Category:LBS/Biosynthesis

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Ceramide Metabolism セラミドの代謝

Ceramide synthesis

Ceramide is synthesized at the cytosolic surface of the endoplasmic reticulum (ER), and is transferred to Golgi by CERT (ceramide transfer protein).[1][2]

First, serine and palmitoyl-CoA are condensed by SPT to synthesize 3-ketodihydrosphingosine (3-KDS or 3-ketosphinganine), followed by reduction by KDSR to produce dihydrosphingosine (DHS or sphinganine, d18:0). Then DHS is acylated by the ceramide synthase family enzymes (CerS1-6) to form dihydroceramide (DHCer). Each DHCer of different length is then desaturated by respective desaturase to ceramide (Cer). DHCer and Cer have many possible fates such as (DH)Cer phosphate, (DH)sphingomyelin, glycosyl (DH)Cer, or hydrolysis to the free sphingoid base.

セラミド (Cer) は小胞体の細胞質側膜上で合成され、その後CERTによりゴルジ体に移動します。

まず、セリンとパルミトイルCoAが酵素SPTにより縮合し、3-ケトジヒドロスフィンゴシン(3-KDS, 3-ケトスフィンガニン)になり、酵素KDSRにより還元されてスフィンガニン (d18:0) になります。次にセラミド合成酵素ファミリーによってアシル化され、ジヒドロセラミド (DHCer) ができます。各 DHCer はそれぞれ不飽和化酵素により Cer になります。DHCer と Cer は、リン酸化(DH)Cer、(DH)スフィンゴミエリン、グリコシル(DH)Cer または遊離スフィンゴイド塩基への加水分解など、多岐に変化します。

  1. Tidhar R, Futerman AH (2013) "The complexity of sphingolipid biosynthesis in the endoplasmic reticulum" Biochim Biophys Acta 1833:2511-8. PMID 23611790
  2. Yamaji T, Hanada K (2014) "Sphingolipid metabolism and interorganellar transport: localization of sphingolipid enzymes and lipid transfer proteins" Traffic 16: 101-122. PMID 25382749
serine
+
palmitoyl (16:0)-CoA

Arrow00r.png
 serine palmitoyl
  transferase
3-ketodihydro-
  sphingosine
(3-KDS)

Arrow00r.png
  3-KDS
  reductase
dihydrosphingosine
(DHS, d18:0)
Cer synthase
Arrow1rr.png
fatty acyl CoA
dihydroceramide
(DHCer)

Arrow00r.png
  DHCer
  desaturase
ceramide
(Cer)
Cytosolic surface of the endoplasmic reticulum (ER)

Ceramide degradation

Ceramides are degraded by reversible hydrolysis between the long chain base (LCB) and fatty acyl (FA). Much work has been done in mammals and yeast, and ceramidases are classified by their pH optima as acidic, neutral, or alkaline ceramidase. In mammals, sphingosine (d18:1Δ4E) is produced only by the hydrolysis (no de novo synthesis), therefore the cell signalling by d18:1Δ4E-1P (S1P) is modulated by the degradation. Most sphingosine come from sphingomyelin.[1]

セラミドは可逆的な加水分解により長鎖塩基 (LCB) と脂肪酸 (FA) に分かれます。研究の多くは動物や酵母を用いておこなわれ、セラミド分解酵素は至適pHにより、酸性、中性、アルカリセラミダーゼに分けられます。動物では スフィンゴシン (d18:1Δ4E) が分解経路のみによって生じるため(直接合成されない)、d18:1Δ4E-1P (S1P) による細胞シグナリングはセラミド分解に依存します。多くのスフィンゴシンはスフィンゴミエリン由来です。

  1. Mao C, Obeid LM. “Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate” Biochim Biophys Acta. 2008;1781:424-34. PMID 18619555
ceramide  ceramidase
Arrow2rr.png
   fatty acid
sphingosine S1P phosphatase
Arrow00h.png
 
sphingosine
1-phosphate
S1P lyase
Arrow2rr.png
  phosphoethanolamine
hexadecenal  
Arrow00r35.png
 
hexadecanal  
Arrow00r35.png
 
palmitate
ER, Golgi and Lysosomes

Glycosphingolipid in Plant 植物のスフィンゴ糖脂質

Higher plants contain glucosylceramide (GlcCer), its derivatives, and glycosyl phosphoinositolceramides (GIPC). Sphingolipid comprises more than 40% of the total lipid of the cytoplasmic membrane and is also major in tonoplast. GlcCer and GIPC form membrane rafts. The major component of rafts in animal cells is sphingomyelin (SM). Plant does not synthesize SM, however, and GIPC is considered to replace it. GlcCer and GIPC show different compositions of their long chain bases and fatty acids. Different ceramides are probably selected at the time of glycosyltransfer. Many responsible genes for sphingolipid biosynthesis are identified in the last decade.[1]

高等植物にはグルコシルセラミド(GlcCer)由来の系列とグリコシルイノシトールホスホセラミド(GIPC)が存在します。スフィンゴ脂質は植物細胞膜の脂質の40%以上を占め、液胞膜にも多く含まれます。GlcCerやGIPCは細胞膜のラフトに多く存在します。 動物細胞のラフトにはスフィンゴミエリン(SM)が多いですが、植物はSMを含まず、GIPCがSMを代替すると考えられます。GlcCerとGIPCのセラミド部分を構成する長鎖塩基や脂肪酸は組成が異なり、糖が結合する際に異なるセラミドが選択されると考えられています。スフィンゴ脂質の生合成に関わる酵素遺伝子の多くはこの10年間に同定されました。

Glycosphingolipid biosynthetic pathway

palmitoyl (16:0)-CoA
+
serine
SPT
Arrow00r.png
3-keto sphinganine KSR
Arrow00r.png
sphinganine
d18:0
LCB C-4 OHase
Arrow00r.png
phytosphinganine
t18:0
Arrow1ld35.png
LCFA-CoA
CS I[2]
Lumen of endoplasmic
reticulum (ER)
Arrow1ld35.png
VLCFA-CoA
CS II
Abbreviations
CS I/II (dihydro)ceramide synthase I/II
DAG diacylglycerol
DES desaturase
FA OHase Fatty-acid hydroxylase
GCS glucosylceramide synthase
IPCS inositol phosphoceramide synthase
KSR 3-ketosphinganine reductase
LCB long-chain base
LCFA long-chain fatty acid
MT methyltransferase
PI phosphatidylinositol
SPT serine palmitoyltransferase
VLCFA very long-chain fatty acid
d18:0-LCFA t18:0-VLCFA
Arrow00d35.png
Δ8 DES
Δ4 DES
FA-αOHase
(C-9 MT in fungi)
Arrow00d35.png
Δ8 DES
FA-αOHase
Bold font = ceramides
d18:1Δ8E/Z-hLCFA t18:1Δ8E/Z-hVLCFA
Arrow00dr35.png +UDP-Glc +UDP-Glc Arrow00dl35.png transport Arrow00dr35.png
Glc-ceramide
Glc-d18:2 4E,8E/Z-hLCFA
Glc-d18:1 8E/Z-hLCFA
Glc-t18:1-hVLCFA
Golgi t18:1Δ8E/Z-hVLCFA
Arrow3ld.png
PI
IPCS[3]
DAG
GIPC
  1. Chen M, Cahoon EB "Plant sphingolipids:structure, synthesis and function" in Lipid in photosynthesis: essential and regulatory functions (Wada H, Murata N, eds), 2009 pp.77-115, Springer, ISBN 978-90-481-2863-1
  2. CS can utilize a range of FA-CoAs (C16-24) but not hydroxy-FA-CoAs. See Sperling P, Heinz E. “Plant sphingolipids: structural diversity, biosynthesis, first genes and functions” Biochim Biophys Acta. 2003 10;1632:1-15. PMID 12782146
  3. Activity of IPCS is high in Fabaceae. See Bromley PE, Li YO, Murphy SM, Sumner CM, Lynch DV. “Complex sphingolipid synthesis in plants: characterization of inositolphosphorylceramide synthase activity in bean microsomes” Arch Biochem Biophys. 2003 15;417:219-26. PMID 12941304

Glycosphingolipid in Fungi 菌類のスフィンゴ糖脂質

Fungi synthesize derivative series of GlcCer and GalCer, and GIPC. GIPC includes inositol phosphoceramide (IPC), mannosyl-inositol phosphoceramide (MIPC), and mannosyl-diinositol phosphoceramide (M(IP)2C). As in higher plants, fungi do not synthesize sphingomyelin. The lipid membrane rafts contain ergosterols and glycosphingolipids. Long chain bases of GlcCer are often methylated at their C-9 position. Long chain bases of GIPC are phytosphingosines.[1] GIPC also occur as membrane anchors (GPI anchors) of proteins in yeast[2] and plants [3].

菌類には、グルコシルセラミド(GlcCer)とガラクトシルセラミド(GalCer)の派生物に加え、グリコシルイノシトールホスホセラミド(GIPC)もあります。GIPCにはイノシトールホスホセラミド(IPC)にマンノースが結合したマンノシルイノシトールホスホセラミド(MIPC)、マンノシルジイノシトールホスホセラミド[M(IP)2C)]が含まれます。植物と同様、菌類もスフィンゴミエリンは持ちません。細胞膜のラフトにはエルゴステロールとスフィンゴ糖脂質が多く含まれます。GlcCer系列のセラミドは、長鎖塩基のC-9位がメチル化されます。GIPCの長鎖塩基はフィトスフィンゴシンです。GIPCは酵母や植物においてタンパク質の膜アンカー (GPIアンカー) としても存在します。

  1. Guimarães LL, Toledo MS, Ferreira FA, Straus AH, Takahashi HK. “Structural diversity and biological significance of glycosphingolipids in pathogenic and opportunistic fungi”Front Cell Infect Microbiol. 2014;4:138 PMID 25309884
  2. Conzelmann A, Puoti A, Lester RL, Desponds C (1992) EMBO J, 11:457–466 PMID 1531630
  3. Svetek J, Yadav MP, Nothnagel EA (1999) J Biol Chem, 274:14724–14733 PMID 10329668

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