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Volume 271, Number 29, Issue of July 19, 1996 pp. 17330-17334
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Molecular Cloning of Human Phosphomevalonate Kinase and Identification of a Consensus Peroxisomal Targeting Sequence

(Received for publication, March 15, 1996, and in revised form, May 29, 1996)

Ken L. Chambliss , Clive A. Slaughter ^§ , Rupert Schreiner ^¶ , Georg F. Hoffmann ^¶ and K. Michael Gibson

From the  Institute of Metabolic Disease, Baylor Research Institute and Baylor University Medical Center, Dallas, Texas 75226, the ^§ Department of Biochemistry, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75235, the ^¶ Department of Metabolic Diseases and Neuropediatrics, University of Marburg, D-35033 Germany, and the  Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas 75235

Two overlapping cDNAs which encode human liver phosphomevalonate kinase (PMKase) were isolated. The human PMKase cDNAs predict a 191-amino acid protein with a molecular weight of 21,862, consistent with previous reports for mammalian PMKase (M_r = 21,000-22,500). Further verification of the clones was obtained by expression of PMKase activity in bacteria using a composite 1024-base pair cDNA clone. Northern blot analysis of several human tissues revealed a doublet of transcripts at approximately 1 kilobase (kb) in heart, liver, skeletal muscle, kidney, and pancreas and lower but detectable transcript levels in brain, placenta, and lung. Analysis of transcripts from human lymphoblasts subcultured in lipid-depleted sera (LDS) and LDS supplemented with lovastatin indicated that PMKase gene expression is subject to regulation by sterol at the level of transcription. Southern blotting indicated that PMKase is a single copy gene covering less than 15 kb in the human genome. The human PMKase amino acid sequence contains a consensus peroxisomal targeting sequence (PTS-1), Ser-Arg-Leu, at the C terminus of the protein. This is the first report of a cholesterol biosynthetic protein which contains a consensus PTS-1, providing further evidence for the concept that early cholesterol and nonsterol isoprenoid biosynthesis may occur in the peroxisome.

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