Inactivation of glyceraldehyde-3-phosphate dehydrogenase by the dopamine metabolite, 3,4-dihydroxyphenylacetaldehyde

Biochem Biophys Res Commun. 2017 Oct 14;492(2):275-281. doi: 10.1016/j.bbrc.2017.08.067. Epub 2017 Aug 19.

Abstract

Background: The aldehyde metabolite of dopamine, 3,4-dihydroxyphenylacetaldehyde (DOPAL) is an endogenous neurotoxin implicated in Parkinson's Disease. Elucidating protein targets of DOPAL is essential in understanding it's pathology. The enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a target of DOPAL.

Methods: GAPDH activity was measured via reduction of NAD+ cofactor (340 nm). Protein aggregation was assessed with SDS-PAGE methods and specific modification via chemical probes.

Results: Low micromolar levels of DOPAL caused extensive GAPDH aggregation and irreversibly inhibited enzyme activity. The inactivation of GAPDH was dependent on both the catechol and aldehyde moieties of DOPAL. It is suggested that Cys are modified and oxidized by DOPAL.

Conclusions: The mechanism by which DOPAL modifies GAPDH can serve as a mechanistic explanation to the pathological events in Parkinson's Disease.

Keywords: 3,4-Dihydroxyphenylacetaldehyde; Biogenic aldehyde; Glyceraldehyde-3-phosphate dehydrogenase; Parkinson's disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / analogs & derivatives*
  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • Animals
  • Dopamine / metabolism
  • Enzyme Induction
  • Glyceraldehyde-3-Phosphate Dehydrogenases / chemistry
  • Glyceraldehyde-3-Phosphate Dehydrogenases / metabolism*
  • Humans
  • Parkinson Disease / metabolism
  • Protein Aggregates
  • Rabbits
  • Rats

Substances

  • Protein Aggregates
  • 3,4-Dihydroxyphenylacetic Acid
  • 3,4-dihydroxyphenylacetaldehyde
  • Glyceraldehyde-3-Phosphate Dehydrogenases
  • Dopamine