Question

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Question

• Galactosemia has three variant types, each
  involving its own enzyme. What are the enzymes
  involved in each specific variant, and what is it
  responsible for in the Leloir pathway?

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Galactosemia

• By Brandon Sebring

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What is Galactosemia?

• Autosomal Recessive Disorder
• Inability to properly metabolize Galactose

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• http//en.wikipedia.org/wiki/Galactose
• http//en.wikipedia.org/wiki/Glucose

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Symptoms

• Cataracts
• Mental Retardation
• Diarrhea
• Jaundice
• Stunted Growth
• Death

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Leloir Pathway
Voet and Voet
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Types of Galactosemia

• Three types of Galactosemia
• Type II Galactosemia
• Classical (Type I) Galactosemia
• Type III Galactosemia
• Peripheral
• Generalized

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Type II Galactosemia

• Involves Galactokinase
• Conversion of Galactose to Galactose-1-phosphate
• Extra Galactose Transported to eye cells
• High amounts of Aldose Reductase
• Causes Cataracts
• Cataracts form from Galacticol Build up

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Leloir Pathway
Voet and Voet
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How Galactokinase works

• ATP enters the active site and is bound to the
  guanidinium group of Arg-36
• Galactose enters and is bound by its C-1 hydroxyl
  group to the Asp-183 residue and the guanidinium
  group of the Arg-36 residue
• Galactokinase transfers the phosphate from ATP to
  the C-1 hydroxyl group by removing the hydrogen,
  lowering the pKa of the hydroxyl group
• ADP and Gal-1-P are released

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Galactokinase Mutation

• Normal galactokinases active site contains a
  highly reserved histidine residue(His44) which
  forms part of the binding site for the galactose
  substrate
• In the mutation, His44 is replaced by a tyrosine
  and is known as the H44Y mutation
• The bulkier side chain of tyr causes steric
  hinderance
• Improper folding of the protein
• Decreases interaction with Galactose

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Classical Galactosemia

• Utilizes Galactose-1-phosphateuridylyl
  transferase (GALT)
• Converts Galactose-1-phosphate to UDP-Galactose
• Converts UDP-Glucose to Glucose-1-phosphate
• Acts as a dimer, completing two half reactions
  simultaneously

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Leloir Pathway
Voet and Voet
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How GALT Works

• Gal-1-P enters active site and attacks the
  uridylylated nitrogen of the his in active site
• Dissociates with the uridylyl group
• UDP Glucose enters the UMP-GALT site and is
  attacked by the his N residue from first half rxn
• G-1-P formed

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Classic Galactosemia Symptoms

• Build up of Galactose-1-phosphate
• Jaundice, diarrhea, vomitting, mental
  retardation, ovarian failure
• Most common leads to death by age 2

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Type III Galactosemia

• Involves UDP-galactose-4-epimerase (GALE)
• Converts UDP-Galactose to UDP-Glucose
• Two Types Peripheral and Generalized
• Peripheral only affects the circulating red blood
  cells, clinically benign
• Generalized appears in all tissue cells and can
  cause development issues

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Leloir Pathway
Voet and Voet
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How GALE Works

• The 4-hydroxyl hydrogen is extracted by an
  enzymatic base and hydride is transferred from
  C-4 of the sugar to the si-face of the
  nicotinamide ring of NAD.
• The resulting 4-keptopyranose intermediate in
  the active site is rotated to present the
  opposite face of the sugar to the reduced
  dinucleotide.
• In the last step, the hydride from the
  nicotinamide ring of NADH is transferred back to
  the C-4 of the sugar and the C-4 oxygen is
  reprotonated

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http//www.uic.edu/classes/bios/bios100/lectf03am/
NADH.jpghttp//www.uic.edu/classes/phar/phar332/C
linical_Cases/carbo20metab20cases/udp-glu.gif
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Type III Symptoms

• Peripheral Slight decrease in the hGALE activity
  in the RBCs and WBCs
• Generalized Displays non-lethal symptoms of
  Classic Galactosemia (diarrhea, vomitting, growth
  issues, and premature ovarian failure)

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Treatments

• Type I Screening done at early ages, diet
  consisting of no galactose or lactosestill may
  not live past 10 years of age
• Type II Diet consisting of no galactose or
  lactose
• Type III Diet consisting of no galactose or
  glucose

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The End