C16.-ceramidi ja sfingosiini-1-fosfaatti (S1P) rintasyöpäsolun proliferaatiossa

Abstract Recently, sphingolipid derivatives, such as ceramide and sphingosine‑1‑phosphate (S1P), have emerged as key modulators in apoptotic cell death and cell proliferation.
This study aimed to clarify the underlying signaling pathways of ceramide and S1P involved in breast cancer cell proliferation.
 Ceramide acyl chain length is determined by six mammalian ceramide synthases (CerS). We overexpressed CerS1 to 6 in MCF‑7 cells to examine whether ceramide signaling propagation varies as a function of acyl chain length.
 Among the six CerS, only CerS6 overexpression reduced phosphorylation of Akt, S6 kinase (S6K), and extracellular signal‑regulated kinases (ERK) as shown by western blotting.
 In addition, CerS6 overexpression reduced MCF‑7 cell proliferation. This effect was partially reversed by co‑treatment with MHY1485, an activator of mammalian target of rapamycin (mTOR), demonstrating an important role for the mTOR pathway in the CerS6‑mediated decrease in MCF‑7 cell proliferation. ERK inhibition, but not Akt inhibition, along with mTOR inhibition synergistically reduced MCF‑7 cell proliferation as measured by MTT assay.
Notably, the expression of CerS6 and S1P receptor 2 (S1PR2), or CerS6 and sphingosine kinase 1 (SphK1), were negatively correlated according to the invasive breast carcinoma patient cohort in The Cancer Genome Atlas database.
In addition, both SphK1 overexpression and S1P addition increased mTOR phosphorylation as shown by ELISA, while S1PR2 inhibition had the inverse effect. These data suggest that CerS6 and SphK1 regulate mTOR signaling in breast cancer cell proliferation. Moreover, mTOR activity can be regulated by the balance between S1P and C16‑ceramide, which is generated by CerS6.

PMID:

30226616

DOI:

10.3892/or.2018.6689

[Indexed for MEDLINE] 

 

 

Sinkkisormiproteiini ZDHHC5 osallistuu S1P :n reseptorin S1PR syklin säätelyyn

https://www.ncbi.nlm.nih.gov/gene/25921

Official Symbol

ZDHHC5

Official Full Name

zinc finger DHHC-type palmitoyltransferase 5

Also known as

DHHC5; ZNF375

Expression

Ubiquitous expression in esophagus (RPKM 30.1), thyroid (RPKM 23.7) and 25 other tissues See more

Preferred Names

palmitoyltransferase ZDHHC5

Names

DHHC-5

membrane-associated DHHC5 zinc finger protein

probable palmitoyltransferase ZDHHC5

zinc finger DHHC domain-containing protein 5

zinc finger DHHC-type containing 5

zinc finger protein 375

zinc finger, DHHC domain containing 5

Related articles in PubMed

1. DHHC5-mediated palmitoylation of S1P receptor subtype 1 determines G-protein coupling. Badawy SMM, et al. Sci Rep, 2017 Nov 29. PMID 29185452, Free PMC Article Abstract
   Sphingosine 1-phosphate (S1P) is a pleiotropic lipid mediator involved in the regulation of immune cell trafficking and vascular permeability acting mainly through G-protein-coupled S1P receptors (S1PRs). However, mechanism underlying how S1PRs are coupled with G-proteins remains unknown. Here we have uncovered that palmitoylation of a prototypical subtype S1P₁R is prerequisite for subsequent inhibitory G-protein (Gi) coupling. We have identified ZDHHC5 as an enzyme for palmitoylation of S1P₁R. Under basal conditions, S1P₁R was functionally associated with DHHC5 in the plasma membranes (PM) and was fully palmitoylated, enabling Gi coupling. Upon stimulation, the receptor underwent internalisation leaving DHHC5 in PM, resulting in depalmitoylation of S1P₁R. We also revealed that while physiological agonist S1P-induced endocytosed S1P₁R readily recycled back to PM, pharmacological FTY720-P-induced endocytosed S1P₁R-positive vesicles became associated with DHHC5 in the later phase, persistently transmitting Gi signals there. This indicates that FTY720-P switches off the S1P signal in PM, while switching on its signal continuously inside the cells. We propose that DHHC5-mediated palmitoylation of S1P₁R determines Gi coupling and its signalling in a spatio/temporal manner.

   PMID:

   29185452

   PMCID:

   PMC5707436

   DOI:

   10.1038/s41598-017-16457-4

2. Systematic siRNA Screen Unmasks NSCLC Growth Dependence by Palmitoyltransferase DHHC5. Tian H, et al. Mol Cancer Res, 2015 Apr. PMID 25573953, Free PMC Article
3. EZH2 Palmitoylation Mediated by ZDHHC5 in p53-Mutant Glioma Drives Malignant Development and Progression. Chen X, et al. Cancer Res, 2017 Sep 15. PMID 28775165
4. Palmitoylation of NOD1 and NOD2 is required for bacterial sensing. Lu Y, et al. Science, 2019 Oct 25. PMID 31649195
5. LXR Activation Down-regulates Lipid Raft Markers FLOT2 and DHHC5 in MCF-7 Breast Cancer Cells. Carbonnelle D, et al. Anticancer Res, 2017 Aug. PMID 28739689

See all (36) 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. ZDHHC5-mediated S-palmitoylation is indispensable for NOD1/2 recruitment to bacteria containing phagosomes.
2. DHHC4 and DHHC5 function at different subcellular localizations to control the palmitoylation, plasma membrane localization, and fatty acid uptake activity of the scavenger receptor CD36.
3. High ZDHHC5 expression is associated with Glioma.
4. We demonstrated that LXR stimulation decreases mRNA and protein expression of FLOT2 and DHHC5 in MCF-7 cells. LXR stimulation also reduces Akt phosphorylation and its localization at the plasma membrane
5. Data indicate that DHHC5 has oncogenic capacity and contributes to tumor formation in non-small cell lung cancer.
6. ZDHHC5 and SSTR5 are colocalized at the plasma membrane and coexpression of ZDHHC5 increased palmitoylation of SSTR5 whereas knock-down of endogenous ZDHHC5 by siRNAs decreased it.Many G-protein coupled receptors are palmitoylated in their C-terminal, intracellular regions. So far no enzymes responsible for this modification have been described. We identified an interaction of the membrane proximal helix 8 of somatostatin receptor 5 (SSTR5) with the N-terminal region of the putative palmitoyltransferase ZDHHC5 using the Ras recruitment interaction screening system. ZDHHC5 and SSTR5 are colocalized at the plasma membrane and can be efficiently coimmunoprecipitated from transfected cells. Coexpression of ZDHHC5 in HEK293 cells increased palmitoylation of SSTR5 whereas knock-down of endogenous ZDHHC5 by siRNAs decreased it. Our data identify the first palmitoyltransferase for a G-protein coupled receptor.
7. Data show that palmitoyl acyltransferases DHHC5, DHHC6, and DHHC8 appear to be S-acylated on three cysteine residues within a novel CCX(7-13)C(S/T) motif downstream of a conserved Asp-His-His-Cys cysteine-rich domain.

Rintasyöpä , C16- cer ja S1P keskiössä, mahdollisesti uusia terapiakohteita .

https://www.ncbi.nlm.nih.gov/pubmed/30226616

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Oncol Rep. 2018 Nov;40(5):2977-2987. doi: 10.3892/or.2018.6689. Epub 2018 Sep 7.

C16‑ceramide and sphingosine 1‑phosphate/S1PR2 have opposite effects on cell growth through mTOR signaling pathway regulation.

Kim MH¹, Park JW², Lee EJ³, Kim S⁴, Shin SH², Ahn JH², Jung Y⁵, Park I⁶, Park WJ³.

Author information

Abstract

Recently, sphingolipid derivatives, such as ceramide and sphingosine‑1‑phosphate (S1P), have emerged as key modulators in apoptotic cell death and cell proliferation. This study aimed to clarify the underlying signaling pathways of ceramide and S1P involved in breast cancer cell proliferation. Ceramide acyl chain length is determined by six mammalian ceramide synthases (CerS). We overexpressed CerS1 to 6 in MCF‑7 cells to examine whether ceramide signaling propagation varies as a function of acyl chain length. Among the six CerS, only CerS6 overexpression reduced phosphorylation of Akt, S6 kinase (S6K), and extracellular signal‑regulated kinases (ERK) as shown by western blotting. In addition, CerS6 overexpression reduced MCF‑7 cell proliferation. This effect was partially reversed by co‑treatment with MHY1485, an activator of mammalian target of rapamycin (mTOR), demonstrating an important role for the mTOR pathway in the CerS6‑mediated decrease in MCF‑7 cell proliferation. ERK inhibition, but not Akt inhibition, along with mTOR inhibition synergistically reduced MCF‑7 cell proliferation as measured by MTT assay. Notably, the expression of CerS6 and S1P receptor 2 (S1PR2), or CerS6 and sphingosine kinase 1 (SphK1), were negatively correlated according to the invasive breast carcinoma patient cohort in The Cancer Genome Atlas database. In addition, both SphK1 overexpression and S1P addition increased mTOR phosphorylation as shown by ELISA, while S1PR2 inhibition had the inverse effect. These data suggest that CerS6 and SphK1 regulate mTOR signaling in breast cancer cell proliferation. Moreover, mTOR activity can be regulated by the balance between S1P and C16‑ceramide, which is generated by CerS6

Keramidisyntaasit (CERS) ja sfingolipidien keramidien rasvahappopituuksien (N-acyl chain length) määrytyminen

https://www.ncbi.nlm.nih.gov/pubmed/29632068/
 J Biol Chem. 2018 Jun 22;293(25):9912-9921. doi: 10.1074/jbc.RA118.001936. Epub 2018 Apr 9.

Eleven residues determine the acyl chain specificity of ceramide synthases.

Tidhar R¹, Zelnik ID¹ et al. Abstract

Lipids display large structural complexity, with ∼40,000 different lipids identified to date, ∼4000 of which are sphingolipids. A critical factor determining the biological activities of the sphingolipid, ceramide, and of more complex sphingolipids is their N-acyl chain length, which in mammals is determined by a family of six ceramide synthases (CerS). Little information is available about the CerS regions that determine specificity toward different acyl-CoA substrates. We previously demonstrated that substrate specificity resides in a region of ∼150 residues in the Tram-Lag-CLN8 domain. Using site-directed mutagenesis and biochemical analyses, we now narrow specificity down to an 11-residue sequence in a loop located between the last two putative transmembrane domains (TMDs) of the CerS.
The specificity of a chimeric protein, CerS5^{(299-309→CerS2)}, based on the backbone of CerS5 (which generates C16-ceramide), but containing 11 residues from CerS2 (which generates C22-C24-ceramides), was altered such that it generated C22-C24 and other ceramides.
 Moreover, a chimeric protein, CerS4^{(291-301→CerS2)}, based on CerS4 (which normally generates C18-C22 ceramides) displayed significant activity toward C24:1-CoA.
Additional data supported the notion that substitutions of these 11 residues alter the specificities of the CerS toward their cognate acyl-CoAs.

Our findings may suggest that this short loop may restrict adjacent TMDs, leading to a more open conformation in the membrane, and that the CerS acting on shorter acyl-CoAs may have a longer, more flexible loop, permitting TMD flexibility. In summary, we have identified an 11-residue region that determines the acyl-CoA specificity of CerS. © 2018 Tidhar et al.

KEYWORDS: ceramide (Cer) ; ceramide synthase (CERS) ; lipid; membrane; sphingolipid

DOI:

10.1074/jbc.RA118.001936

Free PMC Article

http://www.jbc.org/content/293/25/9912

keramidien rasvahappopituuksien määräytyminen keramidisyntaasilla on kartoitettu 2018 aikoihin. On kuusi keramidisyntaasia. Israelissa ollaan tästä kiinnostuneita. 

Suomennosta artikkelista 3.1. 2019: 

LIPIDEILLA on laaja rakenteellinen kompleksisuutensa . Näihin mennessä on tunnistettu noin 40 000 erilaista lipidiä ja niistä kuuluu sfingolipidien luokkaan noin 4000 .
Kriittisenä tekijänä sfingolipidien, keramidien ja monimutkaisempien sfingolipidien biologisessa aktiivisuudessa on niiden aktivoituneiden  N-rasvahappojen (N-Acyl CoA) pituus;  imettäväisissä se määräytyy keramidisyntaasientsyymien avulla (CERS-perhe) Ihmisellä on kuusi CERS- entsyymiä CERS1- CERS6.
On olemassa vain vähän informaatiota siitä, mitkä CERS- entsyymin kohdat  määrittävät spesifisyyden eri rasvahappo-CoA- substraatteja kohtaan.
Aiemmin tämä tutkijaryhmä on osoittanut, että substraattispesifisyys on Tram- Lag-CLN8 domaanin 150:n aminohapon kohdalla.
 Käyttämällä kohdennettua mutageneesiä ja biokemiallisia analyysejä he nyt kaventavat spesifisyyden 11 aminohapon sekvenssiin eräässä silmukassa, joka sijaitsee kahden transmembraanisen domeenin (TMD) välissä keramidisyntaasissa (CERS) .

C16-keramidikokoa tuottavan CERS5 runkoon perustuva kimeerinen CerS5( 299-309 jakso-CerS2::sta). jossa on myös 11 aminohappoa CERS2 entsyymistä (joka taas tuottaa C22- C24 keramideja), aiheutti sellaisen muuntumisen CERS-spesifisyyteen, että tuottui C22- C24 - ja muita keramideja.

Lisäksi sellainen CERS4- perusteinen keramidisyntaasi ( jotka tuottaa normaalisti C18-C22 keramideja) muutettuna kimeeriseksi proteiiniksi CERS(291-301 jakso CERS2:sta) , osoittaa merkitsevää spesifisyyttä aktiivoitua C24:1- rasvahappoa (C24:1-CoA) kohtaan.

Lisätiedot tukevat havaintoa niden 11 aminohapon kyvystä muuntaa CERS entsyymien spesifisyyksiä niille tyypillisiä aktivoituja rasvahappoja kohtaan. Tutkijoiden havainnot viittanevat siihen, että tämä lyhyt silmukka rajoittanee toisiaan lähellä olevia transmembraanisia domaaneja (TMD) johtaen kalvon avoimempaan konfrontaatioon ja ne CERS entsyymit, jotka vaikuttavat lyhyehköihin aktivoituneisiin rasvahappoihin saattavat omata pidempiä, taipuvaisempia silmukoita sallien transmembraanidomaaneille joustoa. Yhteenvetona tutkijat ovat tunnistaneet 11 aminohapon alueen, joka määrittää CERS entsyymin spesifisyyden aktiivia rasvahappoa kohtaan.

Keramidisyntaasit 1-6 , CERS1- CERS6

CERS1(19p13.11) , EPM8, GDF1, LAG1, UOG1, GDF-1, LASS1.

Tämä  entsyymi tuottaa C18-keramideja  aivojen neuroneissa. Jos  geenin ilmentymä on koholla se merkitse  neuronin  pitkäikäisyyttä, kuntaas  alentunut ilmenemä assosioituu  myoklooniseen epilepsiaan.  ja dementiaan ihmisessä.

https://www.ncbi.nlm.nih.gov/gene/10715

Official Symbol

CERS1

Official Full Name

ceramide synthase 1

Also known as

EPM8; GDF1; LAG1; UOG1; GDF-1; LASS1

Summary

This gene encodes a ceramide synthase enzyme, which catalyzes the synthesis of ceramide, the hydrophobic moiety of sphingolipids. The encoded enzyme synthesizes 18-carbon (C18) ceramide in brain neurons. Elevated expression of this gene may be associated with increased longevity, while decreased expression of this gene may be associated with myoclonus epilepsy with dementia in human patients. This protein is transcribed from a monocistronic mRNA as well as a bicistronic mRNA, which also encodes growth differentiation factor 1. [provided by RefSeq, Jul 2016]

Expression

Biased expression in brain (RPKM 22.5) and testis (RPKM 5.1).

Preferred Names

ceramide synthase 1

Names

Embryonic growth/differentiation factor 1; (EPM8)

longevity assurance (LAG1, S. cerevisiae) homolog 1

longevity assurance gene 1 protein homolog 1 (LASS1)

protein UOG-1

upstream of GDF1; (UOG1)

CERS2  (1q21.3), TMSG1 (  Tuumormetastasis-suppressor gene 1 protein )

https://www.ncbi.nlm.nih.gov/gene/29956

Also known as

L3; LASS2; SP260; TMSG1

Summary

This gene encodes a protein that has sequence similarity to yeast longevity assurance gene 1. Mutation or overexpression of the related gene in yeast has been shown to alter yeast lifespan. The human protein may play a role in the regulation of cell growth. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jul 2008]

Expression

Ubiquitous expression in liver (RPKM 113.9), adrenal (RPKM 85.4) and 25 other tissues See more

Preferred Names

ceramide synthase 2

Names

LAG1 homolog, ceramide synthase 2

LAG1 longevity assurance 2

longevity assurance (LAG1, S. cerevisiae) homolog 2

sphingosine N-acyltransferase CERS2

tumor metastasis-suppressor gene 1 protein

( 299-309 aminohapot : FFGYYFFNSMM

ff
      301 gyyffnsmm) 

CERS3 (5q21.3), 

 https://www.ncbi.nlm.nih.gov/gene/204219

Also known as

ARCI9; LASS3

Summary

This gene is a member of the ceramide synthase family of genes. The ceramide synthase enzymes regulate sphingolipid synthesis by catalyzing the formation of ceramides from sphingoid base and acyl-coA substrates. This family member is involved in the synthesis of ceramides with ultra-long-chain acyl moieties (ULC-Cers), important to the epidermis in its role in creating a protective barrier from the environment. The protein encoded by this gene has also been implicated in modification of the lipid structures required for spermatogenesis. Mutations in this gene have been associated with male fertility defects, and epidermal defects, including ichthyosis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

Expression

Biased expression in skin (RPKM 15.5), esophagus (RPKM 13.5) and 1 other tissue See more

Preferred Names

ceramide synthase 3

Names

LAG1 homolog, ceramide synthase 3

LAG1 longevity assurance homolog 3

dihydroceramide synthase 3

sphingosine N-acyltransferase CERS3

NM_001290341.2 → NP_001277270.1  ceramide synthase 3 isoform 1

CERS4 (19p13.2),

 https://www.ncbi.nlm.nih.gov/gene/79603

Also known as

Trh1; LASS4

Expression

Ubiquitous expression in thyroid (RPKM 13.9), prostate (RPKM 10.3) and 24 other tissues See more

Orthologs

mouse all

CERS5 (12q13.12),

 https://www.ncbi.nlm.nih.gov/gene/91012

Also known as

Trh4; LASS5

Summary

This gene encodes a protein that belongs to the TLC (TRAM, LAG1 and CLN8 homology domains) family of proteins. The encoded protein functions in the synthesis of ceramide, a lipid molecule that is involved in a several cellular signaling pathways. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

Expression

Ubiquitous expression in endometrium (RPKM 6.0), placenta (RPKM 5.6) and 25 other tissues See more

Preferred Names

ceramide synthase 5

Names

LAG1 homolog, ceramide synthase 5

LAG1 longevity assurance homolog 5

TRAM homolog 4

sphingosine N-acyltransferase CERS5

 NM_001281731.1 → NP_001268660.1  ceramide synthase 5 isoform 2

J Biol Chem. 2008 Sep 26;283(39):26509-17. doi: 10.1074/jbc.M801597200. Epub 2008 Aug 1.

Ceramide generated by sphingomyelin hydrolysis and the salvage pathway is involved in hypoxia/reoxygenation-induced Bax redistribution to mitochondria in NT-2 cells.

Jin J¹, Hou Q, Mullen TD,et al.

CERS6 (2q24.3),

 https://www.ncbi.nlm.nih.gov/gene/253782

Also known as

CERS5; LASS6

Expression

Ubiquitous expression in colon (RPKM 18.1), thyroid (RPKM 16.4) and 25 other tissues See more

Preferred Names

ceramide synthase 6

Names

LAG1 homolog, ceramide synthase 6

longevity assurance homolog 6

NM_001256126.2 → NP_001243055.1  ceramide synthase 6 isoform 1.

TRAM, LAG1 and CLN8: members of a novel family of lipid-sensing domains?Trends Biochem. Sci. 2002 Aug ; 27(8):381-3

The human CERS6 gene promoter harbors a large CpG island (94 CpGs) and multiple transcription factor binding sites (TFBS), which support precise transcriptional regulation and signaling functions

Additional regulation is conferred by 15 microRNA
            (miRNA) target sites identified in the CERS6 3'-UTR region
            Publication Status: Online-Only

 JOURNAL   FASEB J. 24 (1), 296-308 (2010)
   PUBMED   19723703
  REMARK    GeneRIF: Mechanistically, regulation of ER-stress-induced apoptosis
            by CerS6/C(16)-ceramide was linked to the activation of a specific
            arm, ATF6/CHOP, of the unfolded protein response pathway.

 https://www.ncbi.nlm.nih.gov/pubmed/26887952

ihmisen sytosolisesta AcetylCoa syntetaasista ACSS2 (20q11.22)

 (Mainitsen että aiemmin sain eräästä lähteestä tietää, että vain sirtuiini SIRT1 pystyy deasetyloimaan tätä sytosolista asetyyliCoA-syntaasia, kun taas mitokondriaalista deasetyloi SIRT3. )


 ACSS2 ( 20q11.22), sytosolinen asetyyliCoA syntetaasi, etikkahapon aktivoija.
https://www.ncbi.nlm.nih.gov/gene/55902
Tämä geeni koodaa sytosolista etnsyymiä, joka  katalysoi etikkahapon aktivoitumista   ja  tämä aktivoitunut etikkahappo  voi käyttyä lipidisynteesiin tai energian generoimiseen. Proteiini toimii monomeerina ja  tuottaa asetyyli-CoA:n etikkahaposta reaktiossa, joka vaatii ATP:tä.
 Tämän geenin ilmentymää säätelee SREB- proteiinit, transkriptiotekijät, jotka aktivoivat geenejä, mitä vaaditaan  kolesterolin ja tyydyttymättömien rasvahappojen synteesin. Vaihtoehtoispleissauksista tulee useita  transkriptivariantteja. Geeniä ilmentyy laajasti rasvakudoksessa, pohjukaissuolesas ja 24 muussa kudoksessa. 

Official Symbol ACSS2

Official Full Name acyl-CoA synthetase short chain family member 2

Also known as ACS; ACSA; ACAS2; ACECS; dJ1161H23.1

Summary: This gene encodes a cytosolic enzyme that catalyzes the activation of acetate for use in lipid synthesis and energy generation. The protein acts as a monomer and produces acetyl-CoA from acetate in a reaction that requires ATP.

 Expression of this gene is regulated by sterol regulatory element-binding proteins, transcription factors that activate genes required for the synthesis of cholesterol and unsaturated fatty acids. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2009]

Expression: Broad expression in fat (RPKM 49.2), duodenum (RPKM 47.1) and 24 other tissues See more. Orthologs. mouse all.

Preferred Names

acetyl-coenzyme A synthetase, cytoplasmic

Names

acetate thiokinase

acetate-CoA ligase

acetyl-Coenzyme A synthetase 2 (ADP forming)

acyl-activating enzyme

cytoplasmic acetyl-coenzyme A synthetase

 

( Millä tavalla sytosolinen ja mitokondriaalinen ACSS eroavat  toisistaan rakenteellisesti? Mm. vaikuttaa olevan kuusi seriinifosforylaatiota ja vain yksi N-lysiiniasetylaatio tässä sytosolisessa. Tämä geeni sijaitsee saman kromosomin q päädyssä, kun mitokondrinen  ACSS taas sijaitsee p-päädyssä).

  

Features. 

NM_001076552.2 → NP_001070020.2  acetyl-coenzyme A synthetase, cytoplasmic isoform 2

 

FEATURES             Location/Qualifiers
     source          1..714
                     /organism="Homo sapiens"
                     /db_xref="taxon:9606"
                     /chromosome="20"
                     /map="20q11.22"
     Protein         1..714
                     /product="acetyl-coenzyme A synthetase, cytoplasmic
                     isoform 2"
                     /EC_number="6.2.1.1"
                     /note="acetyl-Coenzyme A synthetase 2 (ADP forming);
                     cytoplasmic acetyl-coenzyme A synthetase; acetate-CoA
                     ligase; acyl-activating enzyme; acetate thiokinase;
                     acetyl-coenzyme A synthetase, cytoplasmic"
                     /calculated_mol_wt=79957
     Site            28
                     /site_type="phosphorylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="Phosphoserine. {ECO:0000244|PubMed:23186163,
                     ECO:0000244|PubMed:24275569}; propagated from
                     UniProtKB/Swiss-Prot (Q9NR19.1)"
     Site            30
                     /site_type="phosphorylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="Phosphoserine. {ECO:0000244|PubMed:18669648,
                     ECO:0000244|PubMed:23186163, ECO:0000244|PubMed:24275569};
                     propagated from UniProtKB/Swiss-Prot (Q9NR19.1)"
     Region          31..705
                     /region_name="PRK00174"
                     /note="acetyl-CoA synthetase; Provisional"
                     /db_xref="CDD:234677"
     Site            36
                     /site_type="phosphorylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="Phosphoserine. {ECO:0000244|PubMed:24275569};
                     propagated from UniProtKB/Swiss-Prot (Q9NR19.1)"
     Region          51..698
                     /region_name="ACS"
                     /note="Acetyl-CoA synthetase (also known as acetate-CoA
                     ligase and acetyl-activating enzyme); cd05966"
                     /db_xref="CDD:213313"
     Site            order(191..193,219,222,224,370,375..376,398..400,424..425,
                     428,451..454,476..481,565,577,580,588..591,649,654..655)
                     /site_type="active"
                     /db_xref="CDD:213313"
     Site            order(191..193,219,222,224,370,376,398..400,424..425,428,
                     588..590,649,654)
                     /site_type="other"
                     /note="CoA binding site [chemical binding]"
                     /db_xref="CDD:213313"
     Region          219..222
                     /region_name="Coenzyme A binding. {ECO:0000250}"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="propagated from UniProtKB/Swiss-Prot (Q9NR19.1)"
     Site            263
                     /site_type="phosphorylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="Phosphoserine. {ECO:0000250|UniProtKB:Q9QXG4};
                     propagated from UniProtKB/Swiss-Prot (Q9NR19.1)"
     Site            265
                     /site_type="phosphorylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="Phosphoserine. {ECO:0000250|UniProtKB:Q9QXG4};
                     propagated from UniProtKB/Swiss-Prot (Q9NR19.1)"
     Site            267
                     /site_type="phosphorylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="Phosphoserine. {ECO:0000244|PubMed:18669648,
                     ECO:0000244|PubMed:20068231, ECO:0000244|PubMed:23186163,
                     ECO:0000244|PubMed:24275569}; propagated from
                     UniProtKB/Swiss-Prot (Q9NR19.1)"
     Site            order(326,329..334,336..337)
                     /site_type="other"
                     /note="acyl-activating enzyme (AAE) consensus motif"
                     /db_xref="CDD:213313"
     Site            order(375..376,451..454,476..481,565,577,580,591)
                     /site_type="other"
                     /note="AMP binding site [chemical binding]"
                     /db_xref="CDD:213313"
     Site            order(375..376,451..452,479)
                     /site_type="other"
                     /note="acetate binding site [chemical binding]"
                     /db_xref="CDD:213313"
     Site            431
                     /site_type="acetylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="N6-acetyllysine. {ECO:0000244|PubMed:19608861};
                     propagated from UniProtKB/Swiss-Prot (Q9NR19.1)"
     CDS             1..714
                     /gene="ACSS2"
                     /gene_synonym="ACAS2; ACECS; ACS; ACSA; dJ1161H23.1"
                     /coded_by="NM_001076552.2:122..2266"
                     /note="isoform 2 is encoded by transcript variant 2"
                     /db_xref="CCDS:CCDS42868.2"
                     /db_xref="GeneID:55902"
                     /db_xref="HGNC:HGNC:15814"
                     /db_xref="MIM:605832"
ORIGIN      
        1 mglpeervrs gsgsrgqeea gaggrarsws pppevsrsah vpslqryrel hrrsveepre
       61 fwgdiakefy wktpcpgpfl rynfdvtkgk ifiewmkgat tnicynvldr nvhekklgdk
      121 vafywegnep gettqityhq llvqvcqfsn vlrkqgiqkg drvaiympmi pelvvamlac
      181 arigalhsiv fagfsseslc erildsscsl littdafyrg eklvnlkela dealqkcqek
      241 gfpvrccivv khlgraelgm gdstsqsppi krscpdvqgk lkekskrvqp qiswnqgidl
      301 wwhelmqeag decepewcda edplfilyts gstgkpkgvv htvggymlyv attfkyvfdf
      361 haedvfwcta digwitghsy vtygplanga tsvlfegipt ypdvnrlwsi vdkykvtkfy
      421 taptairllm Kfgdepvtkh sraslqvlgt vgepinpeaw lwyhrvvgaq rcpivdtfwq
      481 tetgghmltp lpgatpmkpg satfpffgva pailnesgee legeaegylv fkqpwpgimr
      541 tvygnherfe ttyfkkfpgy yvtgdgcqrd qdgyywitgr iddmlnvsgh llstaevesa
      601 lveheavaea avvghphpvk geclycfvtl cdghtfspkl teelkkqire kigpiatpdy
      661 iqnapglpkt rsgkimrrvl rkiaqndhdl gdmstvadps vishlfshrc ltiq
//

(Mitä tietoja on tästä proteiinista saatu tähän mennessä?)

 

Related articles in PubMed

1. Acetyl-CoA synthetase 2 enhances tumorigenesis and is indicative of a poor prognosis for patients with renal cell carcinoma. Zhang S, et al. Urol Oncol, 2018 May. PMID 29503142
2. Acetyl-CoA Synthetase 2 Promotes Cell Migration and Invasion of Renal Cell Carcinoma by Upregulating Lysosomal-Associated Membrane Protein 1 Expression. Yao L, et al. Cell Physiol Biochem, 2018. PMID 29444517
3. Local histone acetylation by ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Li X, et al. Autophagy, 2017 Oct 3. PMID 28820290, Free PMC Article
4. Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy. Li X, et al. Mol Cell, 2017 Jun 1. PMID 28552616, Free PMC Article
5. Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation. Bulusu V, et al. Cell Rep, 2017 Jan 17. PMID 28099844, Free PMC Article

See all (32) citations in PubMed

GeneRIFs: Gene References Into Functions

1. High ACSS2 expression is associated with renal cell carcinoma.
2. A novel biologic role for ACSS2 in recycling of nuclear acetate for histone acetylation to promote lysosomal and autophagy-related gene expression and counteract nutritional stress, highlighting the importance of ACSS2 in maintaining autophagy and lysosome-mediated cellular energy homeostasis during tumor development.
3. ACLY and ACSS2 are both activated to produce cytosolic Ac-CoA from glucose carbon for lipogenesis during human cytomegalovirus infection.
4. ACSS2 is an important factor for promoting RCC development and is essential for cell migration and invasion, which it promotes by increasing the expression of LAMP1.
5. these findings suggest that downregulation of acetyl-CoA synthetase-2 expression is a metabolic hallmark of tumor progression and aggressive behavior in colorectal carcinoma.
6. Exogenous acetate augments Acss2/HIF-2 dependent cancer growth and metastasis in cell culture and mouse models
7. The nuclear-cytosolic acetyl-CoA synthetase 2 recaptures acetate released from histone deacetylation for recycling by histone acetyltransferases.
8. In a Honduran population, the odds of having nonsyndromic cleft lip/palate (NSCLP) among carriers of the ACSS2 variant was 4.0 with a carrier frequency of 7.1% in unrelated affected and 1.9% in unrelated unaffected individuals. In a Colombian population, the odds of having NSCLP among carriers of the ACSS2 variant was 2.6 with a carrier frequency of 10.0% in unrelated affected and 4.1% in unrelated unaffected individuals.
9. In the nucleus, ACSS2 binds to transcription factor EB and translocates to lysosomal and autophagy gene promoter regions, where ACSS2 incorporates acetate generated from histone acetylation turnover to locally produce acetyl-CoA for histone H3 acetylation in these regions and promote lysosomal biogenesis, autophagy, cell survival, and brain tumorigenesis.
10. ACSS2 is essential for glucose-independent acetate-mediated cell survival and tumor growth.

Submit: New GeneRIF Correction See all GeneRIFs (21)

https://www.ncbi.nlm.nih.gov/pubmed/?term=ACSS2%2C+Sirtuins 
https://www.ncbi.nlm.nih.gov/pubmed/?term=ACSS2%2C++hypercholesterolemia 
(Joku toinenkin on kiinnittänyt huomion ACSS- geenien  sijaintiin ja ominaisuuksiin ja  ei koodaavan pitkän RNA:n mahdolliseen  osuuteen. Otan aivan  tuoreen artikkelin pohdittavaksi. ACSS1 ja ACSS2  pitävät lyhyistä ja keskipitkistä rasvahapoista C2-C5  ensisijaisena kohteena C2 etikkahappoa.)  
https://www.ncbi.nlm.nih.gov/pubmed/31281828 

Int J Genomics. 2019 Jun 2;2019:5070975. doi: 10.1155/2019/5070975. eCollection 2019.

Identification of lncRNAs and Genes Responsible for Fatness and Fatty Acid Composition Traits between the Tibetan and Yorkshire Pigs.

Shang P¹, Li W², Liu G³, Zhang J¹, Li M¹, Wu L¹, Wang K², Chamba Y¹.

Abstract

Tibetan pigs from the Tibetan Plateau are characterized with a significant phenotypic difference relative to lowland pigs. In this study, a significant difference of the fatness and fatty acid composition traits was observed between the Tibetan and Yorkshire pigs. To uncover the involved mechanism, the expression profile of long noncoding RNAs (lncRNAs) and genes was compared between them. After serial filtered steps, 1,964 lncRNAs were obtained through our computational pipeline. In total, 63 and 715 lncRNAs and genes were identified to be differentially expressed. Evidence from cis- and trans-targeting analysis of lncRNAs demonstrated that some lncRNAs, such as MSTRG.14097 and MSTRG.8034, played important roles in the fatness and fatty acid composition traits. Bioinformatics analysis revealed that many candidate genes were responsible for the two traits. Of these, FASN, ACACA, SCD, ME3, PDHB, ACSS1, ACSS2, and ACLY were identified, which functioned in regulating the level of hexadecanoic acid, hexadecenoic acid, octadecenoic acid, and monounsaturated fatty acid. And LPGAT1, PDK4, ACAA1, and ADIPOQ were associated with the content of stearic acid, octadecadienoic acid, and polyunsaturated fatty acid. Candidate genes, which were responsible for fatness trait, consisted of FGF2, PLAG1, ADIPOQ, IRX3, MIF, IL-34, ADAM8, HMOX1, Vav1, and TLR8. In addition, association analysis also revealed that 34 and 57 genes significantly correlated to the fatness and fatty acid composition trait, respectively. Working out the mechanism caused by these lncRNAs and candidate genes is proven to be complicated but is invaluable to our understanding of fatness and fatty acid composition traits.

Aktivoidusta etikkahaposta ihmisen solussa ja mitokondriassa. Mitokondriaalinen ACSS1( 20p11.21)

AceSC1 ja AceC2
https://www.ncbi.nlm.nih.gov/pubmed/11150295
Näillä on nykyisin toiset  nimetm joissa numero on päinvastoin siis  ACSS2 sytosolinen  (AceCS1 ennen) ja  ACSS1 mitokondriaalinen ( AceCS2 ennen). Mitokondriaalista on eniten sydämessä ja maksasta se puuttuu.

AseCS1 on mitokondriaalinen asetyyli-CoA-syntetaasi. (Asetaatti-CoA ligaasi;  etikkahapon CoA-ligaasi) ,  Sillä on ainakin hiirissä - (joilla ei liikuntafaktoristaole puutetta)    tärkeä osuus sitruunahapposyklissä (CSC, TCA) , jossa se katalysoi asetaatit eli etikkahapon konversiota aktiiviksi etikkahapoksi , asetyyli CoA:ksi.( AsetyyliCoA taas on se perustava molekyyli, jolla on heti käyttöä monenmoisiin  metabolisiin teihin! Pelkkä etikkahappo taas tuottaa  harmia, jos se ei  kykene aktivoitumaan).  Geenistä pleissautuu  vaihtoehtoisia transkriptejä, jotka koodaavat  monia isoformeja. Tätä geeniä ilmentyy istukassa, pohjukaisisuolessa ja 24 muussa kudoksessa.
Geenin virallinen symboli nykyään on ACSS1, muita nimiä ovat ACAS2L, ACECS1, AceCS2L

ACSS1 (20p11.21) . acyl-CoA synthetase short chain family member 1 [ Homo sapiens (human) ]
https://www.ncbi.nlm.nih.gov/gene/84532

Official Symbol ACSS1

Official Full Name acyl-CoA synthetase short chain family member 1

Also known as ACAS2L; ACECS1; AceCS2L

Summary:  This gene encodes a mitochondrial acetyl-CoA synthetase enzyme. A similar protein in mice plays an important role in the tricarboxylic acid cycle by catalyzing the conversion of acetate to acetyl CoA. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

Expression Broad expression in placenta (RPKM 70.4), duodenum (RPKM 23.0) and 24 other tissues See more Orthologs mouse all

Preferred Names: acetyl-coenzyme A synthetase 2-like, mitochondrial

Names: acetate--CoA ligase 2

Features: NM_001252675.1 → NP_001239604.1  acetyl-coenzyme A synthetase 2-like, mitochondrial isoform 2 precursor   ( Plenty of  isoforms!)

 

 

FEATURES             Location/Qualifiers
     source          1..687
                     /organism="Homo sapiens"
                     /db_xref="taxon:9606"
                     /chromosome="20"
                     /map="20p11.21"
     Protein         1..687
                     /product="acetyl-coenzyme A synthetase 2-like,
                     mitochondrial isoform 2 precursor"
                     /EC_number="6.2.1.1"
                     /note="acetyl-coenzyme A synthetase 2-like, mitochondrial;
                     acetate--CoA ligase 2"
                     /calculated_mol_wt=70901
     transit_peptide 1..37
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="Mitochondrion. {ECO:0000269|PubMed:16788062};
                     propagated from UniProtKB/Swiss-Prot (Q9NUB1.2)"
                     /calculated_mol_wt=3743
     Region          54..674
                     /region_name="Ac_CoA_lig_AcsA"
                     /note="acetate--CoA ligase; TIGR02188"
                     /db_xref="CDD:274022"
     Region          64..665
                     /region_name="ACS"
                     /note="Acetyl-CoA synthetase (also known as acetate-CoA
                     ligase and acetyl-activating enzyme); cd05966"
                     /db_xref="CDD:213313"

Acetyl-CoA synthetase (also known as acetate-CoA ligase and acetyl-activating enzyme)
Acetyl-CoA
 synthetase (ACS) catalyzes the formation of acetyl-CoA from acetate, 
CoA, and ATP. Synthesis of acetyl-CoA is carried out in a two-step 
reaction. In the first step, the enzyme catalyzes the synthesis of 
acetyl-AMP intermediate from acetate and ATP. In the second step, 
acetyl-AMP reacts with CoA to produce acetyl-CoA. This enzyme is widely 
present in all living organisms. The activity of this enzyme is crucial 
for maintaining the required levels of acetyl-CoA, a key intermediate in
 many important biosynthetic and catabolic processes. Acetyl-CoA is used
 in the biosynthesis of glucose, fatty acids, and cholesterol. It can 
also be used in the production of energy in the citric acid cycle. 
Eukaryotes typically have two isoforms of acetyl-CoA synthetase, a 
cytosolic form involved in biosynthetic processes and a mitochondrial 
form primarily involved in energy generation.
     Site            order(196..198,224,227,229,335,340..341,363..365,389..390,
                     393,416..419,441..446,531,543,546,554..557,615,620..621)
                     /site_type="active"
                     /db_xref="CDD:213313"
     Site            order(196..198,224,227,229,335,341,363..365,389..390,393,
                     554..556,615,620)
                     /site_type="other"
                     /note="CoA binding site [chemical binding]"
                     /db_xref="CDD:213313"
     Region          224..227  (RGGR)
                     /region_name="Coenzyme A binding. {ECO:0000250}"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="propagated from UniProtKB/Swiss-Prot (Q9NUB1.2)"
     Site            order(291,294..299,301..302)
                     /site_type="other"
                     /note="acyl-activating enzyme (AAE) consensus motif"
                     /db_xref="CDD:213313"
     Site            order(340..341,416..419,441..446,531,543,546,557)
                     /site_type="other"
                     /note="AMP binding site [chemical binding]"
                     /db_xref="CDD:213313"
     Site            order(340..341,416..417,444)
                     /site_type="other"
                     /note="acetate binding site [chemical binding]"
                     /db_xref="CDD:213313"
     Site            396 K
                     /site_type="acetylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="N6-acetyllysine. {ECO:0000244|PubMed:19608861};
                     propagated from UniProtKB/Swiss-Prot (Q9NUB1.2)"
     Site            640 K
                     /site_type="acetylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="N6-acetyllysine. {ECO:0000269|PubMed:16788062};
                     propagated from UniProtKB/Swiss-Prot (Q9NUB1.2)"
     CDS             1..687
                     /gene="ACSS1"
                     /gene_synonym="ACAS2L; ACECS1; AceCS2L"
                     /coded_by="NM_001252675.1:81..2144"
                     /note="isoform 2 precursor is encoded by transcript
                     variant 2"
                     /db_xref="GeneID:84532"
                     /db_xref="HGNC:HGNC:16091"
                     /db_xref="MIM:614355"
ORIGIN      
        1 maartlgrgv grllgslrgl sgqparppcg vsaprraasg psgsapavaa aaaqpgsypa
       61 lsaqaarepa afwgplardt lvwdtpyhtv wdcdfstgki gwflggqlnv svncldqhvr
      121 kspesvaliw erdepgtevr ityrellett crlantlkrh gvhrgdrvai ympvsplava
      181 amlacariga vhtvifagfs aeslagrind akckvvitfn qglrggrvve lkkivdeavk
      241 hcptvqhvlv ahrtdnkvhm gdldvpleqe makedpvcap esmgsedmlf mlytsgstgm
      301 pkgivhtqag yllyaalthk lvfdhqpgdi fgcvadigwi tghsyvvygp lcngatsvlf
      361 estpvypnag rywetverlk inqfygapta vrlllKygda wvkkydrssl rtlgsvgepi
      421 nceawewlhr vvgdsrctlv dtwwqtggic iaprpseega eilpamamrp ffgivpvlmd
      481 ekgsvvegsn vsgalcisqa wpgmartiyg dhqrfvdayf kaypgyyftg dgayrteggy
      541 yqitgrmddv inisghrlgt aeiedaiadh pavpesavig yphdikgeaa fafivvkdsa
      601 gdsdvvvqel ksmvatkiak yavpdeilvv krlpktrsgK vmrrllrkii tseaqelgdt
      661 ttledpsiia eilsvyqkck dkqaaak
//

 

 

 

 

Mitä  tutkimuksia tästä geenituotteesta on saatavilla?  Huomaa SIRT3:n osuus mitokondriassa!

Related articles in PubMed

1. Gene network analysis reveals a novel 22-gene signature of carbon metabolism in hepatocellular carcinoma. Zhang J, et al. Oncotarget, 2016 Aug 2. PMID 27363021, Free PMC Article
2. A novel Acetyl-CoA synthetase short-chain subfamily member 1 (Acss1) gene indicates a dynamic history of paralogue retention and loss in vertebrates. Castro LF, et al. Gene, 2012 Apr 15. PMID 22313524
3. The importance of acetyl coenzyme A synthetase for 11C-acetate uptake and cell survival in hepatocellular carcinoma. Yun M, et al. J Nucl Med, 2009 Aug. PMID 19617323
4. Crystal structures of human SIRT3 displaying substrate-induced conformational changes. Jin L, et al. J Biol Chem, 2009 Sep 4. PMID 19535340, Free PMC ArticleAbstract
   SIRT3 is a major mitochondrial NAD(+)-dependent protein deacetylase playing important roles in regulating mitochondrial metabolism and energy production and has been linked to the beneficial effects of exercise and caloric restriction. SIRT3 is emerging as a potential therapeutic target to treat metabolic and neurological diseases. We report the first sets of crystal structures of human SIRT3, an apo-structure with no substrate, a structure with a peptide containing acetyl lysine of its natural substrate acetyl-CoA synthetase 2 (ACSS1) , a reaction intermediate structure trapped by a thioacetyl peptide, and a structure with the dethioacetylated peptide bound. These structures provide insights into the conformational changes induced by the two substrates required for the reaction, the acetylated substrate peptide and NAD(+). In addition, the binding study by isothermal titration calorimetry suggests that the acetylated peptide is the first substrate to bind to SIRT3, before NAD(+). These structures and biophysical studies provide key insight into the structural and functional relationship of the SIRT3 deacetylation activity. DOI:10.1074/jbc.M109.014928[Indexed for MEDLINE]
   Free PMC Article  
   http://www.jbc.org/content/284/36/24394/F5.expansion.html
5. Glucose-independent Acetate Metabolism Promotes Melanoma Cell Survival and Tumor Growth. Lakhter AJ, et al. J Biol Chem, 2016 Oct 14. PMID 27539851, Free PMC ArticleTumors rely on multiple nutrients to meet cellular bioenergetics and macromolecular synthesis demands of rapidly dividing cells. Although the role of glucose and glutamine in cancer metabolism is well understood, the relative contribution of acetate metabolism remains to be clarified. We show that glutamine supplementation is not sufficient to prevent loss of cell viability in a subset of glucose-deprived melanoma cells, but synergizes with acetate to support cell survival. Glucose-deprived melanoma cells depend on both oxidative phosphorylation and acetate metabolism for cell survival. Acetate supplementation significantly contributed to maintenance of ATP levels in glucose-starved cells. Unlike acetate, short chain fatty acids such as butyrate and propionate failed to prevent loss of cell viability from glucose deprivation. In vivo studies revealed that in addition to nucleo-cytoplasmic acetate assimilating enzyme ACSS2, mitochondrial ACSS1 was critical for melanoma tumor growth in mice. Our data indicate that acetate metabolism may be a potential therapeutic target for BRAF mutant melanoma.

See all (24) citations in PubMed

GeneRIFs: Gene References Into Functions

1. citrate synthase and ACSS1 have tumorigenic functions in hepatocellular carcinoma
2. ACSS1 is essential for glucose-independent acetate-mediated cell survival and tumor growth.
3. Clinical trial of gene-disease association and gene-environment interaction. (HuGE Navigator)
4. Observational study of gene-disease association. (HuGE Navigator)

Kommentti: Kommentti seuraavan otsikon alla siteeraan lähdetietoa systolisesta asetyyliCoA syntetaasista.