8gr9
Crystal structure of peroxisomal citrate synthase (Cit2) from Saccharomyces cerevisiae in complex with oxaloacetate and coenzyme-A
Structural highlights
FunctionCISY2_YEAST Peroxisomal citrate synthase involved in the citrate homeostasis (PubMed:25982115, PubMed:3023912). Catalyzes the condensation of acetyl coenzyme A and oxaloacetate to form citrate (PubMed:25982115, PubMed:3023912). Citrate synthase is the rate-limiting enzyme of the tricarboxylic acid (TCA) cycle (Probable).[1] [2] [3] Publication Abstract from PubMedDeficiencies in mitochondrial protein import are associated with a number of diseases. However, although nonimported mitochondrial proteins are at great risk of aggregation, it remains largely unclear how their accumulation causes cell dysfunction. Here, we show that nonimported citrate synthase is targeted for proteasomal degradation by the ubiquitin ligase SCF(Ucc1). Unexpectedly, our structural and genetic analyses revealed that nonimported citrate synthase appears to form an enzymatically active conformation in the cytosol. Its excess accumulation caused ectopic citrate synthesis, which, in turn, led to an imbalance in carbon flux of sugar, a reduction of the pool of amino acids and nucleotides, and a growth defect. Under these conditions, translation repression is induced and acts as a protective mechanism that mitigates the growth defect. We propose that the consequence of mitochondrial import failure is not limited to proteotoxic insults, but that the accumulation of a nonimported metabolic enzyme elicits ectopic metabolic stress. Defective import of mitochondrial metabolic enzyme elicits ectopic metabolic stress.,Nishio K, Kawarasaki T, Sugiura Y, Matsumoto S, Konoshima A, Takano Y, Hayashi M, Okumura F, Kamura T, Mizushima T, Nakatsukasa K Sci Adv. 2023 Apr 14;9(15):eadf1956. doi: 10.1126/sciadv.adf1956. Epub 2023 Apr , 14. PMID:37058555[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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