Category:LBSC
Cerebroside
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Glucosylceramide (GlcCer)
GlcCer is widely observed not only in Animal, Plant or Fungi kingdoms, but also in Protozoa Kingdom[1]. Ceramide structures (hydrocarbon chain length, the number and position of double bonds, existence of hydroxy and other modification groups) may vary, and become complex especially in Plant and Fungi Kingdoms, and Protostomia [2]. In Animal Kingdom, GlcCer is the basic structure for different derivative series such as Globo, Lacto, and Ganglio Series. In Protostomia, GlcCer is the major ceramide in its nerve tissue, e.g. shrimp brain [3], and its amide-linked fatty acids do not contain hydroxy groups. GlcCer in plants contains many α-hydroxy fatty acids. In some cold-resistant plants ω9-unsaturated fatty acids are detected. In Mammalia (of Deuterostomia), GlcCer is major in the spleen, blood, and skin. Gaucher's disease is an inborn metabolic disorder in which GlcCer accumulates in the liver and spleen because of the deficiency of the enzyme glucocerebrosidase to dissociate glucose from the ceramide structure [4]. |
GlcCerは系統発生的にみると動物の各組織に広く分布するだけでなく、植物界や菌界、原生生物界にも含まれます。セラミド構造（炭化水素の鎖長、二重結合の数と位置、水酸基の有無、修飾基の有無など）の組み合わせは多岐にわたり、特に植物界や菌界、旧口動物のセラミドは複雑です。動物界において、GlcCerはさまざまな糖鎖を持つ糖脂質の基本構造になり、グロボ系列、ラクト系列、ガングリオ系列などが生成されます。旧口（前口）動物の神経系にはGlcCerが多く含まれ（例えばエビ）、セラミド骨格の脂肪酸に水酸基を含みません。対して、植物は α-水酸化の脂肪酸が多く、耐冷性植物の一部からは ω9-不飽和の脂肪酸も見いだされます。後口動物の哺乳綱において、GlcCerは、脾臓、血液、皮膚などに多く含まれます。 先天性代謝異常症であるゴーシェ (Gaucher) 病は、GlcCerを分解するグルコセレブロシダーゼが欠損し、肝臓や脾臓にGlcCerが蓄積して発症します。 |
Galactosylceramide (GalCer)
GalCer has been observed in Eubacterial Domain, but not in Protozoa, Plant, or Fungi (except Ascomycota). It is widely observed in Animal Kingdom, but not in Ecdysozoa (cuticle-shedding animals) of Protostomia. Its ceramide structure differs widely as in GlcCer but not so complex as GlcCer in Plant and Fungi. GalCer is the basic structure for sulfatide (3-O-sulfogalactosylceramide or SM4) and Gala Series often found in Annelida (segmented worm). In Mammalia (of Deuterostomia), GalCer is major in the nerve tissue, especially myelin sheath, whose amido-linked fatty acids are hydroxylated at the C-2 position for more than 50%. Krabbe disease (globoid cell leukodystrophy) is an inborn metabolic disorder in which a small amount of psychosine (galactosylsphingosine, i.e., the lyso form of GalCer) induces demyelination because of the deficiency of the enzyme galactosylceramidase [5]. α-GalCer, found from Porifera (marine sponge), in which galactose is α-bonded to ceramide (not the usual β-bond), uniquely binds to human or mouse NKT cells and is considered a potent anti-tumor agent.[6] Recently, α-linked GlcCer and GalCer were reported in NKT cells in trace amount[7]. |
GalCerは真正細菌に存在しますが、原生生物界、植物界、菌界（子嚢菌を除く）では報告がありません。動物界に広く分布しますが旧口動物である脱皮動物には確認されていません。セラミド構造は、GlcCerと同様に多様ですが、植物や菌類のGlcCerほど複雑ではありません。GalCerはスルファチド (3-O-硫酸化ガラクトシルセラミドまたはSM4) や環形動物門に多く含まれるガラ系列の基本構造です。 後口動物である哺乳綱では神経系、特にミエリン鞘にGalCerが多く含まれ、その脂肪酸の50%以上は、C2位が水酸化されています。 クラッベ病（グロボイド細胞ロイコジストロフィー; GLD）はガラクトシルセラミダーゼの欠損により微量のサイコシン（ガラクトシルスフィンゴシン、つまり GalCer のリゾ体）が蓄積して脱髄（ミエリンの破壊）を起こす遺伝性疾患です。また、海綿動物門に発見されたα-GalCerは、ガラクトースがセラミドに（通常のβでなく）α結合しており、ヒトやマウスのナチュラルキラーT (NKT) 細胞に特異的に結合し抗腫瘍効果がみられます。α結合型の GlcCer および GalCer はNKT細胞に微量に存在します。 |
- ↑ Tan RX, Chen JH. "The cerebrosides" Nat Prod Rep. 2003;20:509-34.PMID 14620845, Yu R.K. Yanagisawa M. Ariga T. Glycosphingolipid Structures,in Comprehensive Glycoscience Vol.1,pp. 73-122,doi 10.1016/B978-044451967-2/00003-9, Itonori S, Sugita M. Glycophylogenetic Aspects of Lower Animals. in Comprehensive Glycoscience Vol.3, pp. 253-84, doi 10.1016/B978-044451967-2/00050-7 (J.P. Kamerling, ed.) Elsevier, Oxford (UK). (2007)
- ↑ Sphingoid base chain may terminate with an isopropyl group in spongia, annelida, echinodermata, and bacteria. Terminal isobutyl or sec-pentyl group has been found only in echinodermata. Methylated or cyclopropane-containing sphingoid base is found in spongia, echinodermata, protochordata, and fungi.
- ↑ Okamura N, Stoskopf M, Hendricks F, Kishimoto Y. "Phylogenetic dichotomy of nerve glycosphingolipids" Proc Natl Acad Sci, 1985 82:6779-6782 PMID 3863128
- ↑ Brady RO, Kanfer JN, Shapiro D. "Metabolism of glucocerebrosides. II. Evidence of an enzymatic deficiency in Gaucher's desease" Biochem Biophys Res Commun. 1965;18:221-5 PMID 14282020
- ↑ Suzuki K. "Globoid cell leukodystrophy (Krabbe's disease): update" J Child Neurol. 2003;18:595-603.PMID 14572137, Suzuki K. "Evolving concept of the pathogenesis of globoid cell leukodystrophy (Krabbe disease)" Proc Jpn Acad Ser B Phys Biol Sci 2003; 79:1-8
- ↑ Kitamura H, Iwakabe K, Yahata T, Nishimura S, Ohta A, Ohmi Y, Sato M, Takeda K, Okumura K, Van Kaer L, Kawano T, Taniguchi M, Nishimura T. "The natural killer T (NKT) cell ligand alpha-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells" J Exp Med. 1999; 5;189(7):1121-8. PMID 10190903
- ↑ Kain L et al. Immunity 41(4), 543-554, 2014
Cerebrosides in Mammals
Lipids in Heart Muscle
| Lipid (% wet weight) | Phospholipid (% dry weight) | Phosphatidylethanolamine PE (% dry weight) |
Phosphatidylcholine PC (% dry weight) |
Sphingomyelin (% dry weight) | Cerebroside (% dry weight) | Total cholesterol (% dry weight) | |
|---|---|---|---|---|---|---|---|
| Human | 8.3 | 6.3 - 7.5 | 1.4 - 2.8 | 3.3 - 5.7 | 0.2 - 0.5 | - | - |
| Cow | 3.1 - 19.5 | 7.4 - 11.8 | 5.3 | 4 | 0.5 | 2 | 0.4 (free) |
| Rat | 0.4 - 2.4 | 5 - 8 | 0.84 (% wet) | 2 (% wet) | 0.14 (% wet) | 1.4 | 0.4 - 0.6 |
| 生化学データブック[I] 14. 臓器・組織の成分、心臓 脂質 p1636 1981 日本生化学会編 東京化学同人 ISBN 978-4-807901-74-6 | |||||||
Lipids in Rat Testis
| Fraction | Total Lipid (mg/mg protein) | Phosphate (ug/mg protein) | Phospholipid (% total lipid) |
Neutral Lipid (% total lipid) |
Cerebroside (% total lipid) | Sulfated glycolipid (nmol/g total weight) |
|---|---|---|---|---|---|---|
| Total testis | 0.40 | 62.88 | 62.9 | 34.6 | 2.5 | 556 ± 34 |
| Golgi | 1.26 | 18.49 | 58.3 | 39.4 | 2.3 | - |
| Remnant granule | 0.60 | 19.67 | 29.5 | 68.0 | 2.5 | - |
| Microsome | 0.63 | 53.21 | 83.8 | 14.5 | 1.7 | - |
| Lipid corpuscle | > 19 | 12 | 1.5 | 98.5 | - | - |
| Keenan TW et al. "Lipid composition of subcellular fractions from rat testis"Biochim Biophys Acta 1972; 270:433-443, PMID 4340988 Suzuki A et al. "Decrease of seminolipid content in the testes of rats with vitamin A deficiency determined by high performance liquid chromatography"J Biochem 1977; 82:461-7 PMID 91479 | ||||||
Cerebroside and Sulfatide Ratio in Animal Brain
| Animal | Kerasin (GalCer with straight fatty-acyl chain) |
Phrenosin (GalCer with hydroxy fatty-acyl chain) |
Sulfatide |
|---|---|---|---|
| Human cinerea (gray matter) | 25 | 52 | 23 |
| Human alba (white matter) | 28 | 47 | 25 |
| Cow cinerea | 15 | 56 | 29 |
| Cow alba | 35 | 48 | 17 |
| Dog | 21 | 57 | 22 |
| Cat | 21 | 60 | 19 |
| Mouse (4 weeks) | 24 | 56 | 20 |
| Rat (10 days) | 35 | 42 | 23 |
| Rat (35 days) | 21 | 61 | 18 |
| Rabbit | 13 | 66 | 21 |
| Guinea pig | 28 | 54 | 18 |
| Sheep | 27 | 47 | 26 |
| Chicken | 44 | 37 | 19 |
| Tuna | 50 | 25 | 25 |
| Shark | 44 | 24 | 32 |
| (weight %) From: Yamakawa T, Nishimura S. "Cerebroside composition in animal brain" Jpn J Exp 1966; 36:101-2 PMID 5297247 | |||
Fatty acid composition of bovine brains
| Nonhydroxy fatty acid (adjusted GC peak %) | Hydroxy fatty acid | ||||||
|---|---|---|---|---|---|---|---|
| fatty acid | Ceramide | Sphingomyelin | Cerebroside | Sulfatide | fatty acid | Cerebroside | Sulfatide |
| 12:0 | - | 12h:0 | 0.4 | 0.3 | |||
| 13:0 | - | 13h:0 | 0.2 | 0.2 | |||
| 14:0 | 0.6 | 0.3 | 0.2 | 0.8 | 14h:0 | 0.8 | 3.9 |
| 15:0 | 0.2 | 0.1 | tr. | 0.3 | 15h:0 | tr. | 0.3 |
| 16:0 | 4.5 | 5.9 | 3.5 | 4.1 | 16h:0 | 0.1 | 0.7 |
| 16:1 | 0.4 | tr. | 0.1 | 0.7 | 16h:1 | tr. | 1.7 |
| 17:0 | tr. | 0.3 | tr. | tr. | 17h:0 | 0.2 | 0.9 |
| 18:0 | 35.2 | 40.1 | 5.8 | 3.3 | 18h:0 | 16.2 | 12.3 |
| 18:1 | 2.1 | 0.7 | 2.7 | 5.2 | 18h:1 | - | - |
| 19:0 | 0.1 | 0.1 | 0.2 | 0.3 | 19h:0 | 0.4 | 0.3 |
| 20:0 | 1.0 | 0.4 | 0.6 | 0.3 | 20h:0 | 0.5 | 0.7 |
| 20:1 | 0.5 | tr. | 0.3 | 0.4 | 20h:1 | - | - |
| 21:0 | tr. | tr. | - | - | 21h:1 | - | - |
| 22:0 | 3.3 | 3.5 | 3.6 | 3.5 | 22h:0 | 5.8 | 7.7 |
| 22:1 | 0.5 | 0.6 | 0.6 | 0.6 | 22h:1 | - | - |
| 23:0 | 3.7 | 2.8 | 5.2 | 3.1 | 23h:0 | 8.9 | 6.5 |
| 23:1 | 1.0 | 1.0 | 1.2 | 0.8 | 23h:1 | - | - |
| 24:0 | 9.8 | 10.7 | 17.4 | 17.8 | 24h:0 | 30.1 | 26.0 |
| 24:1 | 18.4 | 24.6 | 39.3 | 39.5 | 24h:1 | 14.6 | 16.7 |
| 25:0 | 1.4 | 1.5 | 3.6 | 2.2 | 25h:0 | 7.0 | 4.5 |
| 25:1 | 3.0 | 3.3 | 6.2 | 5.2 | 25h:1 | 3.0 | 2.8 |
| 26:0 | 2.3 | 0.6 | 1.7 | 2.3 | 26h:0 | 3.9 | 3.8 |
| 26:1 | 3.6 | 2.6 | 7.6 | 8.5 | 26h:1 | 6.3 | 6.5 |
| 27:0 | 2.9 | - | - | - | 27h:0 | - | - |
| 27:1 | 1.8 | - | tr. | - | 27h:1 | - | - |
| From: O'Brien JS, Rouser G "The fatty acid composition of brain sphingolipids: sphingomyelin, ceramide, cerebroside, and cerebroside sulfate"J Lipid Res1964; 5:339-342.PMID 5873370 Per cent of FA of each column. No PUFA, trace amount of hydroxy FA in ceramide, no hydroxy FA in sphingomyelin. The total ratio of nonhydroxy to hydroxy acids in cerebroside and sulfatide were 42:58 and 77:23, respectively (77:13 in the original paper). Human brain has a similar composition. | |||||||
Sphingolipids in All Kingdoms
The table lists biological species from which sphingolipids were identified. Icons indicate representative species. The icons are used in sphingolipid references together with |
ここに示す分類表にはスフィンゴ脂質が報告された生物が記載されており、アイコンは代表種を表します。スフィンゴ脂質関連の文献にはこれらのアイコンの他、化学合成を表す |
Biosynthesis
In Mammalia, GlcCer is synthesized by ceramide glucosyltransferase (CGlcT) at the cytosolic membrane of the Golgi apparatus, and GalCer is synthesized by ceramide galactosyltransferase (CGalT) at the lumen of the endoplasmic reticulum (ER). These enzymes do not share any sequence similarity and CGlcT possesses its transmembrane region at the N-terminal (type III) whereas CGalT possesses it at the C-terminal (type I).[1] |
哺乳動物では、ゴルジ装置の細胞質側に局在するグルコシルセラミド合成酵素（CGlcT）によって GlcCer が、小胞体の内腔側に局在するガラクトシルセラミド合成酵素（CGalT）によって GalCer が作られます。これらの酵素は配列相同性が無く、CGlcT は膜貫通領域が N 末端側（III型酵素）、CGalT は C 末端側（I型酵素）です。 |
| GlcCer | GalCer | |
|---|---|---|
| Enzyme | CGlcT (EC 2.4.1.80) | CGalT (EC 2.4.1.45) |
| Reaction | Ceramide + UDP-glucose → GlcCer + UDP | Ceramide + UDP-galactose → GalCer + UDP |
| Location | Golgi (outside) → flipflop → Golgi (inside) | ER lumen |
Since all glycolipid synthesizing enzymes (except for CGlcT and CGalT) reside at the lumen of the Golgi apparatus, GlcCer must be flip-flopped from the cytosolic side to the lumen by an eyzyme called flippase. To synthesize GalCer, UDP-galactose and ceramide must transport the ER membrane. UDP-galactose transporter 2 (UGT2) is considered to be responsible. GalT can also work on glycerolipid, and synthsizes sulfated glyceroglycolipid in mammalian testis, called seminolipid. |
CGlcT, CGalT 以外の糖脂質合成酵素はゴルジ装置の内腔側にあり、GlcCer はゴルジ膜の細胞質側から内腔側にフリッパーゼと呼ばれる酵素で移動（フリップフロップ）します。GalCer の場合は、UDPガラクトースとセラミドが小胞体膜を通過します。UDPガラクトーストランスポータ2 (UGT2) が関与するようです。 CGalTはグリセロ脂質にも作用し、精巣の硫酸化グリセロ糖脂質であるセミノリピドも合成します。 |
- ↑ Sprong H, Degroote S, Nilsson T, Kawakita M, Ishida N, van der Sluijs P, van Meer G "Association of the Golgi UDP-galactose transporter with UDP-galactose:ceramide galactosyltransferase allows UDP-galactose import in the endoplasmic reticulum" Mol Biol Cell. 2003;4:3482-93 PMID 12925779
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