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Originally published In Press as doi:10.1074/jbc.M100274200 on January 18, 2001

J. Biol. Chem., Vol. 276, Issue 16, 12702-12711, April 20, 2001
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The Effect of the erg26-1 Mutation on the Regulation of Lipid Metabolism in Saccharomyces cerevisiae*

Karen BaudryDagger , Evelyn SwainDagger , Alain Rahier§, Melody GermannDagger , Ashok Batta, Sabine Rondet§, Suzanne Mandala||, Karl Henry**, G. Stephen Tint, Thomas Edlind**, Myra Kurtz||, and Joseph T. Nickels Jr.Dagger Dagger Dagger

From the Departments of Dagger  Biochemistry and ** Microbiology and Immunology, MCP Hahnemann University, Philadelphia, Pennsylvania 19129, the § Departement d'Enzymologie Cellulaire et Moleculaire, Institut de Botanique, Strasbourg Cedex, France, the  Department of Veteran Affairs, New Jersey Medical School, East Orange, New Jersey 07018, and the || Department of Biochemistry, Merck Research Laboratories, Rahway, New Jersey 07065

A temperature-sensitive Saccharomyces cerevisiae mutant harboring a lesion in the ERG26 gene has been isolated. ERG26 encodes 4alpha -carboxysterol-C3 dehydrogenase, one of three enzymatic activities required for the conversion of 4,4-dimethylzymosterol to zymosterol. Gas chromatography/mass spectrometry analyses of sterols in this mutant, designated erg26-1, revealed the aberrant accumulation of a 4-methyl-4-carboxy zymosterol intermediate, as well as a novel 4-carboxysterol. Neutral lipid radiolabeling studies showed that erg26-1 cells also harbored defects in the rate of biosynthesis and steady-state levels of mono-, di-, and triglycerides. Phospholipid radiolabeling studies showed defects in the rate of biosynthesis of both phosphatidic acid and phosphatidylinositol. Biochemical studies revealed that microsomes isolated from erg26-1 cells contained greatly reduced 4alpha -carboxysterol-C3 dehydrogenase activity when compared with microsomes from wild type cells. Previous studies have shown that loss of function mutations in either of the fatty acid elongase genes SUR4/ELO3 or FEN1/GNS1/ELO2 can "bypass" the essentiality of certain ERG genes (Ladeveze, V., Marcireau, C., Delourme, D., and Karst, F. (1993) Lipids 28, 907-912; Silve, S., Leplatois, P., Josse, A., Dupuy, P. H., Lanau, C., Kaghad, M., Dhers, C., Picard, C., Rahier, A., Taton, M., Le Fur, G., Caput, D., Ferrara, P., and Loison, G. (1996) Mol. Cell. Biol. 16, 2719-2727). Studies presented here have shown that this sphingolipid-dependent "bypass" mechanism did not suppress the essential requirement for zymosterol biosynthesis. However, studies aimed at understanding the underlying physiology behind the temperature-sensitive growth defect of erg26-1 cells showed that the addition of several antifungal compounds to the growth media of erg26-1 cells could suppress the temperature-sensitive growth defect. Fluorescence microscopic analysis showed that GFP-Erg26p and GFP-Erg27p fusion proteins were localized to the endoplasmic reticulum. Two-hybrid analysis indicated that Erg25p, Erg26p, and Erg27p, which are required for the biosynthesis of zymosterol, form a complex within the cell.

* This work was supported by Mid-Atlantic American Heart Association Grants 0051102U and 9805529U (to J. N.) and by the March of Dimes Foundation Basil O'Connor Starter Scholarship Grant FY99-277 (to J. N.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Dagger To whom correspondence should be addressed: 245 N. 15th St., Philadelphia, PA 19102. Tel.: 215-762-1941; Fax: 215-762-4452; E-mail: Joseph.Nickels@drexel.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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