LIPID AHMAD FARIDI, SP, MKM

LIPID

AHMAD FARIDI, SP, MKM

PENDAHULUAN

 Lemak : bentuk padat

 Minyak : bentuk cair pada suhu ruang

 Zat lain : lipoprotein, kolesterol

 Sifat : larut dlm pelarut non polar sep. etanol, eter, kloroform dan benzena

Fungsi

 Sumber energi

 Sumber asam lemak esensial

 Alat angkut vitamin larut lemak

 Menghemat protein

 Memberi rasa kenyang dan kelezatan

 Sebagai pelumas

 Memelihara suhu tubuh

 Pelindung organ

KLASIFIKASI

1. LIPID SEDERHANA

2. LIPID MAJEMUK

3. LIPID TURUNAN

LIPID SEDERHANA

 Asam lemak

 Lemak netral: monogliserida, digliserida dan trigliserida (ester asam lemak dan gliserol)

 Ester asam lemak dan alkohol BM tinggi :

malam, ester sterol, ester nonsterol, vit. A dan vit. D

LIPID MAJEMUK

 FOSFOLIPID

1. asam fosfatidat (sep. lecitin, sefalin) 2. plasmalogens

3. sfingomyelin

 GLIKOLIPID (mengandung KH)

 LIPOPROTEIN

LIPID TURUNAN

 Turunan dari lipid sederhana dan majemuk.

Bentuk cincin

 Sterol : kolesterol, ergosterol, hormon steroid, vit D, garam empedu

 Lain-lain : karotenoid, vit. E, vit. K

ASAM LEMAK

 Satu rantai atom karbon dan hidrogen

 Jml atom karbon biasanya genap, tetapi pjg berbeda

 Asam lemak rantai pendek (4-6 atom C)

 Asam lemak rantai sdg (8-12 atom C)

 Asam lemak rantai pjg (14-18 atom C)

 Asam lemak rantai sgt pjg (> 20 atom C)

IKATAN ATOM KARBON

1. ASAM LEMAK JENUH

 Tdk dpt lagi menerima atom hidrogen

 Semua ikatan diantara karbon berupa ikatan tunggal CH3 CH2CH2 COOH

2. ASAM LEMAK TAK JENUH

 Ada ikatan rangkap

 Msh dpt menerima aton hidrogen

 CH3-(CH2)nCH=CH(CH2)n-COOH

n = 4 butyric acid (butanoic acid) n = 6 caproic acid (hexanoic acid) n = 8 caprylic acid (octanoic acid) n = 10 capric acid (decanoic acid)

n = 12: lauric acid (n-dodecanoic acid; C_12:0)

n = 14: myristic acid (n-tetradecanoic acid; C_14:0) n = 16: palmitic acid (n-hexadecanoic acid; C_16:0) n = 18; stearic acid (n-octadecanoic acid; C_18:0) n = 20; arachidic (eicosanoic acid; C_20:0)

n= 22; behenic acid n = 24; lignoceric acid n = 26; cerotic acid

 16:1, 9 w7: palmitoleic acid (cis-9-hexadecenoic acid)

 18:1, 9 w9: oleic acid (cis-9-octadecenoic acid)

 18:1, 9 w9: elaidic acid (trans-9-octadecenoic acid)

 22:1, 13 w9: erucic acid (cis-13-docosenoic acid)

 24:1, 15 w9: nervonic acid (cis-15-tetracosenoic acid)

ASAM LEMAK ESENSIAL

 Dibutuhkan tbh dan tidak dpt mensintesisnya

 Asam linoleat dan linolenat

 Turunan asam lemak yg berasal dari ALE adalah :

 asam arakidonat dan EPA dan DHA

TRIGLISERIDA

 Sebgn besar lemak dan minyk dlm alam tdd 98-99% trigliserida

 Ester gliserol suatu alkohol trihidrat dn asam lemak (triasil gliserol)

 Tiga asam lemak sama trigliserida sederhana

 Tk kepdtan meningkat dg bertmbh pjg rantai asam lemak dan tk kejnhan

FOSFOLIPID

 Terdpt dlm sel hidup, dibentuk di hati

 Trigliserida dimana AL pd posisi karbon 3 ditempati gugus fosfat dan gugus

mengandung N

 Gugus basa menentukan nama fosfolipid : fosfatidilkolin (lesitin), terdpt gugus kolin

 Fungsi : membtk membran

 Sifat polar dan non polar

 Gugus fosfat (-) dan basa (+) dpt menarik air (hidrofilik)

 Asam lemak tdk bermuatan (hidrofobik/lipofilik)

 Sifat amfilitik mempunyai daya tarik yg sama thd zat larut air dan lemak vit dan hormon keluar

masuk

 Dlm drh sebagai alat angkut lipid

STEROL

 Sekelompok senyawa yg mempunyai

karakteristik struktur cincin kompleks steroid

 Kolesterol dlm jaringan hewan, ergosterol dlm khamir dan berasitosterol dlm nabati

Kebutuhan lemak

 WHO, 1990 : menganjurkan konsumsi 15- 30% dari kebutuhan energi total

 10% dari kebutuhan energi total berasal dari lemak jenuh

 3-7% dari lemak tidak jenuh ganda

 Kolesterol dianjurkan adalah ≤ 300 mg sehari

Sumber

 Minyak nabati (minyak kelapa, kacang- kacangan, dll)

 Mentega, margarin

 Lemak hewan

 Daging, susu, kuning telur, dll

 Kolesterol hny dlm mknan asal hewan (hati, ginjal, kuning telur, daging, susu, keju, udang, kerang)

 Lemak (tgc) mell sistem limfe dg membtk kilomikron

 Ke jrg adiposa dan otot (lipoprot lipase)

 Lipogenesis (adiposa dan hati)

 TGC pd adiposa, cdgan energi

 Asam lemak bebas dilepaskan ke peredran darah utk dibawa ke seluruh jaringan (kec. Otak dan sel drh merah) utk

digunakan sbg energi atau diesterifikasi menjadi asilgliserol

 Di hati kelebihan asam lemak bebas diubah menjadi benda keton (ketogenesis)

 Benda keton dibawa ke jaringan ekstra hepatik sbg sumber energi pada saat kelaparan panjang

PENCERNAAN

 PENCERNAAN

proses emulsifikasi, agar lemak dpt

bercampur baik dg air dan enzim dpt bekerja mencerna lemak

MULUT : kunyah, campur dg air liur danditelan, kelenjar ludah mengeluarkan lipase

ESOFAGUS : tdk ada pencernaan

LAMBUNG

 Lipase lingual dlm jml terbts hidrolisis TGC digliserida dan asam lemak

 Lemak susu lbh byk dihidrolisis

 Lipase lambung menghidrolisis lemak dlm jml terbts

USUS HALUS

 Kolesistokinin ktg empedu cairan empedu mengemulsi lemak

 Lipase pankreas dan ddg usus hls menghidrolisis lmk digliserida,

monogliserida, gliserol dan asam lemak

 Fosfolipase dr pankreas menghidrolisis fosfolipid asam lemak lisofosfogliserida

 Kolesterol esterase dari pankreas menghidrolisis ester kolesterol

 Usus besar : sedikit lemak darikolesterol dlm serat mknan dikeluarkan melalui feses

ABSORBSI DAN TRANSPORTASI

 Absorbsi di jejunum

 Hsl pencernaan lipid diabsorbsi dlm membran mukosa usus halus dg cara difusi pasif

 Protein mengikat asam lemak sel

 Monogliserida dan AL rantai pjg trigliserida

 TGC, kolesterol dan fosfolipid dg protein lipoprotein

ABSORBSI LIPID DLM DARAH

HASIL PENCERNAAN LIPID ABSORBSI

Gliserol

AL rnt pendek AL rnt menengah

Lgsg ke drh

AL rnt pjg monogliserida

Diubah menjd TGC dlm sel usus hls

TGC

Kolesterol fosfolipid

Membtk kilomikron, msk dlm limfe dlm aliran drh

PENGARUH HORMON

 INSULIN

Menghmbt utilisasi lemak dan meningkatkan sintesis lemak dg :

1. Mengaktifkan lipoprotein lipase hidrolisis TGC

2. Menurunkan aktifitas hormon sensitif lipase lemak dr jaringan adipos AL bebas

 TIROKSIN

Meningkatkan mobilisasi lemak (tak lgsg) dg meningkatkan kec. Metab. Energi pd sel

 GLUKOKORTIKOID

Meningkatkan mobilisasi lemak dg

meningkatkan permeabilitas membran sel lemak

 ADRENOKORTIKOID

Meningkatkan mobilisasi lemak (lgsg) aktifitas HSL

 EPINEFRIN DAN NOREPINEFRIN

Meningkatkan mobilisasi lemak dg menstimulasi aktifitas HSL pelepasan AL dr sel lemak metabolisme

KOMPOSISI LIPOPROTEIN

LP TGC

(%)

KOLESTEROL (%)

FOSFO LIPID (%)

PROTEIN (%)

Kilomikron 80-90 2-7 3-6 1-2

VLDL 55-65 10-15 15-20 5-10

LDL 10 45 22 25

HDL 5 20 30 45-50

Lipid Transport in Blood

 Lipids are not water soluble

◼ Blood is mainly water…

 Pack lipids in protein

◼ Chylomicrons

 Made in the enterocytes (small intestine)

◼ Lipoproteins

(lipids and proteins)

 VLDL, LDL, HDL made in liver

Groff & Gropper, 1999

KILOMIKRON

 LP yg mengangkut lipid dr sal cerna (usu halus) aliran darah

 Sebgn besar TGC dari makanan

 Dlm aliran drh TGC dipecah gliserol dan AL bebas oleh enzim lipoprotein lipase yg berada pd sel endotel kapiler

 Diabsorbsi sel otot, digunakan sbg smbr

energi atau diubah TGC dan disimpan dlm sel lemak

VLDL

 Sisa kilomikron hati dimetab

 Hati mensintesis TG dari kolesterol

 VLDL LP yg dibtk dlm hati

 VLDL meninggalkan hati LP lipase

memcah TGC yg ada pd VLDL dan menikat kolesterol dlm sirkulasi drh

 VLDL LDL

LDL

 Bersirkulasi dlm tbh dan dibawa ke sel otot, lmk dan sel lain

 Kolesterol dan fosfolipid pembuatan membran sel, hormon atau disimpan

 Reseptor LDL dlm hati mengeluarkan LDL dari sirkulasi

 Dlm pembuluh drh ada sel perusak yg dpt mengoksidasi tdk dpt msk kembali kealiran drh

 Kolesterol yg byk dlm LDL menumpuk dlm sel perusak plak

 Plak bercampur dg protein dan ditutupi sel otot dan kalsium aterosklerosis

HDL

 Sel-sel lemak membebaskan gliserol dan asam lemak kolesterol dan fosfolipid dikembalikan ke dlm aliran drh

 Hati dan usus hls memproduksi HDL HDL mengambil kolesterol dan fosfolipid dlm

aliran drh lipoproein lain hati dikeluarkan tbh

Sumber pembtkan asam lmk rantai panjang adalah makanan dan asetil koA

Asetil koA dari hsl β oksidasi msk ke dlm siklus kreb’s, prekursor utk sintesis kolesterol (koleterogenesis) dan steroid dan di hati kelebihan asetil koA dibtk menjadi benda keton

Adipose Tissue

 Adipocytes are the major storage site for triglycerides

◼ Contains up to approximately 85% lipid

◼ Contains approximately 90%

DM

 What is the DM content of muscle?

◼ Only 20-25% DM!!!

METAB ASAM LEMAK DAN GLISEROL

 TGC proses lipolisis gliserol dan AL

 Gliserol (5% dr lemak) jalur metab di antara glukosa dan piruvat glukosa dan piruvat asetil KoA siklus TCA

 AL dipecah mell proses oksidasi unit yg tdd 2 karbon mengikat 1 molekul KoA

asetil KoA (proses beta oksidasi) siklus TCA energi atau membentuk lemak

 Sel tubuh dpt membuat glukosa dr piruvat dan ikatan 3 karbon lain

 Glukosa tdk dpt dibuat dr pecahan 2 karbon yg dihslkan asam lemak

 Lmk tdk dpt digunakan sbg sumber energi organ tbh yg memerlukan glukosa (otak dan saraf)

 Pembtkan glukosa dr gliserol tdk berarti

Triglyceride Catabolism

 Hydrolysis of triglycerides yields

◼ One glycerol

◼ Three FFA

 Glycerol is used for energy or gluconeogenesis

◼ Glycerol enters glycolytic pathways

 FFA are oxidized to CO₂ and H₂O

◼ -Oxidation

◼ Takes place in mitochondria

 FA’s cannot be used for gluconeogenesis

GLYCERIDES

O OH OH

R O

O OH O

R O

R

O

O

O

R O

R

O O

R

O

MONOGLYCERIDE DIGLYCERIDE TRIGLYCERIDE

Function: storage of energy in compact form and cushioning

Beta Oxidation

β-oxidation – Saturated Fatty Acids

 Fatty acids are a rich energy source

 Oxidation occurs only in mitochondria of specific tissues

◼ Skeletal & cardiac muscle

◼ Liver

◼ Adipose tissue

β-oxidation – Saturated Fatty Acids

 Cleaves two carbons at a time from the carboxyl end

◼ Produces NADH, FADH₂ and acetyl-CoA

 Acetyl-CoA enters TCA cycle

 NADH and FADH₂ enter electron transport chain

◼ Yield ATP

O

CH₃–C–CoA

=

1

^st

Step in Beta-Oxidation

Activation: Use 2 ATP equivalents to attach CoA

Oxidation: FAD takes H, Creates new double bond between C 2 & 3 Hydration: add

water across double bond

Oxidation: NAD takes H’s, new O=

formed Addition &

Cleavage: Add new CoA, cleave off

acetyl-CoA. Lose 2 C

C₁ C₂

C₃ C₄

C₅ C₆

C₇ C₈

C₉ C₁₀

C₁₁C₁₂

C₁₃C₁₄

C₁₅C₁₆ CoA

O O

-Oxidation

 Palmitate (16:0)

◼ Carbon–carbon cleavage

 1 FADH₂ + 1 NADH  5 ATP (via electron transport chain)

 7 cleavage points x 5 ATP = 35 ATP

◼ Oxidation of acetyl–CoA

 8 acetyl-CoA units entering TCA cycle x 12 ATP = 96 ATP

◼ Total ATP  35 + 96 = 131 – 2 ATP = 129 ATP

 2 ATP used for fatty acid activation and entry into mitochondria

1st 2nd 3rd 4th 5th 6th last

Summary of

β-oxidation

Beta Oxidation

Special Considerations

 Why doesn’t muscle utilize fatty acids during exercise?

◼ Requires oxygen available for oxidation

◼ Use anaerobic fermentation of glucose to lactate preferentially

 Why don’t red blood cells utilize fatty acids for their energy metabolism?

◼ No mitochondria in RBC’s

Unsaturated Fatty Acid’s

 Unsaturated fatty acids must be saturated before beta-oxidation

◼ Isomerase converts cis to trans and moves double bond to the 2 position

◼ In polyunsaturated: need reductase

 Add H’s to second double bond

Odd Chain Fatty Acids

 Minor species, odd chains made by microbes, degradation of AA’s

 B-oxidation occurs to end:

◼ Left with 3 carbon + CoA (propionyl CoA)

 Vitamin B12 cobalamin co-enzyme

◼ Catalyzes conversion of propionyl CoA (3 C) to succinyl-CoA (4 C)

 Citric acid cycle intermediate

Refsum’s Disease

 A rare inherited disorder in which phytanic acid accumulates in tissues:

 Possibly due to defect or deficiency of the - hydroxylase

 Nerve and retinal damage

 Spastic movement

 Bone and skin changes

 Treatment: Avoidance of chlorophyll-containing foods, including meat from plant-eating animals

H₃C

CH₃ CH₃ CH₃ CH₃

COOH

PHYTANIC ACID

A plant derived fatty acid with 16 carbons and branches at C 3, C7, C11 and C15. Present in dairy products and ruminant fats.

A peroxisome responsible for the metabolism of phytanic acid is defective in some individuals. This leads to a disease called Refsum’s disease

Refsum’s disease is characterized by peripheral polyneuropathy, cerebellar ataxia and retinitis pigmentosa

Hepatic Ketone Body Synthesis

figure 20-11

 Occurs during starvation or prolonged exercise

◼ result of elevated FFA

 high HSL activity

◼ High FFA exceeds liver energy needs

◼ KB are partially oxidized FA

 7 kcal/g

Utilization of Ketone Bodies by Extrahepatic Tissues figure 20-11

 When [KB] = 1-3mM, then KB oxidation takes place

◼ 3 days starvation [KB]=3mM

◼ 3 weeks starvation [KB]=7mM

◼ brain succ-CoA-AcAc-CoA transferase induced when [KB]=2-3mM

 Allows the brain to utilize KB as energy source

 Markedly reduces

◼ glucose needs

◼ protein catabolism for gluconeogenesis

Ketone Bodies (Ketogenesis)

 Acetone, acetoacetate, β-hydroxybutyrate

 Produced in liver from incomplete oxidation of fatty acids

 Used by extra-hepatic (non-liver) tissue in preference to fatty acids as energy

◼ Turned into acetyl-CoA

 Excess spills over into urine or exhaled as acetone

Ketone Bodies

Ketone Bodies

Ketone Bodies

Lipid Synthesis

Figure 25.10

Fatty Acid Synthesis vs.

Degradation

Intermediates

Site

Enzymes Redox

Coenzymes

Synthesis Degradation

Linked to SH in Linked to CoASH Proteins

(Acyl Carrier Proteins)

Cytosol Mitochondria

Components of Separate Polypeptides Single Peptide

NADP⁺ / NADPH NAD⁺ / NADH

Fatty Acid Biosynthesis

 Occurs in cytosol

 Starts with acetyl CoA

 Problem:

 Most acetyl CoA produced in mitochondria

 Acetyl CoA unable to traverse mitochondrial membrane

Mitochondrial membrane

Cytosol Mitochondria

Glucose Pyruvate Pyruvate Acetyl CoA Fatty Acids

Oxalo- acetate Citrate

Citrate Acetyl CoA

ATP-Citrate Lyase

Amino acids

Pyruvate Dehydrogenase

Beta

Oxidation

Fatty Acids

Fatty Acid Biosynthesis:

Formation of Malonyl CoA

CH₃COSCoA + ATP + HCO₃^{- -}O₂CCH₂COSCoA

Acetyl CoA Carboxylase

+ ADP + P_i + H⁺ Malonyl CoA

• Committed step in fatty acid synthesis

• Reaction is irreversible

• Regulation of acetyl CoA carboxylase activity:

by palmitoyl CoA by citrate

• Malonyl CoA inhibits carnitine acyl transferase I

• Blocks beta oxidation

Fatty Acid Biosynthesis:

Role of Acyl Carrier Proteins

CH₃COSCoA CH₃CO-S-ACP

-O₂CCH₂COSCoA ^-O₂CCH₂CO-S-ACP

Acetyl Transferase

Malonyl Transferase

Acetyl ACP

Malonyl ACP ACP = Acyl carrier protein

Fatty Acid Biosynthesis:

Formation of Acetoacetyl ACP

CH₃CO-S-ACP + ^-O₂CCH₂CO-S-ACP

CH₃COCH₂CO-S-ACP + CO₂

Acetoacetyl ACP

-Ketoacyl ACP Synthetase

Fatty Acid Biosynthesis:

Formation of Butyryl ACP

CH₃COCH₂CO-S-ACP CH₃CCH₂CO-S-ACP

OH

H Acetoacetyl ACP

-D-Hydroxybutyryl ACP

-Ketoacyl ACP reductase

NADPH + H⁺

NADP⁺

CH₃C=C-CO-S-ACP

H

H

-Hydroxyacyl ACP dehydratase

- H₂O

Crotonyl ACP

CH₃CH₂CH₂CO-S-ACP

Butyryl ACP

2,3-trans- Enoyl ACP reductase

NADPH + H⁺ NADP⁺

Fatty Acid Biosynthesis:

Sources of NADPH

Pentose Phosphate Pathway:

CHO OH OH OH OP HO

CO₂^- OH OH OH OP HO

NADP⁺

NADPH

+ H⁺ NADP⁺

NADPH + H⁺

CO₂

OH OH OH OP O

Ribulose-5- phosphate 6-Phospho-

gluconate Glucose-6-

phosphate

Malic Enzyme:

HO-CH-CO₂^- CH₂CO₂^-

Malate

CO₂ NADP⁺

NADPH + H⁺

Malic Enzyme

CH₃CCO₂^- O

Pyruvate

Fatty Acid Biosynthesis:

Chain Elongation

CH₃CH₂CH₂CO-S-ACP ₊ ^-O₂CCH₂CO-S-ACP

CH₃CH₂CH₂COCH₂CO-S-ACP

CH₂CH₂CH₂CHCH₂CO-S-ACP CH₃CH₂CH₂C=CCO-S-ACP

H

H OH

Fatty Acid Biosynthesis:

Chain Elongation (Cont’d)

CH₃(CH₂)₃CH₂CO-S-ACP CH₃CH₂CH₂C=CCO-S-ACP

H

H

NADPH

+ H⁺ NADP⁺

CH₃(CH₂)₁₃CH₂CO-S-ACP

5 Cycles

Palmitoyl ACP

CH₃(CH₂)₁₃CH₂CO₂^-

Palmitate

Further Processing of Fatty Acids:

Elongation

CH₃(CH₂)₁₃CH₂CO₂^-

Palmitate

CH₃(CH₂)₁₃CH₂COCH₂COSCoA

CH₃(CH₂)₁₃CH₂CCH₂COSCoA

OH

H

NADH + H⁺

NAD⁺

Thiolase

Dehydrogenase

L- Configuration CH₃COSCoA

In mitochondria and at surface of

endoplasmic reticulum

Further Processing of Fatty Acids:

Elongation (Cont’d)

CH₃(CH₂)₁₃CH₂CCH₂COSCoA

OH

H

CH₃(CH₂)₁₃CH₂C=CCOSCoA

H

H

- H₂O Hydratase

CH₃(CH₂)₁₃CH₂CH₂CH₂COSCoA

Stearoyl CoA

NADPH + H⁺

NADP⁺ Dehydrogenase

Further Processing of Fatty Acids:

Unsaturation

CH₃(CH₂)₁₃CH₂CH₂CH₂COSCoA

CH₃(CH₂)₇C=C(CH₂)₇COSCoA + H₂O

H H

Stearoyl CoA

Oleoyl CoA

This reaction occurs in eukaryotes Endoplasmic reticulum membrane

Stearoyl CoA Desaturase O₂

Further Processing of Fatty Acids:

Polyunsaturation

CH₃(CH₂)₇C=C(CH₂)₇CO₂H

H H

Oleic acid

Plants: Further unsaturation occurs primarily in this region

Animals: Further unsaturation occurs primarily in this region

CO₂H (18:1^9)

9

Linoleic acid (18:2^{9, 12})

12 9

Linolenic acid (18:3^{9, 12, 15})

15 12 9

Essential dietary fatty acids in mammals

CO₂H

Formation of Arachidonate in Mammals

Linoleic acid

CO₂H

14 11 8 5

Arachidonic acid (20:45, 8, 11, 14

) (Eicosa-5,-8,11,14-tetraenoic acid)

As CoA ester:

1) Elongation

2) Desaturation x 2

Prostaglandins

CO₂H

Omega-3 Fatty Acids

CO₂H

CO₂H

w-3 double bond Eicosapentaenoic acid (20:55, 8, 11, 14, 17

)

Docahexaenoic acid (22:64, 7, 10, 13, 16, 19

)

• Found in fish oils, esp. cold water fish

• Important in:

Growth regulation

Modulation of inflammation Platelet activation

Lipoprotein metabolism

Metabolite Regulation of Fatty Acid Synthesis and Breakdown

Pyruvate Acetyl CoA Malonyl CoA

Palmitoyl CoA Citrate

Inhibits

Stimulates

Beta Oxidation Blocks

Glucose

Hormonal Regulation of Fatty Acid Synthesis and Breakdown

ATP cAMP AMPAdenylyl cyclase

Glucagon

Stimulates

Phosphodiesterase

Insulin

Stimulates

Activates Protein Kinase

Inactivates ACC by phosphorylation Inhibition of

fatty acid synthesis

Activates triacyl- glycerollipase

Inactivates lipase

Phospholipids

 the major components of cell membranes

◼ phosphoglycerides

O R

O R'

O P

O O

O O-

X O

fatty acids (hydrophobic tail) glycerol

phosphate

Phospholipids are generally composed of FAs, a nitrogenous base, phosphoric acid and either glycerol, inositol or sphingosine

O R

O R'

O P

O O

O O-

X O

fatty acids (hydrophobic tail) glycerol

phosphate

X = H (phosphatidic acid) - precursor to other phospholipids X = CH₂-CH₂-N⁺(CH₃)₃ phosphatidyl choline

X = CH₂-CH(COO^-)NH₃⁺ phosphatidyl serine X = CH₂-CH₂-NH₃⁺ phosphatidyl ethanolamine

Sphingomyelin

NH O

HO R

P

O O-

O

N(CH₃)+

R' O

usually palmitic acid

phosphatidyl choline (also can be ethanolamine)

Ether glycerophospholipids

 Possess an ether linkage instead of an acyl group at the C-1 position of glycerol

◼ PAF ( platelet activating factor)

◼ A potent mediator in inflammation, allergic response and in shock (also responsible for asthma-like symptoms)

◼ Plasmalogens: cis ,-unsaturated ethers

Ether glycerophospholipids

H2C CH O

CH2

O O P O

-O O

C O

CH₃

CH2 CH2 N CH3

CH3

CH3

platelet activating factor or PAF

H₂C CH O

CH₂ O

O P O

-O O

C O

CH₂ CH₂ N CH3

CH₃ CH₃

A choline plasmalogen H

H

Synthesis of Phosphatidic Acid

O^- O

O^- O

O

O

O CH₂OC-R₁

CHOC-R₂

CH₂OC-R₃ CHO₂C-R₂

CH₂O₂C-R₁

CH₂OH

CH₂O-P-O^- CH₂O₂C-R₁

CHO₂C-R₂ C=O

CH₂OH

CH₂O-P-O^- CH₂OH

CHOH CH₂OH

Dihydroxyacetone Phosphate (from glycolysis)

Glycerol

Phosphatidic acid

Diacylglycerol (important in cell signaling)

R₃COSCoA

Diacylglycerol acyltransferase

Triacylglycerol

Synthesis of

Glycerophospholipids

CH₂OH CH₂O₂C-R₁

CHO₂C-R₂

N N NH₂

O O

OH OH R₃NCH+ ₂CH₂OPOPO

R=H; CDP ethanolamine R=CH₃; CDP choline

CDP = cytidine diphosphate Diacylglycerol

+ Transferase

R₃=NH₃; Phosphatidylethanolamine R₃=N(CH₃)₃; Phosphatidylcholine

O^- O

CO₂^- CH₂O-P-O-CH₂CHNH₃ CH₂O₂C-R₁

CHO₂C-R₂

+

+

CO₂^- HOCH₂CHNH₃

HOCH₂CH₂NH₃

+ Serine

Ethanolamine O^- O CHO₂C-R₂ CH₂O₂C-R₁

CH₂O-P-O-CH₂CH₂R₃ +

+

Phosphatidylserine

Synthesis of Glycero- phospholipids (Cont’d)

O^- O CHO₂C-R₂ CH₂O₂C-R₁

CH₂O-P-O^- CH₂O-CDP CH₂O₂C-R₁

CHO₂C-R₂

Phosphatidic acid Cytidine diphosphate (CDP) diacylglycerol

Phosphatidyl- inositol

O^- O

OH OH HO

OH OH

CH₂O-P-O CH₂O₂C-R₁

CHO₂C-R₂

OH OPO₃H₂ H₂O₃PO

OH OH

OPO₃H₂

CH₂OH CH₂O₂C-R₁

CHO₂C-R₂

+

Diacylglycerol (DAG) Phospholipase C

Both IP₃ and DAG are

important second messengers in cell signaling pathways

Inositol-1,4,5- triphosphate (IP₃)

Synthesis of Glycero-phospholipids (Cont’d)

O^-

O O

O^- OH

CHO₂C-R₃ CH₂O₂C-R₄

CH₂O-P-O-CH₂CHCH₂-O-P-O-CH₂ CH₂O₂C-R₁

CHO₂C-R₂

CH₂O-CDP CH₂O₂C-R₁

CHO₂C-R₂

Cytidine diphosphate (CDP)

diacylglycerol Cardiolipin

Synthesis of Glycero-phospholipids (Cont’d)

O^- O

CH₂O-P-O^- CH₂OH

C=O

Dihydroxyacetone Phosphate

(from glycolysis)

O^- O

CH₂O-P-O-CH₂CH₂NH₃ CH₂-O-CH=CHR₁

CHO₂C-R₂

+

Plasmalogens

(Abundant in cardiac tissue and CNS)

Sphingolipids

OH NH₂

OH

NH₂ OH

HO R long chain hydrocarbon

attach fatty acid here

attach polar head group here sphingosine

Based on sphingosine instead of glycerol

Synthesis of Sphingolipids

+

CO₂^- HOCH₂CHNH₃

CH₃(CH₂)₁₄COSCoA +

HCO₃^-2 CoASH

3-Ketosphingosine synthase

CH₃(CH₂)₁₄CO-CHCH₂OH

NH₃⁺ 2S,3-Ketosphinganine 3 Steps

CH₃(CH₂)₁₂CH=CH-CH-CH-CH₂OH OH

CH₃(CH₂)_nCONH

Ceramide Palmitoyl CoA

Serine

trans

Synthesis of Sphingolipids (Cont’d)

CH₃(CH₂)₁₂CH=CH-CH-CH-CH₂OH CH₃(CH₂)_nCONH

OH

Ceramide

O^-

O ₊

CH₂O-P-O-CH₂CH₂N(CH₃)₃ CH₂O₂C-R₁

CHO₂C-R₂

Phosphatidylcholine Diacylglycerol

CH₃(CH₂)₁₂CH=CH-CH-CH-CH₂O-P-OCH₂CH₂N(CH₃)₃ CH₃(CH₂)_nCONH

OH O

O^-

+

Sphingomyelin

Cerebrosides Gangliosides

trans

trans

glycolipids

NH O

HO R

R' O

SUGAR polar head is a sugar

beta linkage

There are different types of glycolipids: cerebrosides, gangliosides, lactosylceramides

GLYCOLIPIDS

 Cerebrosides

 One sugar molecule

◼ Galactocerebroside – in neuronal membranes

◼ Glucocerebrosides – elsewhere in the body

 Sulfatides or sulfogalactocerebrosides

 A sulfuric acid ester of galactocerebroside

 Globosides: ceramide oligosaccharides

 Lactosylceramide

◼ 2 sugars ( eg. lactose)

 Gangliosides

 Have a more complex oligosaccharide attached

 Biological functions: cell-cell recognition; receptors for hormones

Gangliosides

 complex glycosphingolipids that consist of a ceramide backbone with 3 or more sugars

esterified,one of these being a sialic acid such as N-acetylneuraminic acid

 common gangliosides: G_M1, G_M2, G_M3, G_D1a, G_D1b, G_T1a, GT_1b, G_q1b

Ganglioside nomenclature

 letter G refers to the name ganglioside

 the subscripts M, D, T and Q indicate mono-, di-, tri, and quatra(tetra)-sialic-containing

gangliosides

 the numerical subscripts 1, 2, and 3 designate the carbohydrate sequence attached to

ceramide

Ganglioside nomenclature

 Numerical subscripts:

 1. Gal-GalNAc-Gal-Glc-ceramide

 2. GalNAc-Gal-Glc-ceramide

 3. Gal-Glc-ceramide