3-Hydroxy-3-methylglutaryl coenzyme A lyase: targeting and processing in peroxisomes and mitochondria

J Lipid Res. 1999 Jan;40(1):70-5.


3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL, E.C. has a unique dual localization in both mitochondria and peroxisomes. Mitochondrial HL ( approximately 31.0 kDa) catalyzes the last step of ketogenesis; the function of peroxisomal HL ( approximately 33.5 kDa) is unknown. On density gradient fractionation, normal human lymphoblasts contain both peroxisomal and mitochondrial HL whereas in lymphoblasts from a patient with Zellweger syndrome, in which functional peroxisomes are absent, only the mitochondrial HL isoform was present. To study the kinetics of the dual targeting of HL, we performed pulse-chase experiments in normal and Zellweger cells. Pulse-chase studies revealed a biphasic curve for processing of the HL precursor. The first phase, with a calculated half-life of approximately 3 h in both normal and Zellweger fibroblasts and lymphoblasts and in HepG2 cells, presumably reflects mitochondrial import and processing of the precursor; the second (t1/2, 12-19 h) is present only in normal cells and presumably represents the half-life of peroxisomal HL. The half-life of mature mitochondrial HL was 14 to 19 h in both normal and Zellweger cells. Studies of the HMG-CoA lyase precursor in isolated rat mitochondria showed a rate of processing approximately 2.6-fold lower than that of the ornithine transcarbamylase precursor.

MeSH terms

  • Animals
  • Catalase / metabolism
  • Cell Line
  • Enzyme Precursors / genetics
  • Enzyme Precursors / metabolism
  • Fibroblasts / enzymology
  • Glutamate Dehydrogenase / metabolism
  • Half-Life
  • Humans
  • In Vitro Techniques
  • Kinetics
  • Lymphocytes / enzymology
  • Microbodies / metabolism*
  • Mitochondria / metabolism*
  • Oxo-Acid-Lyases / genetics
  • Oxo-Acid-Lyases / metabolism*
  • Protein Processing, Post-Translational
  • Rats
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Zellweger Syndrome / enzymology


  • Enzyme Precursors
  • Recombinant Proteins
  • Catalase
  • Glutamate Dehydrogenase
  • Oxo-Acid-Lyases
  • 3-hydroxy-3-methylglutaryl-coenzyme A lyase