Original Article

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

Correspondence to: Grant A. Mitchell

3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL, E.C. 4.1.3.4) has a unique dual localization in both mitochondria and peroxisomes. Mitochondrial HL (~31.0 kDa) catalyzes the last step of ketogenesis; the function of peroxisomal HL (~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 ~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 (t_1/2, 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 ~2.6-fold lower than that of the ornithine transcarbamylase precursor.—Ashmarina, L. I., A. V. Pshezhetsky, S. S. Branda, G. Isaya, and G. A. Mitchell. 3-Hydroxy-3-methylglutaryl coenzyme A. J. Lipid Res. 1999. 40: 70–75.

Supplementary key words: ketoacid lyases, hydroxymethylglutaryl CoA, ketone bodies, amino acid metabolism, inborn errors, mitochondria, peroxisomes

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. M. Rodriguez, P. Ruiz-Sala, M. Ugarte, and M. A. Penalva Fungal Metabolic Model for Type I 3-Methylglutaconic Aciduria J. Biol. Chem., July 30, 2004; 279(31): 32385 - 32392. [Abstract] [Full Text] [PDF]

				L. M. Olivier, W. Kovacs, K. Masuda, G.-A. Keller, and S. K. Krisans Identification of peroxisomal targeting signals in cholesterol biosynthetic enzymes: AA-CoA thiolase, HMG-CoA synthase, MPPD, and FPP synthase J. Lipid Res., December 1, 2000; 41(12): 1921 - 1935. [Abstract] [Full Text]

				L. Amery, M. Fransen, K. De Nys, G. P. Mannaerts, and P. P. Van Veldhoven Mitochondrial and peroxisomal targeting of 2-methylacyl-CoA racemase in humans J. Lipid Res., November 1, 2000; 41(11): 1752 - 1759. [Abstract] [Full Text]