Category:LBS/Biosynthesis: Difference between revisions

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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。

serine + palmitoyl (16:0)-CoA	serine palmitoyl transferase	3-ketodihydro- sphingosine (3-KDS)	3-KDS reductase	dihydrosphingosine (DHS, d18:0)	Cer synthase fatty acyl CoA	dihydroceramide (DHCer)	DHCer desaturase	ceramide (Cer)
Cytosolic surface of the endoplasmic reticulum (ER)

Enzyme function in the Human Genome
Protein name	Gene name (Uniprot)	Location
Serine palmitoyl transferase (SPT)	SPTLC1(LCB1)	9q22.31	A heterodimer membrane protein (LCB1-LCB2 or LCB1-LCB3) whose catalytic site faces the cytosol. In addition, small subunits (SPTSSA or SPTSSB) are essential for the full enzymatic activity. SPTSSA/B has no homology with the Tsc3p subunit in yeast.^[3] SPTLC1-SPTLC2-SPTSSA ... C16-CoA SPTLC1-SPTLC3-SPTSSA ... C14- and C16-CoA SPTLC1-SPTLC2-SPTSSB ... C18-CoA SPTLC1-SPTLC3-SPTSSB ... broad specificity
	SPTLC2 (LCB2,LCB2A)	14q24.3
	SPTLC3(LCB2B)	20p12.1
	SPTSSA(ssSPTa)	14q13.1
	SPTSSB(ssSPTb)	3q26.1
3-Ketodihydrosphingosine reductase	KDSR(FVT1)	18q21.33
Ceramide synthase ^[4]	CERS1 (LASS1,LAG1)	19p13.11	Brain, skeletal muscle, testis for C18
	CERS2 (LASS2,TMSG1)	1q21.3	Kidney, liver and other >12 organs for C20-C26
	CERS3(LASS3)	15q26.3	Skin, testis for C22-C26 α-hydroxy chains
	CERS4(LASS4)	19p13.2	Low in all tissues for C18-C22. Esp. skin, leucocytes, heart, liver.
	CERS5(LASS5)	12q13.12	Low in all tissues for C16. Esp. muscle and brain. Major in lung epithelia.
	CERS6(LASS6)	2q24.3	Low in all tissues for C14-C16
Dihydroceramide Δ4-desaturase	DEGS1(DES1)	1q42.11	The enzyme hydroxylates DES to form phytoceramide.^[5]
Dihydroceramide Δ4-desaturase	DEGS2(DES2)	14q32.2	The enzyme hydroxylates DES to form phytoceramide.^[5]
↑ Tidhar R, Futerman AH (2013) "The complexity of sphingolipid biosynthesis in the endoplasmic reticulum" Biochim Biophys Acta 1833:2511-8. PMID 23611790 ↑ Yamaji T, Hanada K (2014) "Sphingolipid metabolism and interorganellar transport: localization of sphingolipid enzymes and lipid transfer proteins" Traffic 16: 101-122. PMID ↑ Han G., Gupta S.D., Gable K., Niranjanakumari S., Moitra P., Eichler F., Brown R.H. Jr., Harmon J.M., Dunn T.M. (2009) "Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities" Proc. Natl. Acad. Sci. USA 106:8186-8191 PMID 19416851 ↑ Levy M, Futerman AH (2010) "Mammalian ceramide synthases" IUBMB Life 62(5):347-356 PMID 20222015 ↑ Michel C, van Echten-Deckert G. (1997) "Conversion of dihydroceramide to ceramide occurs at the cytosolic face of the endoplasmic reticulum" FEBS Lett 416(2):153-155 PMID 9369202

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。

ceramide	ceramidase fatty acid	sphingosine	S1P phosphatase	sphingosine 1-phosphate	S1P lyase phosphoethanolamine	hexadecenal		hexadecanal		palmitate
ER, Golgi and Lysosomes

Enzyme function in the Human Genome
Protein name	Gene name (Uniprot)	Location
Acid ceramidase	ASAH1	8p22	Localized in lysosome. Its deficiency causes lysosomal accumulation of ceramides (Farber disease).^[2]
Neutral ceramidase	ASAH2	10q11.23	Localized to the plasma membrane and expressed in the small intestine and colon. ^[3]
Alkaline ceramidase	ACER1(ASAH3)	19p13.3	Localized to the endoplasmic reticulum (ER) and highly expressed in skin.
	ACER2(ASAH3L)	9p22.1	Localized to the Golgi complex and highly expressed in placenta.
	ACER3(APHC)	11q13.5	Localized to the ER and the Golgi complex, and ubiquitously expressed.
S1P phosphatase	SGPP1	14q23.2	Specifically dephosphorylates sphingosine 1-phosphate (S1P), dihydro-S1P, and phyto-S1P.
S1P phosphatase	SGPP2	2q36.1	Localized to the ER and dephosphorylates S1P and dihydro-S1P.^[4]
S1P lyase	SGPL1	10q22.1
↑ 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 ↑ Ferlinz K, Kopal G, Bernardo K et al. (2001) "Human acid ceramidase: processing, glycosylation, and lysosomal targeting" J Biol Chem 276(38):35352-35360. ↑ Coant N, Sakamoto W, Mao C, Hannun YA (2015) "Ceramidases, roles in sphingolipid metabolism and in health and disease" Adv Biol Regul 63:122-131 ↑ Ogawa C, Kihara A, Gokoh M, Igarashi Y (2003) "Identification and characterization of a novel human sphingosine-1-phosphate phosphohydrolase, hSPP2" J Biol Chem 278(2):1268-1272.

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

3-keto sphinganine

KSR

sphinganine
d18:0

LCB C-4 OHase

phytosphinganine
t18:0

LCFA-CoA

CS I^[2]

Lumen of endoplasmic
reticulum (ER)

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

Δ8 DES
Δ4 DES
FA-αOHase
(C-9 MT in fungi)

Δ8 DES
FA-αOHase

Bold font = ceramides

d18:1Δ8E/Z-hLCFA

t18:1Δ8E/Z-hVLCFA

+UDP-Glc

transport

Glc-ceramide
Glc-d18:2 4E,8E/Z-hLCFA
Glc-d18:1 8E/Z-hLCFA
Glc-t18:1-hVLCFA

Golgi

t18:1Δ8E/Z-hVLCFA

PI

IPCS^[3]

DAG

GIPC

↑ 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
↑ 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
↑ 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。

↑ 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
↑ Conzelmann A, Puoti A, Lester RL, Desponds C (1992) EMBO J, 11:457–466 PMID 1531630
↑ Svetek J, Yadav MP, Nothnagel EA (1999) J Biol Chem, 274:14724–14733 PMID 10329668

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[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

[3] Han G., Gupta S.D., Gable K., Niranjanakumari S., Moitra P., Eichler F., Brown R.H. Jr., Harmon J.M., Dunn T.M. (2009) "Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities" Proc. Natl. Acad. Sci. USA 106:8186-8191 PMID 19416851

[4] Levy M, Futerman AH (2010) "Mammalian ceramide synthases" IUBMB Life 62(5):347-356 PMID 20222015

[5] Michel C, van Echten-Deckert G. (1997) "Conversion of dihydroceramide to ceramide occurs at the cytosolic face of the endoplasmic reticulum" FEBS Lett 416(2):153-155 PMID 9369202

[6] 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

[7] Ferlinz K, Kopal G, Bernardo K et al. (2001) "Human acid ceramidase: processing, glycosylation, and lysosomal targeting" J Biol Chem 276(38):35352-35360.

[8] Coant N, Sakamoto W, Mao C, Hannun YA (2015) "Ceramidases, roles in sphingolipid metabolism and in health and disease" Adv Biol Regul 63:122-131

[9] Ogawa C, Kihara A, Gokoh M, Igarashi Y (2003) "Identification and characterization of a novel human sphingosine-1-phosphate phosphohydrolase, hSPP2" J Biol Chem 278(2):1268-1272.

[10] 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

[11] 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

[12] 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

[13] 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

[14] Conzelmann A, Puoti A, Lester RL, Desponds C (1992) EMBO J, 11:457–466 PMID 1531630

[15] Svetek J, Yadav MP, Nothnagel EA (1999) J Biol Chem, 274:14724–14733 PMID 10329668

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@@ Line 2: / Line 2: @@
 ===Ceramide synthesis===
 {{Twocolumn|
-Dihydroceramide (DHCer) is formed by acylation of sphinganine (d18:0) by ceramide synthases. 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. Synthesis of Cer proceeds at the lumen of the endoplasmic reticulum (ER), but the later processing may occur at different locations.<ref>Tidhar R, Futerman AH. “The complexity of sphingolipid biosynthesis in the endoplasmic reticulum” Biochim Biophys Acta. 2013;1833:2511-8. PMID 23611790</ref>
+Ceramide is synthesized at the cytosolic surface of the endoplasmic reticulum (ER), and is transferred to Golgi by CERT (ceramide transfer protein).<ref>Tidhar R, Futerman AH (2013) "The complexity of sphingolipid biosynthesis in the endoplasmic reticulum" Biochim Biophys Acta 1833:2511-8. PMID 23611790</ref><ref>Yamaji T, Hanada K (2014) "Sphingolipid metabolism and interorganellar transport: localization of sphingolipid enzymes and lipid transfer proteins" Traffic 16: 101-122. PMID </ref>
+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.
 |
-スフィガニン (d18:0) がセラミド合成酵素でアシル化され、ジヒドロセラミド (DHCer) ができます。各 DHCer は不飽和化酵素によりセラミド (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。セラミド合成までは小胞体膜上でおこなわれ、その後のプロセスは各所に別れます。
+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。
 }}