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onsdag 5 juli 2023

CTP, CDP, CMP, Cytidiini, fosfolipidien aineenvaihdunta-alueella ; lesitiini, kefaliini, fosfatidyyli-inositoli, Kardiolipiini, Fosfatidylseriini

 https://pubmed.ncbi.nlm.nih.gov/209024/

Abstract

Growing evidence suggests an involvement of brain membrane phospholipid metabolism in a variety of neurodegenerative and psychiatric conditions. This has prompted the use of drugs (e.g., CDPcholine) aimed at elevating the rate of neural membrane synthesis. However, no information is available regarding the human brain enzymes of phospholipid synthesis which these drugs affect. Thus, the objective of our study was to characterize the enzymes involved, in particular, whether differences existed in the relative affinity of substrates for the enzymes of phosphatidylethanolamine (PE) compared to those of phosphatidylcholine (PC) synthesis. The concentration of choline in rapidly frozen human brain biopsies ranged from 32–186 nmol/g tissue, a concentration similar to that determined previously for ethanolamine. Since human brain ethanolamine kinase possessed a much lower affinity for ethanolamine (Km=460 μM) than choline kinase did for choline (Km=17 μM), the activity of ethanolamine kinase in vivo may be more dependent on substrate availability than that of choline kinase. In addition, whereas ethanolamine kinase was inhibited by choline, and to a lesser extent by phosphocholine, choline kinase activity was unaffected by the presence of ethanolamine, or phosphoethanolamine, and only weakly inhibited by phosphocholine. Phosphoethanolamine cytidylyl-transferase (PECT) and phosphocholine cytidylyltransferase (PCCT) also displayed dissimilar characteristics, with PECT and PCCT being located predominantly in the cytosolic and particulate fractions, respectively. Both PECT and PCCT exhibited a low affinity for CTP (Km approximately 1.2 mM), suggesting that the activities of these enzymes, and by implication, the rate of phospholipid synthesis, are highly dependent upon the cellular concentration of CTP. In conclusion, our data indicate different regulatory properties of PE  (Kephaline) and PC (Lecitine)  synthesis in human brain, and suggest that the rate of PE synthesis may be more dependent upon substrate (ethanolamine) availability than that of PC synthesis.

 

KEUHKOSURFAKTANTIT: Näistä on koe-eläinperäistä tietoa jo 1980 luvulta

https://pubmed.ncbi.nlm.nih.gov/2858175/

. 1985 Mar;131(3):439-60.
doi: 10.1164/arrd.1985.131.3.439. The surfactant system and lung phospholipid biochemistry
S A Rooney DOI: 10.1164/arrd.1985.131.3.439 
  Comparison of the enzyme activities of phosphatidylcholine, phosphatidylglycerol and phosphatidylinositol synthesis in freshly isolated type II pneumocytes and whole lung from the adult rat

 

. 2020 Feb 7;8:63.
doi: 10.3389/fcell.2020.00063. eCollection 2020.

CDP-Diacylglycerol Synthases (CDS): Gateway to Phosphatidylinositol and Cardiolipin Synthesis

Nicholas J Blunsom  1 , Shamshad Cockcroft  1
Affiliations
  • PMID: 32117988
  • PMCID: PMC7018664
  • DOI: 10.3389/fcell.2020.00063 
  • Abstract

    Cytidine diphosphate diacylglycerol (CDP-DAG) is a key intermediate in the synthesis of phosphatidylinositol (PI) (Lipositol)  and cardiolipin (CL). Both PI and CL have highly specialized roles in cells. PI can be phosphorylated and these phosphorylated derivatives play major roles in signal transduction, membrane traffic, and maintenance of the actin cytoskeletal network. 

     CL is the signature lipid of mitochondria and has a plethora of functions including maintenance of cristae morphology, mitochondrial fission, and fusion and for electron transport chain super complex formation. Both lipids are synthesized in different organelles although they share the CTP by enzymes that display CDP-DAG synthase activities.

     Two families of enzymes, CDS and TAMM41, which bear no sequence or structural relationship, have now been identified. TAMM41 is a peripheral membrane protein localized in the inner mitochondrial membrane required for CL synthesis. 

    CDS enzymes are ancient integral membrane proteins found in all three domains of life. In mammals, they provide CDP-DAG for PI synthesis and for phosphatidylglycerol (PG) and CL synthesis in prokaryotes.

     CDS enzymes are critical for maintaining phosphoinositide (PtdIns, PI)  levels during phospholipase C (PLC) signaling. Hydrolysis of PI (4,5) bisphosphate by PLC requires the resynthesis of PI and CDS enzymes catalyze the rate-limiting step in the process. 

    In mammals, the protein products of two CDS genes (CDS1 and CDS2) localize to the ER and it is suggested that CDS2 is the major CDS for this process. Expression of CDS enzymes are regulated by transcription factors and CDS enzymes may also contribute to CL(Cardiolipin)  synthesis in mitochondria.

    Studies of CDS enzymes in protozoa reveal spatial segregation of CDS enzymes from the rest of the machinery required for both PI and CL synthesis identifying a key gap in our understanding of how CDP-DAG can cross the different membrane compartments in protozoa and in mammals.

    Keywords: CDP-diacylglycerol; TAMM41; endoplasmic reticulum; lipid synthesis; mitochondria; phosphatidic acid; phosphatidylinositol; phospholipase C.

     CDS geeniT /Tietoa CDS1 geenistä)

    Aliases for CDS1 Gene

    • GeneCards Symbol: CDS1 2
    • CDP-Diacylglycerol Synthase 1 2 3 4 5
    • CTP:Phosphatidate Cytidylyltransferase 1 3 4
    • Phosphatidate Cytidylyltransferase 1 3 4
    • CDP-Diglyceride Pyrophosphorylase 1 3 4
    • CDP-Diglyceride Synthase 1 3 4
    • CDP-DAG Synthase 1 3 4
    • CDP-DG Synthase 1 3 4
    • EC 2.7.7.41 4 48
    • CDS 1 3 4
    • CDP-Diacylglycerol Synthase (Phosphatidate Cytidylyltransferase) 1 3
    • Phosphatidate Cytidylyltransferase 2
    • CDP-Diglyceride Synthetase 1 3
    • CDP-DG Synthetase 1 3
    • CDS 4
    Breakdown products of phosphoinositides (PtdIns alias PI)  are ubiquitous second messengers that function downstream of many G protein-coupled receptors and tyrosine kinases regulating cell growth, calcium metabolism, and protein kinase C activity. This gene encodes an enzyme which regulates the amount of phosphatidylinositol (PI)  available for signaling by catalyzing the conversion of phosphatidic acid to CDP-diacylglycerol. This enzyme is an integral membrane protein localized to two subcellular domains, the matrix side of the inner mitochondrial membrane where it is thought to be involved in the synthesis of phosphatidylglycerol and cardiolipin and the cytoplasmic side of the endoplasmic reticulum where it functions in phosphatidylinositol biosynthesis. Two genes encoding this enzyme have been identified in humans, one mapping to human chromosome 4q21 and a second to 20p13. [provided by RefSeq, Jul 2008]
    CDS1 (CDP-Diacylglycerol Synthase 1) is a Protein Coding gene. Diseases associated with CDS1 include Muscular Dystrophy, Congenital, With Cataracts And Intellectual Disability and Polymicrogyria, Bilateral Temporooccipital. Among its related pathways are Glycerophospholipid biosynthesis and Metabolism. Gene Ontology (GO) annotations related to this gene include transferase activity, transferring phosphorus-containing groups and phosphatidate cytidylyltransferase activity. An important paralog of this gene is CDS2

    Catalyzes the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG), an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol (PubMed:9407135, 25375833). Exhibits almost no acyl chain preference for PA, showing no discrimination for the sn-1/sn-2 acyl chain composition of PAs (PubMed:25375833). Plays an important role in regulating the growth of lipid droplets which are storage organelles at the center of lipid and energy homeostasis (PubMed:26946540, 31548309). Positively regulates the differentiation and development of adipocytes (By similarity). ( CDS1_HUMAN,Q92903 ) 
    Molecular function for CDS1 Gene according to UniProtKB/Swiss-Prot
    Function:
    • Catalyzes the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG), an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol (PubMed:9407135, 25375833).
      Exhibits almost no acyl chain preference for PA, showing no discrimination for the sn-1/sn-2 acyl chain composition of PAs (PubMed:25375833).
      Plays an important role in regulating the growth of lipid droplets which are storage organelles at the center of lipid and energy homeostasis (PubMed:26946540, 31548309).
      Positively regulates the differentiation and development of adipocytes (By similarity). CDS1_HUMAN,Q92903
    CatalyticActivity: ( ESIMERKKEJÄ Rasvahappovalinnoista sn1 ja sn2 kohtiin. Huomaa essentiellien aminohappojen kuten arakidonin  kanto  kehon kaikkien solukalvojen rakenteisiin)..
    BiophysicochemicalProperties:
    EnzymeRegulation:
    • Inhibited by its anionic phospholipid end products, with phosphatidylinositol-(4,5)- bisphosphate showing the strongest inhibition. CDS1_HUMAN,Q92903
    Biochemistry: CDP-diacylglycerol synthase (CDS) 1, photoreceptor specific,highly expressed in photoreceptor layer of adult retina,regulator of cellular phosphatidylinositol content,involved in phosphoinositide mediated signaling pathway CDS1

    * CDS2 teksti on miltei samanlainen:  Vain linkki Gene Cards:

     https://www.genecards.org/cgi-bin/carddisp.pl?gene=CDS2&keywords=CDS2


    *  Mitokondriaalinen fosfatidaatti - Cytidyl- transferaasi syntetisoi    CDP -diasyyliglyserolia CDP-DAG,

     CDP-DAG on tärkeä välituote  KARDIOLIPIININ, fosfatidylinositolin  ja fosfatidylglyserolin  synteesissä.   (Ptd = fosfatidyyli, PA fosfatidaatti )

    (Tietoa TAMM41 geenistä)  

     Geenituote proteiinin suositeltu nimi "Phosphatidate (PA)  Cytidyltransferase, Mitochondrial"

    • GeneCards Symbol: TAMM41,  3p25.1  
    • TAM41 Mitochondrial Translocator Assembly And Maintenance Homolog 2 3 5
    • Phosphatidate (PA)  Cytidylyltransferase, Mitochondrial 2 3 4
    • C3orf31 3 4 5
    • Mitochondrial Translocator Assembly And Maintenance Protein 41 Homolog 3 4
    • CDP-Diacylglycerol Synthase 3 4
    • CDP-DAG Synthase 3
    Molecular function for TAMM41 Gene according to UniProtKB/Swiss-Prot
     TAMM41 gene  Function: Catalyzes the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG), an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol. TAM41_HUMAN,Q96BW9
    CatalyticActivity:
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