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J. Biol. Chem., Vol. 281, Issue 18, 12308-12314, May 5, 2006

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Hap4 Is Not Essential for Activation of Respiration at Low Specific Growth Rates in Saccharomyces cerevisiae^*

From the Center for Microbial Biotechnology, Building 223, BioCentrum-DTU, Technical University of Denmark, DK 2800, Kongens Lyngby, Denmark

In Saccharomyces cerevisiae, the heme-activated protein complex Hap2/3/4/5 plays a major role in the transcription of genes involved in respiration. Thus, overexpression of HAP4 has been shown to result in a 10% increase in the respiratory capacity. Here the physiology of a HAP4-deleted S. cerevisiae strain was investigated, and we found that the hap4 S. cerevisiae exhibited poor growth on ethanol, although the growth rate on glucose was indifferent from the wild type in aerobic as well as anaerobic cultures. Moreover, it exhibited a large (75%) reduction in the critical glucose uptake rate at which fermentative metabolism is onset, indicating a substantial reduction in respiratory capacity. We also performed whole genome transcription analysis for the hap4 and the wild type, grown in carbon-limited chemostat cultures operated at a dilution rate of 0.05 h^–1. Although both strains exhibited respiratory metabolism, there was significant change in expression of many genes in the hap4 strain. These genes are involved in several different parts of the metabolism, including oxidative stress response, peroxisomal functions, and energy generation. This study strongly indicates that Hap4 activation only occurs at intermediate specific growth rates, below which the transcription of genes responsible for respiration is dependent on the Hap2/3/5 complex and above which the Hap4 protein augments the transcription. Furthermore, statistical analysis of the transcription data and integration of the data with a genome scale metabolic network provided new insight and evidence for the role of Hap4 in transcriptional regulation of mitochondrial respiration.

Received for publication, December 5, 2005 , and in revised form, February 9, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2 and Figs. S1–S4.

¹ To whom correspondence should be addressed: Bldg. 223, BioCentrum-DTU, Technical University of Denmark, DK-2800, Kgs. Lyngby, Denmark. Tel.: 4545252696; Fax: 4545884148; E-mail: jn{at}biocentrum.dtu.dk.

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