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The Journal of Lipid Research, Vol. 40, 70-75, January 1999
Copyright © 1999 by Lipid Research, Inc.

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

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