Glycolysis

Reaction 1:Phosphorylation of Glucose

Reaction 2: Phosphoglucoisomerase
Reaction 3: Phosphofructokinase
Reaction 4: Aldolase
Reaction 5: Triose Phosphate Isomerase
Reaction 6: Glyceraldehyde-3-Phosphate
Dehydrogenase
Reaction 7: Phosphoglycerate Kinase
Reaction 8: Phosphoglycerate Mutase
Reaction 9: Enolase
Reaction 10: Pyruvate Kinase
Summary
 Summary
• Glycolysis is composed of ten enzyme-
catalyzed reactions
• It converts one molecule of glucose to two
molecules of pyruvate
• It produces two ATP and reduces two NAD+
to two NADPH
Phosphofructokinase (PFK)
Deficiency
Leomel Argulla
John Anthony Ara
 PFK Deficiency
• Also known as Glycogen Storage Disease Type
VII (GSD VII) or Tarui’s Disease
• First described by Seiichiru Tarui and his co-
workers in 1965
• Characterized by exercise intolerance and easy
fatigability
• Exist in classical, infantile and late-onset forms
 PFK Deficiency- Pathophysiology
• PFK is the key
regulatory enzyme in
glycolysis
 PFK Deficiency- Pathophysiology
• Tissues deficient in PFK cannot use free or
glycogen derived glucose as energy source
• The lack of PFK action causes accumulation of
hexose monophospates
• This leads to excessive glycogen synthesis
• The presence of G6P in high concentrations
enhances the action of the pentose phosphate
pathway
 PFK Deficiency- Pathophysiology
• PFK is a tetrameric enzyme composed of up to
three different subunits: M-muscle, L-liver and
P-platelets.
• PFK deficiency only affects the M form:
• Muscle cells uses M4 tetramer rendering their
enzymatic activity inactive
• Erythrocytes uses mixed M and L isoforms
making them only partially inactive
 PFK Deficiency-Symptoms
• Exercise intolerance and muscle fatigue
• Myoglobinuria
• Haemolysis
• Jaundice
• Hyperuricaemia
 PFK Deficiency-Cause
• PFK is a genetic disorder caused by the
alteration of the gene coding for the M
subunit of PFK
(gene is found on chromosome 12 p13 with 30 exons)

• Autosomal recessive inheritance

– More cases on male
– Very rare, only described in approximately 100
patients worldwide
 PFK Deficiency-Treatment
• No cure for the disorder but can alleviated
with treatment.
• Symptoms can be treated with specific
medical approach.
• Dietary management
• Abstinence from intense activities and
strenuous work
 Glycolysis
Fructose Intolerance
December 08, 2010
Lovely Kris L. Acuram
Allen Jun Anies
Presentation Outline

Dietary Sources of Fructose

Types of Fructose Metabolism Disorders
- Mechanism of Action
- Symptoms
- Treatment
Summary
References
 Dietary Sources of Fructose

• Dietary fructose comes from a variety of sources:

– Sugar
– Fruits and vegetables (including juices, dried and canned)
– Breakfast cereals
– Chocolates and candies
– Snack bars
– Honey
– High fructose corn syrup
– Beverages (regular soda, sweetened water, sports drinks)

Fructose often comes from sucrose, which is a disaccharide

consisting of glucose and fructose
 Types of Fructose Intolerance
• Hereditary Fructose Intolerance (HFI)
– Rare, genetic metabolic condition that is inherited
– Results from deficiency of 2nd enzyme of fructose pathway aldolase
B (fructose 1,6-bisphosphate aldolase) in liver, kidneys and intestine
– Prevalence 1/20,000 in US, 1/26,100 in central Europe

• Dietary Fructose Malabsorption (DFM)

– Main transporter of fructose is the GLUT5 transporter
– Malabsorption of fructose occurs when ingestion of fructose is much
greater than absorption of fructose into the body
 HFI - Symptoms
• Asymptomatic until fructose or sucrose is ingested
• First incident often seen in infants
• Symptoms are most severe in earlier years of life

• Acute symptoms:
– 20-30 minutes following fructose administration
– Hypoglycemia, sweating, trembling, sleepiness, convulsions
– Abdominal pain, diarrhea, vomiting and flatulence
• Chronic symptoms:
– Jaundice, hepatomegaly, splenomegaly
– Growth retardation, cirrhosis, fibrosis, kidney failure
– Death
HFI – Mechanism of Action
Primary defect in
Hereditary Fructose
Intolerance is a
deficiency of Aldolase
B which functions in
fructose metabolism.

↓Glycogen Production

Fructose-1,6-Bisphosphate Aldolase B

Glycolysis Inhibition

↑Fructose-1-P
HFI – Mechanism of Action

• Patients with hereditaty fructose intolerance are deficient in the liver

aldolase responsible for splitting fructose-1-phosphate into
dihydroxyacetone phosphate and glyceraldehyde. Consumption of
fructose by these patients results in the accumulation of fructose-1-
phosphate and depletion of Pi and ATP in the liver.
• The reactions involved are those catalyzed by fructokinase and the
enzymes of oxidative phosphorylation.

Fructose + ATP fructose-1-phosphate + ADP

ADP + Pi +
"energy provided by electron transport chain" ATP
_______________________________________________________
Net: Pi + fructose fructose-1-phosphate
HFI – Mechanism of Action

• It makes impossible for liver mitochondria to

generate ATP by oxidative phosphorylation. The ATP
levels fall precipitously, making it also impossible for
liver to carry out its normal work functions.
• Damage results to the cells in large part because
they are unable to maintain normal ion gradients by
means of the ATP-dependent cation pumps.
• The cells swell and eventually lose their internal
contents by osmotic lysis.
 HFI – Mechanism of Action
Deficiency in Aldolase B + High activity of Fructokinase

Fructose-1-P accumulation

1) Inhibition of glucose production by blocking

gluconeogenesis and glycogenolysis  hypoglycemia
2) Overutilization and depletion of ATP and Pi 
increase in AMP 
a. Ultrastructural lesions  liver and kidney damage
 HFI – Treatment
• Lifetime avoidance of fructose, sucrose, and
sorbitol with the guidance of an experienced
dietitian
• May treat complications
– i.e. meds to decrease uric acid in blood will
decrease risk for gout
• Patients should wear medic alert bracelets
that prohibit sugars and advise appropriate
treatment for hypoglycemia
 DFM - Symptoms
Symptoms:
• Bloating [gas and increase water in large
bowel]
• Abdominal Discomfort [gas]
• Diarrhea [or constipation]
 DFM – Mechanism of Action
1) Excess fructose remains in intestine due to
incomplete transport of fructose by the
GLUT5 and GLUT2 carriers
2) Fructose carried to large intestine where it is
fermented by colonic flora
3) By-products: hydrogen gas, methane, CO2
and short fatty acid chains
 DFM – Mechanism of Action
• GLUT5 [main fructose transporter]
– High affinity for fructose, low-capacity transporter
– Facilitative transporter that depends on
concentration gradients
– Regulation of GLUT5 gene depend on contents of
stomach
• GLUT2 [general sugar transporter]
– Low affinity for fructose, high capacity transporter
– Transports fructose, galactose, glucose
 DFM - Treatment
• There is no known cure, focus is on symptom reduction
• Dietary manipulation to avoid high fructose foods
• Choose foods where fructose is not in excess of glucose
(excessive fructose avoidance) as glucose increases
fructose absorption
• There is evidence that a fructose free diet reduces
symptoms associated with fructose malabsorption
including gastrointestinal disturbances
• If malabsorption is due to excessive small intestinal
bacteria, antibiotic treatment can help with the
overgrowth
 Summary
HFI
Symptoms -Acute: hypoglycemia, sweating,
trembling, sleepiness, convulsions,
N&V, abdominal symptoms
-Chronic: jaundice, hepatomegaly,
splenomegaly, growth retardation,
cirrhosis, fibrosis, kidney failure, death
MOA -Hereditary metabolic condition from
deficiency of aldolase B in liver, kidneys
and intestine
-Causes Fructose-1-P accumulation that
leads to hypoglycemia, hyperuricaemia,
↓protein synthesis, liver and kidney
damage
Diagnosis -Important to diagnose early in life
-iv fructose loading test
-genetic screening of chromosome 9
-liver biopsy
-experimental CDT
Treatment -Eliminate fructose, sucrose, and
sorbitol from diet
DFM
-Bloating
-Abdominal discomfort
-Diarrhea/Constipation
-Presentation similar to IBS
1)Excess fructose remains in intestine due
to incomplete transport by GLUT5 and
GLUT2
2)Fructose carried to large intestine where
it is fermented by colonic flora
3)By-products: hydrogen gas, CO2 and
short fatty acid chain
-Typically diagnosed by hydrogen breath
test
-Absolute difference between readings
needed for significance is debatable
-Low fructose diet
-Small Fructose/Glucose ratio foods
 References
• Thomas M. Devlin, PhD, Textbook of Biochemistry with clinical correlations, John wiley and sons USA 1997, p285
• Gitzelmann R. Steinmann B and Van den Bergie G, Disorders of fructose metabolism, In: C. R. Scriver A. L. Beaudet, W. S.
Sly and valle (Eds) The Metabolic and Molecular Bases of Inherited Disease 7th ed, New York: McGraw Hill, 1995 pp.
905-934
• Froesch E. R. 1969. Disorders of Fructose Metabolism. Journal of Clinical Pathology 22: 7-12
• hm.utoronto.ca/~jeffh/phm10fructose.ppt