Rare Diseases Symptoms Automatic Extraction

Structural snapshots illustrate the catalytic cycle of β-galactocerebrosidase, the defective enzyme in Krabbe disease.

[krabbe disease]

Glycosphingolipids are ubiquitous components of mammalian cell membranes, and defects in their catabolism by lysosomal enzymes cause a diverse array of diseases. Deficiencies in the enzyme β-galactocerebrosidase (GALC) cause Krabbe disease, a devastating genetic disorder characterized by widespread demyelination and rapid, fatal neurodegeneration. Here, we present a series of high-resolution crystal structures that illustrate key steps in the catalytic cycle of GALC. We have captured a snapshot of the short-lived enzyme-substrate complex illustrating how wild-type GALC binds a bona fide substrate. We have extensively characterized the enzyme kinetics of GALC with this substrate and shown that the enzyme is active in crystallo by determining the structure of the enzyme-product complex following extended soaking of the crystals with this same substrate. We have also determined the structure of a covalent intermediate that, together with the enzyme-substrate and enzyme-product complexes, reveals conformational changes accompanying the catalytic steps and provides key mechanistic insights, laying the foundation for future design of pharmacological chaperones.

Diseases presenting "neurodegeneration" symptom

  • adrenomyeloneuropathy
  • alexander disease
  • cadasil
  • canavan disease
  • classical phenylketonuria
  • fabry disease
  • gm1 gangliosidosis
  • hereditary cerebral hemorrhage with amyloidosis
  • krabbe disease
  • neonatal adrenoleukodystrophy
  • neuralgic amyotrophy
  • oculocutaneous albinism
  • pyruvate dehydrogenase deficiency
  • triple a syndrome
  • wolf-hirschhorn syndrome
  • x-linked adrenoleukodystrophy
  • zellweger syndrome

This symptom has already been validated