Glutaric Aciduria

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Glutaric Aciduria

• By Gaylemarie Kolb

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Metabolic Disorder

• Autosomal recessive disorder
• Problem with the conversion of food to energy
• Deficiency of Glutaryl-CoA Dehydrogenase

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Glutaryl-CoA


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Rare

• Three different types of Glutaric aciduria
• Uncommon metabolic disorder
• Most of the research was found on type 1

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Also Known As

• Many different names
• Glutaric Acidemia
• Glutaric Aciduria
• Glutaryl-CoA dehydrogenase deficiency
• GA1

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Symptoms

• Hypoglycemia
• Vomiting
• Smelly feet odor

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Breakdown

• Inability to properly breakdown amino acids
  lysine and tryptophan
• Lysine one of the most abundant amino acids
• Tryptophan one of the least abundant amino acids

Lys Trp
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Intermediate Build Up

• Incomplete breakdown of amino acids causes
  different intermediates to build-up
• The build up can cause damage to basal ganglia in
  brain
• Deals with movement
• May see spasms, jerking and decreased muscle tone

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Glutaryl-CoA Dehydrogenase

• Member of the Acyl-CoA dehydrogenase family
• Flavoprotein family
• Involved in amino acid oxidation
• Inadequate amounts of enzyme results in
  intermediate build-up

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GCD

• Four subunit molecule
• Each subunit contains one molecule of FAD
• Three domains in the polypeptide fold of GCD
  monomer
• Alpha-helix bundle at N-term
• Beta-Sheet domain in middle
• Alpha-helix bundle at the C-term

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GCD Crystal Structure
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One Subunit of GCD
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Residues Assoc With Active Site

• 133F
• 134G
• 135L
• 136T
• 167T
• 168W
• 169I
• 170T
• 209K
• 217T

• 365A
• 368T
• 369Y
• 370E
• 371G
• 372T
• 374D
• 375I
• 378L
• 390F

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Mutations

• 100 pathogenic mutations identified
• In GA1 patients, mutations are found at C-term of
  enzyme
• 5 specific mutations that can be found as
  ala389val, ala389glu, thr385met, ala377val, and
  ala377thr
• Mutation causes ligand to not bind and pathway
  wont proceed
• Intermediates build up this way

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Mutations

• Compared to other ACDs there is a long extension
  at C-term, causing end residues to stick out
  further
• End residues will have more or different
  interactions with environment or other residues
• Will add to the mutations

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Degradation

• Lys and Trp degradation have different paths
  until a certain point
• Each break down to alpha-aminoadipate through a
  different number of steps
• Lysine degradation through four steps
• Tryptophan degradation through eight steps

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Degradation
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Degradation

Inefficient/ Absent
Intermediate
Crotonyl-CoA will then produce two molecules of
acetyl-CoA and enter TCA Cycle
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Lysine Degradation
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Lysine Degradation
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Tryptophan Degradation

• Eight mechanistic steps
• Eventually goes to alpha-aminoadipate
• Cleavage of a beta-gamma bond occurs rather than
  cleavage of an alpha-beta bond

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Detection

• Difficult to detect until onset of symptoms
• Tandem mass spec. can be used
• Rapid, sensitive and accurate method of detection
• Minimal sample preparation
• Detection in 1 to 2 minutes

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Tandem Mass Spec

• Used to measure and identify butyl esters of
  amino acids in blood and urine
• Two quadrupole mass specs seperated by a reaction
  chamber
• Soft ionization method
• Ions are fragmented
• Data analysis to measure butyl ester in sample

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Glutaric Aciduria

• Rare metabolic disorder
• Problem with lysine and tryptophan degradation
• Newborn screening
• Testing available for newborns to help prevent
  actual onset of symptoms