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Volume 271, Number 37, Issue of September 13, 1996 pp. 22376-22382
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Cloning and Characterization of PDK4 on 7q21.3 Encoding a Fourth Pyruvate Dehydrogenase Kinase Isoenzyme in Human

(Received for publication, April 10, 1996, and in revised form, May 31, 1996)

Joie Rowles , Stephen W. Scherer ^§ , Tina Xi , Martin Majer , David C. Nickle , Johanna M. Rommens ^§ , Kirill M. Popov ^¶ , Robert A. Harris ^¶ , Nancy L. Riebow , James Xia , Lap-Chee Tsui ^§ , Clifton Bogardus and Michal Prochazka

From the  Clinical Diabetes and Nutrition Section, Phoenix Epidemiology and Clinical Research Branch, NIDDK, National Institutes of Health, Phoenix, Arizona 85016, the ^§ Department of Genetics, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada, and the ^¶ Department of Biochemistry and Molecular Biology, Indiana University, School of Medicine, Indianapolis, Indiana 46202

Different isoenzymes of pyruvate dehydrogenase kinase (PDK) inhibit the mitochondrial pyruvate dehydrogenase complex by phosphorylation of the E1 subunit, thus contributing to the regulation of glucose metabolism. By positional cloning in the 7q21.3-q22.1 region linked with insulin resistance and non-insulin-dependent diabetes mellitus in the Pima Indians, we identified a gene encoding an additional human PDK isoform, as evidenced by its amino acid sequence identity (>65%) with other mammalian PDKs, and confirmed by biochemical analyses of the recombinant protein.

We performed detailed comparative analyses of the gene, termed PDK4, in insulin-resistant and insulin-sensitive Pima Indians, and detected five DNA variants with comparable frequencies in both subject groups. Using quantitative reverse transcription polymerase chain reaction, we found that the variants identified in the promoter and 5-untranslated region did not correlate with differences in mRNA level in skeletal muscle and adipose tissue. We conclude that alterations in PDK4 are unlikely to be the molecular basis underlying the observed linkage at 7q21.3-q22.1 in the Pima Indians. Information about the genomic organization and promoter sequences of PDK4 will be useful in studies of other members of this family of mitochondrial protein kinases that are important for the regulation of glucose metabolism.

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