycolysis
- In tissues: lack mitochondria or insufficient of oxygen
- Pyruvate  lactic acid (need NADH)
Preparatory phase Payoff phase
Phosphorylation of glucose and Oxidative conversion of glyceraldehyde
its conversion to glyceraldehyde 3-phosphate to pyruvate and the
3-phosphate coupled formation of ATP and NADH

Lehninger Biochemistry
GLYCOLYTIC REACTION STEP

Lehninger Biochemistry
METABOLIC FATES OF PYRUVATE
GENERAL PRECURSORS OF ACETYL COA
Pathways of aerobic glucose catabolism and their linkage to ATP formation

Vander et al.: Human Physiology: The Mechanism of Body Function

 CLINICAL ASPECTS :
Inhibition of Pyruvate Metabolism Leads to Lactic Acidosis

• Arsenite and mercuric ions react with the -SH groups of lipoic acid  inhibit
pyruvate dehydrogenase  pyruvate to accumulate
A dietary deficiency of thiamin  pyruvate to accumulate
• Nutritionally deprived alcoholics  thiamin-deficient  potentially fatal
pyruvic and lactic acidosis.
• Patients with inherited pyruvate dehydrogenase deficiency (defects in one
or more of the components of the enzyme complex  lactic acidosis
(particularly after a glucose load)
• Because of its dependence on glucose as a fuel, brain is a prominent tissue
where these metabolic defects manifest themselves in neurologic
disturbances.
• Inherited aldolase A deficiency and pyruvate kinase deficiency in
erythrocytes  hemolytic anemia.
 CLINICAL CORRELATION
Alcohol and Barbiturates

• Acute alcohol intoxication causes increased

sensitivity of an individual to the general
depressant effects of barbiturates.
• Surprisingly, the alcoholic when sober is less
sensitive to barbiturates.
Lippincott’s Biochemistry
 GLUCONEOGENESIS
• Gluconeogenesis  Net synthesis or formation of
glucose from various substrates (use of various
amino acids, lactate, pyruvate, propionate, and
glycerol),
• Gluconeogenesis enables the maintenance of
blood glucose levels long after all dietary glucose
has been absorbed and completely oxidized.
• Occurs in the cytosol and mitochondria at the
liver (90 %), kidney (10 %)

Thomas M. Devlin, Textbook of biochemistry: with clinical correlations

 GLUCONEOGENESIS SUBSTRATES

• Glucose synthesis from Glycerol

• Hydrolysis of a triacylglycerol (fat metabolism in

adipose tissue)  three fatty acids and glycerol
(substrate for gluconeogenesis)
• Glycerol transported to the liver  converted to
glycerol 3 phosphate by glycerol kinase (only in liver
and kidney), which can be converted by glycerol 3
phosphate dehydrogenase into dihydroxyacetone
phosphate  convert into lactate (or into pyruvate
for subsequent complete oxidation to CO2 and H2O).
 GLUCONEOGENESIS SUBSTRATES

• All amino acids except leucine and lysine can supply carbon for net
synthesis of glucose by gluconeogenesis. These amino acids are ketogenic
but not glucogenic.
• All other amino acids are classified as glucogenic, or at least both
glucogenic and ketogenic
• Acetyl CoA is the end product of lysine metabolism, and acetoacetate and
acetyl CoA are end products of leucine metabolism. No pathway exists for
converting acetoacetate or acetyl CoA into pyruvate or oxaloacetate in
humans and other animals.

• Glucose synthesis from the glucogenic amino acids

- Alanin the most important as glucogenic amino acids
- When exercising muscle produces large quantities of pyruvate alanine
transported to the liver  reconverted to pyruvate and then to glucose
Glucogenic and Ketogenic Amino Acids
 GLUCONEOGENESIS SUBSTRATES

• Glucose synthesis from lactate

- Lactate is released by cells have low oxygen
concentrations (skeletal muscle, red blood cells)
- In the cori cycle :
lactate is released by skeletal muscle during exercise
 transferred to the liver  pyruvate  glucose 
gluconeogenesis
Relationship between gluconeogenesis in the liver and glycolysis in the rest of the
body.
(a) Cori cycle.
(b) Alanine cycle. Thomas M. Devlin, Textbook of biochemistry: with clinical correlations
 Opposing pathways of glycolysis and
gluconeogenesis

Three reactions of glycolysis are

essentially irreversible in vivo and
cannot be used in gluconeogenesis:

1. the conversion of glucose to glucose 6-

phosphate by hexokinase
2. the phosphorylation of fructose 6-
phosphate to fructose 1,6-bisphosphate
by phosphofructokinase-1
3. the conversion of phosphoenolpyruvate
to pyruvate by pyruvate kinase

In gluconeogenesis, the three irreversible

steps are bypassed by a separate set of
enzymes, catalyzing reactions that are
sufficiently exergonic to be effectively
irreversible in the direction of glucose
synthesis

Lehninger Biochemistry
 Alternative paths
from pyruvate to
phosphoenolpyruvate
The relative importance of the two
pathways depends on the availability of
lactate and the cytosolic requirements
for NADH by gluconeogenesis

• Pyruvate carboxylase, a mitochondrial

enzyme that requires the coenzyme
biotin, converts the pyruvate to
oxaloacetate
• Because the mitochondrial membrane
has no transporter for oxaloacetate,
before export to the cytosol the
oxaloacetate must be reduced to malate
by mitochondrial malate
dehydrogenase, at the expense of NADH
• Malate leaves the mitochondrion
through a specific transporter in the
inner mitochondrial membrane, and in
the cytosol it is reoxidized to
oxaloacetate, with the production of
cytosolic NADH
• The oxaloacetate is then converted to PEP by
phosphoenolpyruvate carboxykinase. This
Mg2-dependent reaction requires GTP as the
phosphoryl group donor

Lehninger Biochemistry
 Alternative paths
from pyruvate to phosphoenolpyruvate
The relative importance of the two
pathways depends on the availability of
lactate and the cytosolic requirements
for NADH by gluconeogenesis

• This pathway makes use of lactate

produced by glycolysis in erythrocytes or
anaerobic muscle, for example
• The conversion of lactate to pyruvate in
the cytosol of hepatocytes yields NADH,
and the export of reducing equivalents
(as malate) from mitochondria is
therefore unnecessary.
• Pyruvate is transported into the
mitochondrion  converted to
oxaloacetate by pyruvate carboxylase
• This oxaloacetate is converted directly to
PEP by a mitochondrial isozyme of PEP
carboxykinase, and the PEP is
transported out of the mitochondrion to
continue on the gluconeogenic path.

Lehninger Biochemistry
• The second glycolytic reaction that cannot participate in
gluconeogenesis is the phosphorylation of fructose 6-
phosphate by PFK-1
• The generation of fructose 6-phosphate from fructose
1,6-bisphosphate is catalyzed by a different enzyme,
Mg2-dependent fructose 1,6-bisphosphatase (FBPase-1)
• The third bypass is the final reaction of gluconeogenesis,
the dephosphorylation of glucose 6-phosphate to yield
glucose
• The reaction catalyzed by glucose 6-phosphatase does
not require synthesis of ATP
 Frc-2,6-bisP effects in liver

• When blood [Glc] is low, glucagon is released, resulting in

increased intracellular [cAMP] in liver.
– Frc-2,6-bisP decreases, stimulates gluconeogenesis
• When blood [Glc] is high, Frc-2,6-bisP increases
– Inhibiting Fructose 1,6 bisphosphatase, inhibiting
gluconeogenesis

• Mg2-activated enzyme is found on the lumenal side of the

endoplasmic reticulum of hepatocytes and renal cells. Muscle
and brain tissue do not contain this enzyme and so cannot
carry out gluconeogenesis.
• Glucose produced by gluconeogenesis in the liver or kidney or
ingested in the diet is delivered to brain and muscle through
the bloodstream.
 Gluconeogenesis Is
Energetically Expensive,
but Essential

2 Pyruvate + 4ATP + 2GTP + 2NADH + 2H +

+ 4H2O  glucose + 4ADP + 2GDP + 6Pi +
2NAD+

• Conversion of glucose to pyruvate by

glycolysis, which requires only two
molecules of ATP :
Glucose 2ADP + 2Pi+ 2NAD + 2
pyruvate + 2ATP + 2NADH + 2H+ + 2H2O

Lippincott’s Biochemistry
 The bypass reactions are in red;
all other reactions are reversible steps of glycolysis
Lippincott’s Biochemistry
 CLINICAL ASPECTS

• The capacity of the tubular system to reabsorb

glucose is limited to a rate of about 350 mg/min,
and in hyperglycemia (as occurs in poorly
controlled diabetes mellitus) the glomerular
filtrate may contain more glucose than can be
reabsorbed, resulting in glucosuria.
• Glucosuria occurs when the venous blood glucose
concentration exceeds 9.5–10.0 mmol/L

Robert K. Murray, Harper’s Illustrated Biochemistry

 CLINICAL CORRELATION
Reactions at High (Left) and Low (Right) Glucose Levels

Dietmar Schomburg, Gerhard Michal , 2012. Biochemical pathways : an atlas of biochemistry and molecular biology 2nd ed.
GLYCOGENOLYSIS AND GLYCOGENESIS
• Glycogenolysis  breakdown of glycogen to glucose or
glucose 6phosphate
• Glycogenesis  synthesis of glycogen.
• Important in almost every tissue but especially in muscle and
liver.

• In the wellfed human, liver glycogen content 10% of wet

weight of this organ. Muscle stores less only 1–2% of its wet
weight.
• Muscle > liver  total muscle glycogen = 2x liver glycogen

Thomas M. Devlin, Textbook of biochemistry: with clinical correlations

 Variation of liver glycogen levels
between meals and during the nocturnal fast

• Glycogen serves as a fuel reserve for the synthesis of ATP within

muscle, whereas liver glycogen functions as a glucose reserve for
the maintenance of blood glucose concentrations.
• Liver glycogen levels vary greatly in response to the intake of food.
After 12–18 hours of fasting, the liver glycogen is almost totally
depleted.
• Liver glycogen is called into play between meals and to a greater
extent during the nocturnal fast.
Thomas M. Devlin, Textbook of biochemistry: with clinical correlations
 MUSCLE GLYCOGEN
• Muscle glycogen is a source of ATP for increased muscular activity.
• Most of the glucose of glycogen is consumed within muscle cells without
formation of free glucose as an intermediate.
• About 8% of muscle glycogen  free glucose.
 bloodstream
 glycolysis in muscle.

• Glucose  glycogen in muscle plays an important role in lowering blood

glucose levels elevated by a high carbohydrate meal.
• Glycogenesis in liver contributes to the lowering of blood glucose but is of
less importance than glycogen synthesis in muscle.

Thomas M. Devlin, Textbook of biochemistry: with clinical correlations

• Exercise of a muscle  mobilization of muscle glycogen 
ATP
• Red muscle fibers (supplied with a rich blood flow,
myoglobin↑, mitochondria(+). Glycogen is converted into
pyruvate CO2 + H2O.
• White muscle fibers (blood supply↓ and mitochondria<<).
Glycogenolysis  lactate.
• White muscle fibers >> glycogenolysis and glycolysis, than red
muscle fibers.

Thomas M. Devlin, Textbook of biochemistry: with clinical correlations

 STIMULATION AND INHIBITION OF GLYCOGEN DEGRADATION

Lippincott’s Biochemistry
 Pathway of
glycogenesis and
glycogenolysis in the
liver.

• Cyclic AMP
integrates the
regulation of
glycogenolysis and
glycogenesis by
promoting the
simultaneous
activation of
phosphorylase and
inhibition of
glycogen synthase.

• Insulin acts
reciprocally by
inhibiting
glycogenolysis and
stimulating
glycogenesis.
Robert K. Murray, Harper’s Illustrated Biochemistry
 Biosynthesis of D glucuronic acid from glucose

• Glucuronic acid is formed by oxidation of UDPglucose catalyzed by

UDPglucose dehydrogenase
• In humans glucuronic acid is converted to Lxylulose  reduced to
xylitol, reoxidized to Dxylulose, and phosphorylated with ATP and
an appropriate kinase to xylulose 5phosphate (reenter the pentose
phosphate pathway ).
• The glucuronic acid pathway operates in adipose tissue, and its
activity can be increased in tissue from starved or diabetic animals.
UDPGlc
pirofosforilasi • Glucuronide formation is important in drug detoxification, steroid
excretion, and bilirubin metabolism.
UDPGlc • Bilirubin is the major metabolic breakdown product of heme. The
dehidrogenase central step in excretion of bilirubin is conjugation with glucuronic
acid by UDPglucuronyltransferase.
• Development of this conjugating mechanism occurs gradually and
may take several days to 2 weeks after birth to become fully active
in humans. So called physiological jaundice of the newborn results
in most cases from the inability of the neonatal liver to form
bilirubin glucuronide at a rate comparable to that of bilirubin
production.
• In humans a similar defect is found in congenital familial
nonhemolytic jaundice (Crigler–Najjar syndrome). Patients with
this condition are also unable to conjugate foreign compounds
efficiently with glucuronic acid.
Thomas M. Devlin, Textbook of biochemistry: with clinical correlations
Lippincott’s Biochemistry
• Why Store Glucose As Glycogen? Why not
store our excess glucose calories entirely as fat
instead of glycogen?

Thomas M. Devlin, Textbook of biochemistry: with clinical correlations

• Inherited deficiencies in specific enzymes of glycogen metabolism in
both liver and muscle are the causes of glycogen storage diseases.

Robert K. Murray, Harper’s Illustrated Biochemistry

 Glucose Is Synthesized from Other Sugars
• Sucrose is hydrolyzed  fructose in the small bowel.
• Fructokinase (its activity is not affected by fasting or by insulin), in liver
(and kidney and intestine) catalyzes the phosphorylation of fructose 
fructose 1-phosphate by aldolase B  dihydroxyacetone phosphate +
glyceraldehyde.

• Glyceraldehyde is phosphorylated  glyceraldehyde 3 phosphate 

glycolysis
• 2 dihydroxyacetone phosphate obtainable (from 1 fructose) can be
converted to glucose by enzymes of gluconeogenesis or, alternatively, into
pyruvate or lactate by the last stage of glycolysis.

• The major energy source of spermatozoa is fructose. Spermatozoa contain

mitochondria  metabolize fructose completely to CO2 and H2O by the
combination of fructolysis and TCA cycle activity  energy demands of
spermatozoa in their search for ova
Robert K. Murray, Harper’s Illustrated Biochemistry

Thomas M. Devlin, Textbook of biochemistry: with clinical correlations

• Diets high in sucrose or in high-fructose syrups 
↑ fructose (and glucose) entering the hepatic
portal vein.

• Glycolysis in the liver of Fructose > rapid than

does glucose because it bypasses the regulatory
step catalyzed by phosphofructokinase  fatty
acid synthesis ↑ , esterification of fatty acids ↑,
 VLDL secretion ↑  serum triacylglycerols ↑
 LDL cholesterol concentrations ↑
Robert K. Murray, Harper’s Illustrated Biochemistry

Thomas M. Devlin, Textbook of biochemistry: with clinical correlations

FRUCTOSE METABOLISM
• Galactose is derived from intestinal hydrolysis of the
disaccharide lactose, the sugar of milk. It is readily
converted in the liver to glucose.
• Galactokinase catalyzes the phosphorylation of galactose,
using ATP as phosphate donor
• Galactose 1-phosphate + uridine diphosphate glucose
(UDPGlc)  uridine diphosphate galactose (UDPGal) +
glucose 1-phosphate, catalyzed by galactose 1-phosphate
uridyl transferase.
• Conversion of UDPGal to UDPGlc is catalyzed by UDPGal 4-
epimerase.
• Glucose 1-phosphate  Glucose 6-phosphate  Glucose

Robert K. Murray, Harper’s Illustrated Biochemistry

 Pathway of conversion of
(A) galactose to glucose in the liver
(B) glucose to lactose in the lactating mammary gland.

Robert K. Murray, Harper’s Illustrated Biochemistry

Dietmar Schomburg, Gerhard Michal , 2012. Biochemical pathways : an atlas of biochemistry and molecular biology 2nd ed.
Dietmar Schomburg, Gerhard Michal , 2012. Biochemical pathways : an atlas of biochemistry and molecular biology 2nd ed.
• The oxidation of glucose 6-phosphate to pentose phosphates  pentose
phosphate pathway (also called the phosphogluconate pathway or the
hexose monophosphate pathway
• In this oxidative pathway, NADP is the electron acceptor, yielding NADPH.
• Rapidly dividing cells, such as those of bone marrow, skin, and intestinal
mucosa, use the pentoses to make RNA, DNA, and such coenzymes as ATP,
NADH, FADH2, and coenzyme A.
• In other tissues, the essential product of the pentose phosphate pathway
is not the pentoses but the electron donor NADPH, needed for reductive
biosynthesis or to counter the damaging effects of oxygen radicals.
• Tissues that carry out extensive fatty acid synthesis (liver, adipose,
lactating mammary gland) or very active synthesis of cholesterol and
steroid hormones (liver, adrenal gland, gonads) require the NADPH
provided by the pathway. Erythrocytes and the cells of the lens and cornea
are directly exposed to oxygen and thus to the damaging free radicals
generated by oxygen.

Lehninger Biochemistry
 Non Oxidative Reactions
• Begins with the conversion of ribulose 5
phosphate to :
- ribose 5 phosphate by ribulose 5
phosphate isomerase
- xylulose 5 phosphate by ribulose 5
phosphate epimerase
• The result of this phase is synthesis of
ribose 5 phosphate, glyceraldehyde 3
phosphate and fructose 6 phosphate

Oxidative reactions of the pentose

phosphate pathway. The end
products are : ribose 5-phosphate,
CO2, and NADPH
 Role of NADPH in
regulating the partitioning
of glucose 6-phosphate
between glycolysis and the
pentose phosphate
pathway.

• When NADPH is forming

faster than it is being used
for biosynthesis and
glutathione reduction
[NADPH]rises and inhibits
the first enzyme in the
pentose phosphate
pathway.
• As a result, more glucose 6-
phosphate is available for
glycolysis.