Fatty acid biosynthesis in yeast

Schweizer, Eckhart; Werkmeister, K.; Jain, Mukesh K.

doi:10.1007/bf00240280

Cited by 74 publications

(37 citation statements)

References 34 publications

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“…Thus, the access of malonate to the enzyme depends strictly on Ser 5421 but acetate may enter the enzyme by both the malonyl and acctyl transacylation domains on subunit ␤ (131). These findings are in accordance with the characteristics of AT mutants, which were consistently leaky and exhibited, in contrast to mutants with mutations of other FAS functions, a considerable amount of residual FAS activity (10 to 20%) (140). According to its acylation characteristics, the MPT domain of yeast FAS is actually a malonyl-/palmityl/-acetyl transacylation site and thus resembles, to some extent, the acetyl-/malonyl transacylation domain of animal FAS (111).…”

Section: Specificity and Interaction Of Substrate Binding Sitessupporting

confidence: 83%

Microbial Type I Fatty Acid Synthases (FAS): Major Players in a Network of Cellular FAS Systems

Schweizer

Hofmann

2004

Microbiol Mol Biol Rev

321

286

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The present review focuses on microbial type I fatty acid synthases (FASs), demonstrating their structural and functional diversity. Depending on their origin and biochemical function, multifunctional type I FAS proteins form dimers or hexamers with characteristic organization of their catalytic domains. A single polypeptide may contain one or more sets of the eight FAS component functions. Alternatively, these functions may split up into two different and mutually complementing subunits. Targeted inactivation of the individual yeast FAS acylation sites allowed us to define their roles during the overall catalytic process. In particular, their pronounced negative cooperativity is presumed to coordinate the FAS initiation and chain elongation reactions. Expression of the unlinked genes, FAS1 and FAS2, is in part constitutive and in part subject to repression by the phospholipid precursors inositol and choline. The interplay of the involved regulatory proteins, Rap1, Reb1, Abf1, Ino2/Ino4, Opi1, Sin3 and TFIIB, has been elucidated in considerable detail. Balanced levels of subunits α and β are ensured by an autoregulatory effect of FAS1 on FAS2 expression and by posttranslational degradation of excess FAS subunits. The functional specificity of type I FAS multienzymes usually requires the presence of multiple FAS systems within the same cell. De novo synthesis of long-chain fatty acids, mitochondrial fatty acid synthesis, acylation of certain secondary metabolites and coenzymes, fatty acid elongation, and the vast diversity of mycobacterial lipids each result from specific FAS activities. The microcompartmentalization of FAS activities in type I multienzymes may thus allow for both the controlled and concerted action of multiple FAS systems within the same cell

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Section: Specificity and Interaction Of Substrate Binding Sitessupporting

confidence: 83%

Microbial Type I Fatty Acid Synthases (FAS): Major Players in a Network of Cellular FAS Systems

Schweizer

Hofmann

2004

Microbiol Mol Biol Rev

321

286

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“…The majority of cellular long-chain fatty acids have 16 or 18 carbons and are synthesized by the soluble fatty acid synthase (FAS) complex that is comprised of two multifunctional subunits encoded by the FAS2 (␣-subunit) and FAS1 (␤-subunit) genes (28,52,53,65). While the bulk of the cellular fatty acids are synthesized by FAS, the VLCFAs are synthesized by membrane-associated fatty acid elongating systems.…”

mentioning

confidence: 99%

Tsc13p Is Required for Fatty Acid Elongation and Localizes to a Novel Structure at the Nuclear-Vacuolar Interface in Saccharomyces cerevisiae

Kohlwein

Eder

et al. 2001

Molecular and Cellular Biology

213

245

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The TSC13/YDL015c gene was identified in a screen for suppressors of the calcium sensitivity of csg2⌬ mutants that are defective in sphingolipid synthesis. The fatty acid moiety of sphingolipids in Saccharomyces cerevisiae is a very long chain fatty acid (VLCFA) that is synthesized by a microsomal enzyme system that lengthens the palmitate produced by cytosolic fatty acid synthase by two carbon units in each cycle of elongation. The TSC13 gene encodes a protein required for elongation, possibly the enoyl reductase that catalyzes the last step in each cycle of elongation. The tsc13 mutant accumulates high levels of long-chain bases as well as ceramides that harbor fatty acids with chain lengths shorter than 26 carbons. These phenotypes are exacerbated by the deletion of either the ELO2 or ELO3 gene, both of which have previously been shown to be required for VLCFA synthesis. Compromising the synthesis of malonyl coenzyme A (malonyl-CoA) by inactivating acetyl-CoA carboxylase in a tsc13 mutant is lethal, further supporting a role of Tsc13p in VLCFA synthesis. Tsc13p coimmunoprecipitates with Elo2p and Elo3p, suggesting that the elongating proteins are organized in a complex. Tsc13p localizes to the endoplasmic reticulum and is highly enriched in a novel structure marking nuclear-vacuolar junctions.

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“…Both FAS systems are encoded by nuclear genes. Although mutational loss of cytoplasmic FAS gives rise to a fatty acid-requiring phenotype (5), mutants defective in one of the mitochondrial FAS-encoding genes are fatty acid-prototrophic but fail to grow on non-fermentative media (2)(3)(4). In accordance with these findings, Brody et al (2) and Wada et al (6) working with either yeast or plant systems suggest that a major function of mitochondrial FAS refers to lipoic acid synthesis by providing the octanoylacyl-carrier protein precursor of this cofactor.…”

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confidence: 99%

HFA1 Encoding an Organelle-specific Acetyl-CoA Carboxylase Controls Mitochondrial Fatty Acid Synthesis in Saccharomyces cerevisiae

Hoja

Marthol

Hofmann

et al. 2004

Journal of Biological Chemistry

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The Saccharomyces cerevisiae gene, HFA1, encodes a >250-kDa protein, which is required for mitochondrial function. Hfa1p exhibits 72% overall sequence similarity (54% identity) to ACC1-encoded yeast cytoplasmic acetyl-CoA carboxylase. Nevertheless, HFA1 and ACC1 functions are not overlapping because mutants of the two genes have different phenotypes and do not complement each other. Whereas ACC1 is involved in cytoplasmic fatty acid synthesis, the phenotype of hfa1⌬ disruptants resembles that of mitochondrial fatty-acid synthase mutants. They fail to grow on lactate or glycerol, and the mitochondrial cofactor, lipoic acid, is reduced to <10% of its normal cellular concentration. Other than Acc1p, the N-terminal sequence of Hfa1p comprises a canonical mitochondrial targeting signal together with a matrix protease cleavage site. Accordingly, the HFA1-encoded protein was specifically assigned by Western blotting of appropriate cell fractions to the mitochondrial compartment. Removal of the mitochondrial targeting sequence abolished the competence of HFA1 DNA to complement hfal null mutants. Conversely and in contrast to the intact HFA1 sequence, the signal sequence-free HFA1 gene complemented the mutational loss of cytoplasmic acetyl-CoA carboxylase. Expression of HFA1 under the control of the ACC1 promoter restored cellular ACC activity in ACC1-defective yeast mutants to wild type levels. From this finding, it is concluded that HFA1 encodes a specific mitochondrial acetyl-CoA carboxylase providing malonyl-CoA for intraorganellar fatty acid and, in particular, lipoic acid synthesis.

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Fatty acid biosynthesis in yeast

Cited by 74 publications

References 34 publications

Microbial Type I Fatty Acid Synthases (FAS): Major Players in a Network of Cellular FAS Systems

Microbial Type I Fatty Acid Synthases (FAS): Major Players in a Network of Cellular FAS Systems

Tsc13p Is Required for Fatty Acid Elongation and Localizes to a Novel Structure at the Nuclear-Vacuolar Interface in Saccharomyces cerevisiae

HFA1 Encoding an Organelle-specific Acetyl-CoA Carboxylase Controls Mitochondrial Fatty Acid Synthesis in Saccharomyces cerevisiae

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