Dimitrios Retalis dimitrios'retalisutoronto'ca

1
Fructose Metabolism
Mmmmm Fructose

• Dimitrios Retalis dimitrios.retalis_at_utoronto.ca
• Joyce Saliba joyce.saliba_at_utoronto.ca
• Rajini Retnasothie rajini.retnasothie_at_utoronto.ca
• Tulika Singh tulika.singh_at_utoronto.ca

2
Introduction to Fructose

• Fructose is a simple reducing sugar
• Important biological monosaccharide, along with
  glucose and galactose
• Hexose, generally existing as a 5-member ring

Voet D, Voet J and Charlotte Pratt. Fundamentals
of Biochemistry. New York Wiley and Sons Inc,
1999.
3
Introduction to Fructose

• Fructose can be found in

4
Fructose Metabolism

• Fructose can be metabolized by the liver and
  muscle

Fructose Metabolism
Liver
Muscle
Voet D, Voet J and Charlotte Pratt. Fundamentals
of Biochemistry. New York Wiley and Sons Inc,
1999.
5
Fructose Metabolism in Muscle
Voet D, Voet J and Charlotte Pratt. Fundamentals
of Biochemistry. New York Wiley and Sons Inc,
1999.
6
Fructose Metabolism in Liver
1.
2.
3.
(4.)
(5.)
(7.)
(6.)
Voet D, Voet J and Charlotte Pratt. Fundamentals
of Biochemistry. New York Wiley and Sons Inc,
1999.
7
Hereditary Fructose Intolerance (HFI)

• Deficiency in fructose-1-phosphate aldolase in
  the liver

Voet D, Voet J and Charlotte Pratt. Fundamentals
of Biochemistry. New York Wiley and Sons Inc,
1999.
8
Overview of HFI

• Incidence 1/40 000 whenever fructose-containing
  foods are introduced into the diet
• Severity life-threatening in infants ranges
  from mild to severe in older children and adults
• Risk factors familial - autosomal recessive
• chrom. 9q22
• gene 1-phosphofructaldolase
• M F

Edgren, Altha Roberts. Hereditary Fructose
intolerance. My Online Wellness. 1999. 1 Mar
2008. http//www.myonlinewellness.com/topic
9
Pathogenesis of HFI

• ?Fructose-1-Phosphate? in the liver, small
  intestine, kidneys
• ?Fructose-1-phosphate? inhibits glucose synthesis
  and glycogen breakdown causing severe
  hypoglycemia following ingestion of fructose

Froesch, E. Disorders of fructose metabolism.
Journal of Clinical Pathology. 227-12.
10
a. Gluconeogenesis inhibition in HFI

• Fructose-1-Phosphate competitively inhibits
  Fructose-1,6-Diphosphate aldolase blocks
  synthesis of glucose

Froesch, E. Disorders of fructose metabolism.
Journal of Clinical Pathology. 227-12.
11
Voet D, Voet J and Charlotte Pratt. Fundamentals
of Biochemistry. New York Wiley and Sons Inc,
1999.
12
b. Glycogenolysis inhibition in HFI

• Fructose-1-Phosphate directly inhibits the action
  of phosphorylase blocks conversion of Glycogen
  to Glucose-1-Phosphate

Froesch, E. Disorders of fructose metabolism.
Journal of Clinical Pathology. 227-12.
13
Voet D, Voet J and Charlotte Pratt. Fundamentals
of Biochemistry. New York Wiley and Sons Inc,
1999.
14
Clinical Manifestations of HFI

• Fructose-1-Phosphate accumulates in hepatocytes
  progressive liver disease
• Fructose-1-Phosphate also accumulates in the
  proximal tubules Fanconi Syndrome

Hereditary Fructose Intolerance. The Pediatric
Database. 2007. University of Western Ontario. 1
Mar. 2008. http//pedbase.org/h/hereditary-fructos
e-intolerance/.
15
1. Hepatic Manifestations

• Diaphoresis (excessive perspiration),
  irritability, tremors, seizures hypoglycemia
• Lethargy -gt coma hypoglycemia
• Jaundice, hepatomegaly progressive liver
  disease

Hereditary Fructose Intolerance. The Pediatric
Database. 2007. University of Western Ontario. 1
Mar. 2008. http//pedbase.org/h/hereditary-fructos
e-intolerance/.
16
2. Renal Manifestations (Fanconi Syndrome)

• episodes of vomiting, dehydration, weakness,
  unexplained fever
• anorexia, constipation
• polydipsia and polyuria
• failure to thrive and growth failure
• rickets

Hereditary Fructose Intolerance. The Pediatric
Database. 2007. University of Western Ontario. 1
Mar. 2008. http//pedbase.org/h/hereditary-fructos
e-intolerance/.
17
Froesch, E. Disorders of fructose metabolism.
Journal of Clinical Pathology. 227-12.
18
Applications to Pharmacy

• Treatment of HFI Diet Control
• Eliminate fructose and sucrose from the diet
• Patients respond within 3 to 4 weeks and recover
  fully if fructose-containing foods are avoided
• Early recognition and treatment of the disease is
  important to avoid damage to the liver, kidneys,
  and small intestine

Ananth N, Praveenkumar, G et al.Two Cases of
Hereditary Fructose Intolerance. Indian Journal
of Clinical Biochemistry. 18(2)87-92.(2003)
19
Prognosis and Prevention of HFI

• Prognosis-If the condition is not recognized and
  the diet is not well controlled, death can occur
  in infants or young children
• -With a well-controlled diet, the child can
  develop normally
•   
• Prevention-Carriers of the gene for hereditary
  fructose intolerance can be identified through
  DNA analysis
• -Assisting at-risk individuals with family
  planning and reproductive decisions via genetic
  counselling

Hereditary Fructose Intolerance. The Pediatric
Database. 2007. University of Western Ontario. 1
Mar. 2008. http//pedbase.org/h/hereditary-fructos
e-intolerance/.
20
Summary 1 Fructose Metabolism

• Fructose can be metabolized in liver or muscle
• In muscle hexokinase phosphorylates fructose
  yielding Fructose-6-Phosphate(F6P), which then
  enters glycolysis
• In liver hexokinase in liver is glucokinase has
  a low affinity for fructose. So, fructose
  metabolism in the liver occurs as follows
• Fructose-1-Phosphate is formed and undergoes an
  aldol cleavage to become Glyceraldehyde
• Glyceraldehyde is then converted to
  Glyceraldehyde-3-Phosphate via 2 pathways
  (directly or indirectly)
• Glyceraldehyde-3-Phosphate then enters glycolysis

21
Summary 2 - HFI

• Caused by a deficiency of Fructose-1-Phosphate
  aldolase in the liver
• ?Fructose-1-Phosphate? in the liver, small
  intestine, kidneys
• ?Fructose-1-phosphate? inhibits glucose synthesis
  and glycogen breakdown causing severe
  hypoglycemia following ingestion of fructose

22
References

• Ananth N, Praveenkumar, G et al.Two Cases of
  Hereditary Fructose Intolerance. Indian Journal
  of Clinical Biochemistry. 18(2)87-92.(2003)
• Edgren, Altha Roberts. Hereditary Fructose
  intolerance. My Online Wellness. 1999. 1 Mar
  2008. http//www.myonlinewellness.com/topic
• Froesch, E. Disorders of fructose metabolism.
  Journal of Clinical Pathology. 227-12.
• Hereditary Fructose Intolerance. The Pediatric
  Database. 2007. University of Western Ontario. 1
  Mar. 2008. http//pedbase.org/h/hereditary-fructos
  e-intolerance/.
• Voet D, Voet J and Charlotte Pratt. Fundamentals
  of Biochemistry. New York Wiley and Sons Inc,
  1999.

23
(No Transcript)