KLHL25 substraattiadaptorin substraatti on ACLY, ATP: citraatti lyaasi, jonk se lähettää silppuriin.

•  http://genesdev.cshlp.org/content/30/17/1956.full.pdf 
  

  • Cullin3–KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipidsynthesis and tumor progressionCen Zhang,1,4Juan Liuet al.

  •  Increased lipid synthesis is a key characteristic of many cancers that is critical for cancer progression. ATP-citratelyase (ACLY), a key enzyme for lipid synthesis, is frequently overexpressed or activated in cancer to promote lipidsynthesis and tumor progression. Cullin3 (CUL3), a core protein for the CUL3–RING ubiquitin ligase complex, has been reported to be a tumor suppressor and frequently down-regulated in lung cancer. Here, we found that CUL3interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells. Through negative regulation of ACLY, CUL3 inhibits lipid synthesis, cell proliferation,and xenograft tumor growth of lung cancer cells. Furthermore, ACLY inhibitor SB-204990 greatly abolishes the promoting effect of CUL3 down-regulation on lipid synthesis, cell proliferation, and tumor growth. Importantly, low CUL3 expression is associated with high ACLY expression and poor prognosis in human lung cancer. In summary,our results identify CUL3–KLHL25 ubiquitin ligase as a novel negative regulator for ACLY and lipid synthesis anddemonstrate that decreased CUL3 expression is an important mechanism for increased ACLY expression and lipid synthesis in lung cancer. These results also reveal that negative regulation of ACLY and lipid synthesis is a novel and critical mechanism for CUL3 in tumor suppression.[Keywords: CUL3; ACLY; KLHL25; ubiquitination; lipid synthesis; tumor

•  MINKÄLAINEN entsyymi on  ATP-sitraattilyaasi?
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• ACL; ATPCL; CLATP,    ATP- SITRAATTILYAASI- entsyymi

Summary

ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. The enzyme is a tetramer (relative molecular weight approximately 440,000) of apparently identical subunits. It catalyzes the formation of acetyl-CoA and oxaloacetate from citrate and CoA with a concomitant hydrolysis of ATP to ADP and phosphate. The product, acetyl-CoA, serves several important biosynthetic pathways, including lipogenesis and cholesterogenesis. In nervous tissue, ATP citrate-lyase may be involved in the biosynthesis of acetylcholine. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Dec 2014]

Expression

Ubiquitous expression in prostate (RPKM 37.3), kidney (RPKM 29.2) and 25 other tissues See more

Orthologs

mouse all

ACLY, ACL, ATPCL, CLATP (17q21.2) 

Sitruunahappokierron molekyylin sitraatin ATP-lyaasin merkityksestä. 

https://www.ncbi.nlm.nih.gov/gene/47 

ACL; ATPCL; CLATP

Summary

ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. The enzyme is a tetramer (relative molecular weight approximately 440,000) of apparently identical subunits. It catalyzes the formation of acetyl-CoA and oxaloacetate from citrate and CoA with a concomitant hydrolysis of ATP to ADP and phosphate. The product, acetyl-CoA, serves several important biosynthetic pathways, including lipogenesis and cholesterogenesis. In nervous tissue, ATP citrate-lyase may be involved in the biosynthesis of acetylcholine. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Dec 2014]

Expression

Ubiquitous expression in prostate (RPKM 37.3), kidney (RPKM 29.2) and 25 other tissues See more

Orthologs

mouse all

https://www.ncbi.nlm.nih.gov/pubmed/29241530

1. Mendelian Randomization Study of ACLY and Cardiovascular Disease. Ference BA, et al. N Engl J Med, 2019 Mar 14. PMID 30865797
2. A role for ATP Citrate Lyase in cell cycle regulation during myeloid differentiation. Rhee J, et al. Blood Cells Mol Dis, 2019 May. PMID 30853332
3. Polarization of Human Macrophages by Interleukin-4 Does Not Require ATP-Citrate Lyase. Namgaladze D, et al. Front Immunol, 2018. PMID 30568658, Free PMC Article
4. Modulation of matrix metabolism by ATP-citrate lyase in articular chondrocytes. Chen LY, et al. J Biol Chem, 2018 Aug 3. PMID 29929979, Free PMC Article
5. Binding of hydroxycitrate  ( source: Garcinia cambogia )to human ATP-citrate lyase. Hu J, et al. Acta Crystallogr D Struct Biol, 2017 Aug 1. PMID 28777081Hydroxycitrate from the fruit of Garcinia cambogia [i.e. (2S,3S)-2-hydroxycitrate] is the best-known inhibitor of ATP-citrate lyase. Well diffracting crystals showing how the inhibitor binds to human ATP-citrate lyase were grown by modifying the protein. The protein was modified by introducing cleavage sites for Tobacco etch virus protease on either side of a disordered linker. The protein crystallized consisted of residues 2-425-ENLYFQ and S-488-810 of human ATP-citrate lyase. (2S,3S)-2-Hydroxycitrate binds in the same orientation as citrate, but the citrate-binding domain (residues 248-421) adopts a different orientation with respect to the rest of the protein (residues 4-247, 490-746 and 748-809) from that previously seen. For the first time, electron density was evident for the loop that contains His760, which is phosphorylated as part of the catalytic mechanism. The pro-S carboxylate of (2S,3S)-2-hydroxycitrate is available to accept a phosphoryl group from His760. However, when co-crystals were grown with ATP and magnesium ions as well as either the inhibitor or citrate, Mg²⁺-ADP was bound and His760 was phosphorylated. The phosphoryl group was not transferred to the organic acid. This led to the interpretation that the active site is trapped in an open conformation. The strategy of designing cleavage sites to remove disordered residues could be useful in determining the crystal structures of other proteins.

See all (130) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into Functions

What's a GeneRIF?

1. Study in human monocyte-derived macrophages suggests that ACLY may not be the major regulator of nucleocytoplasmic acetyl-CoA and IL-4-induced polarization in human macrophages.
2. regulation of ACL activity is a potentially important point of control for cell cycle regulation in the myeloid lineage.
3. Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level.
4. Increased ACLY activity in osteoarthritis chondrocytes increased nucleocytosolic acetyl-CoA, leading to increased matrix catabolism via dysregulated histone and transcription factor acetylation.
5. SLC25A1 and ACLY upregulation suggests that metabolic reprogramming in Behcet's syndrome involves the citrate pathway dysregulation.
6. ACL regulates the net amount of acetyl groups available, leading to alterations in acetylation of H3(K9/14) and H3(K27) at the MYOD locus, thus increasing MYOD expression.
7. Results show that ACLY was up-regulated in human gastric cancer (GC) tissues and cell lines and a critical downstream target of the tumor suppressor activity of miR-133b in GC.
8. ACLY and ACSS2 are both activated to produce cytosolic Ac-CoA from glucose carbon for lipogenesis during human cytomegalovirus infection.
9. ACLY facilitates histone acetylation at double-strand break (DSB) sites, impairing 53BP1 localization and enabling BRCA1 recruitment and DNA repair by homologous recombination. ACLY phosphorylation and nuclear localization are necessary for its role in promoting BRCA1 recruitment.
10. The protein crystallized consisted of residues 2-425-ENLYFQ and S-488-810 of human ATP-citrate lyase. (2S,3S)-2-Hydroxycitrate binds in the same orientation as citrate, but the citrate-binding domain (residues 248-421) adopts a different orientation with respect to the rest of the protein (residues 4-247, 490-746 and 748-809) from that previously seen.