Homocitrate synthase from yeast

Tucci, Anthony F.; Ceci, Louis N.

doi:10.1016/0003-9861(72)90393-1

Cited by 45 publications

(41 citation statements)

References 16 publications

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“…6, 1986 on May 7, 2018 by guest http://mcb.asm.org/ synthase have very similar activities, the condensation of acetyl coenzyme with a-ketoisovalerate (isopropylmalate synthase) or with oxaloacetate (citrate synthase). Yeast cells also contain two forms of homocitrate synthase, the enzyme which catalyzes the committed step of lysine biosynthesis (27).…”

Section: Discussionmentioning

confidence: 99%

Extramitochondrial citrate synthase activity in bakers' yeast.

Rickey¹,

Lewin²

1986

Mol. Cell. Biol.

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We isolated the gene for citrate synthase (citrate oxaloacetate lyase; EC 4.1.3.7) from Saccharomyces cerevisiae and ablated it by inserting the yeast LEU2 gene within its reading frame. This revealed a second, nonmitochondrial citrate synthase. Like the mitochondrial enzyme, this enzyme was sensitive to glucose repression. It did not react with antibodies against mitochondrial citrate synthase. Haploid cells lacking a gene for mitochondrial citrate synthase grew somewhat slower than wild-type yeast cells, but exhibited no auxotrophic growth requirements.

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Section: Discussionmentioning

confidence: 99%

Extramitochondrial citrate synthase activity in bakers' yeast.

Rickey¹,

Lewin²

1986

Mol. Cell. Biol.

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“…An intermediate of the pathway, ␣-aminoadipate semialdehyde, acts as coinducer for this activation mechanism (Ramos et al, 1988). In addition, feedback inhibition by lysine of the first step of the pathway, catalysed by two homocitrate synthase isoenzymes (Tucci and Ceci, 1972;Ramos et al, 1996; G. Volckaert, personal communication; F. Ramos and E. Dubois, unpublished observation), modulates the metabolic flux through the pathway and, consequently, the production of ␣-aminoadipate semialdehyde. An extremely weak inhibition of ␣-aminoadipate reductase has also been reported (Ford and Bhattacharjee, 1995).…”

Section: Introductionmentioning

confidence: 99%

A nonameric core sequence is required upstream of the LYS genes of Saccharomyces cerevisiae for Lys14p‐mediated activation and apparent repression by lysine

Becker

Feller

Alami

et al. 1998

Molecular Microbiology

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SummaryThe expression of the structural genes for lysine (LYS) biosynthesis is controlled by a pathway-specific regulation mediated by the transcriptional activator Lys14 in the presence of ␣-aminoadipate semialdehyde, an intermediate of the pathway acting as a coinducer. Owing to end product inhibition of the first step of the pathway, excess lysine reduces the production of the co-inducer and causes apparent repression of the LYS genes. Analysis of LYS promoters and insertions within an heterologous reporter gene have allowed the characterization of an upstream activating element (UAS LYS ) able to confer Lys14-and ␣-aminoadipate semialdehyde-dependent activation as well as apparent repression by lysine to another yeast gene. This DNA motif is present as one or several copies in the promoters of at least six LYS genes. The consensus sequence derived from the comparison of the UAS LYS showing the highest activation capacities comprises the nonameric core sequence TCCRNYGGA. The RNY sequence of the 3 bp spacer as well as the presence of flanking AT-rich regions on both sides of the core sequence appear essential for optimal activation. Further evidence that this element is the target of Lys14p was provided by the demonstration that Lys14p binds to UAS LYS in vitro. The binding is independent of the presence of the co-inducer and is not affected by lysine. It depends on the integrity of the putative Zn(II) 2 Cys 6 binuclear cluster contained in the Lys14p.

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“…In plants and most bacteria, lysine is synthesized via the diaminopimelate pathway (1). Yeast and other fungi, including the human pathogens Cryptococcus neoformans, Candida albicans, and Aspergillus fumigatus, and certain archaebacteria, including Thermus thermophilus, utilize the ␣-aminoadipate (AAA) 5 pathway to synthesize lysine (2)(3)(4). Because mammals are lysine auxotrophs, the enzymes composing the fungal AAA pathway represent excellent targets for small molecule inhibitors that may hold potential clinical value as broad-spectrum anti-fungal therapeutics, particularly for immunocompromised individuals, such as AIDS and cancer patients and transplant recipients, who are at a higher risk of developing invasive fungal infections (5).…”

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confidence: 99%

Crystal Structure and Functional Analysis of Homocitrate Synthase, an Essential Enzyme in Lysine Biosynthesis

Bulfer¹,

Scott²,

Couture³

et al. 2009

Journal of Biological Chemistry

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Homocitrate synthase (HCS) catalyzes the first and committed step in lysine biosynthesis in many fungi and certain Archaea and is a potential target for antifungal drugs. Here we report the crystal structure of the HCS apoenzyme from Schizosaccharomyces pombe and two distinct structures of the enzyme in complex with the substrate 2-oxoglutarate (2-OG). The structures reveal that HCS forms an intertwined homodimer stabilized by domain-swapping between the N-and C-terminal domains of each monomer. The N-terminal catalytic domain is composed of a TIM barrel fold in which 2-OG binds via hydrogen bonds and coordination to the active site divalent metal ion, whereas the C-terminal domain is composed of mixed ␣/␤ topology. In the structures of the HCS apoenzyme and one of the 2-OG binary complexes, a lid motif from the C-terminal domain occludes the entrance to the active site of the neighboring monomer, whereas in the second 2-OG complex the lid is disordered, suggesting that it regulates substrate access to the active site through its apparent flexibility. Mutations of the active site residues involved in 2-OG binding or implicated in acid-base catalysis impair or abolish activity in vitro and in vivo. Together, these results yield new insights into the structure and catalytic mechanism of HCSs and furnish a platform for developing HCSselective inhibitors.

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Homocitrate synthase from yeast

Cited by 45 publications

References 16 publications

Extramitochondrial citrate synthase activity in bakers' yeast.

Extramitochondrial citrate synthase activity in bakers' yeast.

A nonameric core sequence is required upstream of the LYS genes of Saccharomyces cerevisiae for Lys14p‐mediated activation and apparent repression by lysine

Crystal Structure and Functional Analysis of Homocitrate Synthase, an Essential Enzyme in Lysine Biosynthesis

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