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Category: Microbial Genetics and Molecular Biology; Fungi and Fungal Pathogenesis
Gluconeogenesis, Page 1 of 2
< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555816636/9781555814731_Chap22-1.gif /docserver/preview/fulltext/10.1128/9781555816636/9781555814731_Chap22-2.gifAbstract:
The major pathways of carbon metabolism are glycolytic breakdown of sugars and the tricarboxylic acid (TCA) cycle for energy generation and the synthesis of biosynthetic intermediates. Growth on carbon compounds metabolized via TCA cycle intermediates requires the net formation of sugars from TCA cycle intermediates in the process of gluconeogenesis-a reversal of glycolysis, in which TCA cycle intermediates are converted to sugars. It is likely that mycelia undergoing carbon starvation in the wild are common, and survival depends on the breakdown of cellular components resulting in carbon sources requiring gluconeogenesis. In asexual spores, mRNAs for gluconeogenic, glyoxylate cycle, and β-oxidation enzymes as well as peroxisomes are present, indicating that gluconeogenesis may be significant for spore survival and germination via the use of stored lipids. The shuttling of metabolites between mitochondria, cytosol, and peroxisomes is crucial for gluconeogenesis. The enzymatic generation of the appropriate reducing power in the form of NADH/NADPH in the different compartments is an important factor in the ability to use carbon sources. In Saccharomyces cerevisiae, there are three genes encoding NADP-dependent isocitrate dehydrogenases, each of which is located in just one of the three compartments. This raises the possibility that other genes encoding the reversible enzymes of glycolysis/ gluconeogenesis are subject to dual control.
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Outline of pathways for gluconeogenesis. Numbers in boldface represent key enzymes discussed in the text, as follows: 1, 6-phosphofructo-2-kinase and fructose-2,6-bisphosphatase; 2, fructose-1,6-bisphosphatase; 3, enolase; 4, pyruvate kinase; 5, phosphoenolpyruvate-carboxykinase; 6, malic enzyme; 7, isocitrate lyase; 8, malate synthase; 9, citrate synthase; 10, malate dehydrogenase; 11, isocitrate dehydrogenase; 12, pyruvate dehydrogenase; 13, pyruvate carboxylase. Reversible steps are shown with bidirectional arrows. For a full outline of relevant enzymes see Supplementary Figure S6 in David et al., 2006 .
The logic of transcriptional regulation of gluconeogenic carbon source utilization in S. cerevisiae. The absence of glucose is the key signal. This results in the Snf1 kinase becoming active, leading to the removal of the repressor Mig1 from the nucleus and the activation of the transcriptional activators Cat8, Adr1, Sip4, and Rsd2 (and perhaps YBR239C and YJL103C) by phosphorylation. These activators regulate the transcription of a large number of genes involved in the utilization of carbon sources including both glyoxalate cycle and specific gluconeogenic genes. Each regulated gene is dependent to varying extents on two or more of the activators. The CSRE core element is CCAN5CCG, while the UAS1 consists of two half-sites, TTGGRG. In addition, Adr1, in conjunction with Oaf1 and Pip2, activates genes required for fatty acid utilization ( Hiltunen et al., 2003 ). Based on data from Schuller (2003) ; Young et al. (2003) ; Tachibana et al. (2005 ); and Soontorngun et al. (2007) .
Proposed logic for transcriptional regulation of gluconeogenic carbon source utilization in A. nidulans. In the presence of glucose, the CreA repressor turns off the expression of the specific genes required for the utilization of each carbon source directly and/or by repression of the synthesis of a specific activator. However, this activator also requires an inducer for activity resulting in the genes for the specific pathway being turned on. Pathway-specific activators are given in Table 1 . The specific pathways result in the production of TCA cycle intermediates. The AcuK/AcuM heterodimer is required for expression of the unique genes of gluconeogenesis as well as for at least some of the reversible glycolytic/gluconeogenic genes and is also proposed to increase the levels of at least some TCA cycle enzyme genes in response to the accumulation of TCA cycle intermediates. Black arrows indicate confirmed targets, while open arrows are proposed.
Strong gluconeogenic carbon sources common to filamentous ascomycetes
Carbon source utilization in loss-of-function regulatory gene mutants in A. nidulansa