Poster

Isovaleryl CoA Dehydrogenase: Dehydrogenate This!
Cedarburg SMART Team: Nicholas Grabon, Elizabeth Bougie, Mathew Cira, Colin Erovick, Anne Fahey, Kelsey Jeletz,
Eleanore Kukla, Matthew Murphy, Tim Rohman, Alyssa Sass, Michelle Sella, Laura Tiffany, Samuel Wolff
Teacher: Karen Tiffany
Cedarburg High School, W68N611 Evergreen Blvd, Cedarburg WI, 53012
Mentor: Jung-Ja P. Kim, Ph.D.
Abstract
Although rare, isovaleric acidemia (IVA) is a
potentially fatal metabolic disorder that affects one in
every 250,000 people in the US. IVA results from
lack of an enzyme, isovaleryl-CoA dehydrogenase
(IVD), involved in the breakdown of leucine. Without
this enzyme, leucine catabolism stops and organic
acids accumulate within the body, causing symptoms
of IVA, including vomiting, diarrhea, and fatigue. IVD
belongs to a family of related enzymes called acylCoA dehydrogenases. IVD catalyzes the
dehydrogenation, or removal of a pair of hydrogen
atoms, of a small, branched-chain substrate,
isovaleryl-CoA, during the third step of leucine
catabolism. Glutamate 254 of IVD removes one
hydrogen as a proton from the substrate, and flavin
adenine dinucleotide, FAD, a cofactor of the enzyme,
takes away the other hydrogen from the substrate.
The three-dimensional structure of IVD, as
determined through X-ray diffraction, illustrates how a
small-branched chain substrate is able to fit into the
active site of this enzyme and enables further
investigation of how mutation of the IVD gene could
affect IVD function, thus resulting in IVA. To further
understand the structural impact on substrate
specificity, a physical model of IVD has been
designed and built by the Cedarburg High School
SMART (Students Modeling a Research Topic) Team
using 3D printing technology. Supported by a grant
from NIH-NCRR-SEPA.
Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee WI, 53226
Role of the Enzyme
Cells need anabolic processes to make necessary chemical components as well as catabolic pathways to break them down. For example,
proteins made by linking any of twenty different amino acids together are broken down by breaking peptide bonds connecting the amino acids.
Leucine, an amino acid, is further broken down in a series of reactions, one of which is catalyzed by isovaleryl-CoA dehydrogenase (IVD). If IVD is
lacking or doesn’t work effectively, the breakdown of leucine cannot proceed and organic acids build up in the body, resulting in the disease
isovaleric acidemia (IVA).
Leucine Catabolic Pathway
Substrate Specificity
•Only a short, branched chain fits into the active site of IVD.
Leucine
•The substrate for IVD, isovaleryl-CoA, is short and branched.
α-ketoisocaproate
isovaleryl-CoA
Isovaleryl-CoA
IVD
3-methylcrotonyl-CoA
•Other acyl-CoA dehydrogenase substrates, such as Palmitoyl-CoA are nonbranched and/or longer than isovaleryl-CoA, and thus cannot fit into the
active site of IVD.
3-methylglutaconyl-CoA
3-hydroxy-3-methylglutaryl-CoA
acetyl-CoA
Palmitoyl-CoA
acetoacetate
Helix G
Substrate
FAD
Cell mitochondrion
Catalytic Mechanism
FAD
FAD
Helix E
Glu254
substrate
IVD monomer
Glutamate 254
Glutamate 254
substrate
1IVH.pdb
Isovaleryl-CoA dehydrogenase
Results of IVD Deficiency
• Isovaleryl-CoA and organic acids accumulate in the bloodstream, resulting in the
disease isovaleric acidemia (IVA).
• Symptoms of IVA include a “sweaty foot” odor, poor eating, vomiting, and coma.
Death can occur.
• If diagnosed at birth and protein levels are monitored, symptoms can be prevented.
The IVD monomers are colored
separately. FAD is shaded yellow and
CoA persulfide (a substrate analog) is
colored cyan. In the green monomer, the
side chain of the catalytic glutamate is
shown in red.
Active Site
•Different conformations in Helices E and G
make the bonding pocket in IVD shallower than
in other acyl-CoA dehydrongeases.
•A glycine at position 374 does not have steric
repulsion with the methyl group of isovalerylCoA, allowing for a branched pocket in the IVD
active site.
•In straight chain dehydrogenases, a tyrosine is
present at this location which repels the methyl
group of the IVD substrate.
A SMART Team project supported by the National Institutes of Health (NIH) – National Center for Research Resources Science Education Partnership Award (NCRR-SEPA)