6 7 metabolisme lipid fix

( Komponen Lipid, Katabolisme Asam Lemak, ( Komponen Lipid, Katabolisme Asam Lemak, Biosintesis Asam Lemak)Biosintesis Asam Lemak)

COURSE CONTRACTCOURSE CONTRACT

COURSE TOPICSIntroduction of LipidsBiosynthesis of Fatty Acids and LipidsCatabolism of Fatty Acids (Beta Oxidation)Catabolism of Lipids and Metabolism of ketone body

MIDTERM TEST (UTS)Introduction of Vitamin and Mineral Soluble Water VitaminSoluble Lipids VitaminMineralIntroduction of Nucleic Acids (DNA & RNA)DNA Duplication / ReplicationTranskription & RNA ProcessingTranslation

ASSIGNMENTS• Groups divided into 12 groups.• Each groups present in themes:

a. Biosynthesis of Fatty Acids and Lipids (weeks 7)

b. Catabolism of Fatty Acids and Lipids (weeks 7)

c. Vitamin and Mineral (weeks 2 after midterm test)

d. Nucleic Acids & DNA Replication (weeks 3 after midterm test)

e. Transcription & RNA Processing (weeks 4 after midterm test)

f. Translation (weeks 4 after midterm test)• Each themes consist of 2 groups

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METABOLISME LEMAKPENDAHULUAN :

LEMAK adalah SENYAWA ORGANIK YANG TIDAK LARUT DALAM AIR, TETAPI LARUT DALAM PELARUT NON POLAR ( ETER, ALKO-HOL, BENZEN ); BERUPA ESTER DENGAN ASAM LEMAK.

KEPENTINGAN :

1. Unsur penting dalam makanan

2. Sumber energi tubuh

3. Sebagai isolator ( organ, listrik, saraf )

4. Membran sel

5. Sebagai lipoprotein.

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KLASIFIKASI : 1. LEMAK SEDERHANA : ( SIMPLE LIPID )

-. TRI ASIL GLISERIDA

-. MALAM

2. LEMAK CAMPURAN ( COMPOUND LIPID ) :

-. FOSFOLIPID -. SULFATIDA

-. GLIKOLIPID -. AMINO LIPID

3. LEMAK TURUNAN ( DERIVED LIPID ) :

. ASAM LEMAK . GLISEROL

. KOLESTEROL . BENDA KETON

TRIGLISERIDA O ASAM LEMAK O

O CH2-O-C-R1 H3C-CH2-CH2-CH2- ......-CH-C OH

R2-C-O-CH O O

CH2-O-C-R3 R -CH-C OH

PHYSIOLOGICAL ROLE OF LIPIDS

Energetic role (fuel molecules) Components of membranes (structural role) Precursors for many hormones (steroids) Signal molecules (prostaglandins) Protective role (lipids surround important organs) Enzyme cofactors (vitamin K) Electron carriers (ubiquinone) Insulation against temperature extremes

TRIACYLGLYCEROLS ARE HIGHLY CONCENTRATED ENERGY STORES•Triacylglycerols (TGs) and glycogen - two major forms of stored energy

TGs which are more efficient energy stores because: (1) They are stored in an anhydrous form (2) Their fatty acids are more reduced than monosaccharides.

•Fat breakdown about 50 % of energy in liver, kidney and skeletal muscles up to 95 % of energy cardiac muscle

•Fats are the major source of energy for: fasting animal organism in diabetes

• 1 g of triacylglycerols stores more than six times as much energy as a 1 g of glycogen

• Glycogen reserves are depleted in 12 to 24 hours after eating, triacylglycerols within several weeks.

• Fatty acids and glycerol - substances that are directly used as a fuel by mammalian organisms.

• Fatty acids (FA) and glycerol for metabolic fuels are obtained from triacylglycerols: (1) In the diet(2) Stored in adipocytes (fat storage cells)

• Free fatty acids occur only in trace amounts in cells

•For supplying of fatty acids as a fuel for organism, the triacylglycerols have to be digested

DIGESTION OF DIETARY LIPIDS

Lipids in diet: • triacylglycerols • phospholipids • cholesterolDigestion – in small intestine. Enzyme – pancreatic lipase.Lipase catalyzes hydrolysis at the C1 and C3 positions of TGs producing free fatty acids and 2-monoacylglycerol.

Colipase – protein which is present in the intestine and helps bind the water-soluble lipase to the lipid substrates.Colipase also activates lipase.Bile salts (salts of bile acids) are required for lipids digestion. Bile salts are synthesized in the liver from cholesterol. Taurocholate and glycocholate - the most abundant bile salts.Amphipathic: hydrophilic (blue) and hydrophobic (black)

TGs are water insoluble and lipase is water soluble. Digestion of TGs takes place at lipid-water interfaces. Rate of digestion depends on the surface area of the interface. Bile salts are amphipathic, they act as detergent emulsifying the lipid drops and increasing the surface area of the interface.

Bile salts also activates the lipase.Inadequate production of bile salts results in steatorrhea.

Dietary phospholipids are degraded by phospholipases

Lysophospho-glycerides are absorbed and in the intestinal cells are reesterified back to glycero-phospholipids.

Phospholipases are synthesized in the pancreas.

Major phospholipase is phospholipase A2 (catalyses the hydrolysis of ester bond at C2 of glycerophospholipids and lysophosphoglycerides are formed).

Lysophosphoglycerides can act as detergent and therefore in high concentration can disrupt cellular membranes.

Lysophosphoglyceride is normally present in cells in low concentration.

Snake venom contain phospholipase A2 and causes the lysis of erythrocytes membranes.

Dietary cholesterol• Most dietary cholesterol is unesterified

• Cholesteryl esters are hydrolyzed in the intestine by an intestinal esterase

• Free cholesterol is solublized by bile-salt micelles for absorption

• After absorption in the intestinal cells cholesterol react with acyl-CoA to form cholesteryl ester.

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LIPOPROTEIN PLASMA

. LEMAK TIDAK LARUT DALAM AIR

. MEDIA PELARUT DALAM TUBUH : AIR

TRANSPORTASI LEMAK HARUS DALAM BENTUK

EMULSI. UNTUK MEMBUAT EMULSI DIPERLUKAN

EMULGATOR SENYAWA BIPOLAR : FOSFOLI –

PID ; KOLESTEROL ; PROTEIN.

== LIPOPROTEIN .

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STRUKTUR LIPOPROTEIN :. INTI HIDROFOBIK : TG & KOLESTEROL ESTER

. LAPISAN KULIT AMPIFATIK : APOPROTEIN ; FOSFO– LIPID ( FOSFATIDIL KOLIN / SPINGOMIELIN ) ; KOLESTE- ROL BEBAS.

MACAM LIPOPROTEIN :

1. KILOMIKRON

2. VLDL = VERY LOW DENSITY LIPOPROTEIN

3. LDL = LOW DENSITY LIPOPROTEIN

4. HDL = HIGH DENSITY LIPOPROTEIN

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KOMPOSISI LIPOPROTEIN :

. MENGANDUNG PROTEIN, TG , FOSFOLIPID, KOLES –

TEROL dan KOLESTEROL ESTER DALAM JUMLAH

YANG BERBEDA.

. KANDUNGAN PROTEIN TERBANYAK HDL

KANDUNGAN TG TERBANYAK KILOMIKRON

dan VLDL

KANDUNGAN KOLESTEROL TERBANYAK LDL

• These lipids assemble with phospholipids and apoproteins (apolipoproteins) to form spherical particles called lipoprotein

Structure: Hydrophobic core: -TGs, -cholesteryl estersHydrophilic surfaces: -cholesterol, -phospholipids, -apolipoproteins

TRANSPORT FORMS OF LIPIDS• TGs, cholesterol and cholesterol esters are insoluble in water and cannot be transported in blood or lymph as free molecules

The main classes of lipoproteins1.Chylomicrons.

2.Very low density lipoproteins (VLDL).

3.Intermediate density lipoproteins (IDL).

4.Low density lipoproteins (LDL).

5.High density lipoproteins (HDL).

• are the largest lipoproteins (180 to 500 nm in diameter)• are synthesized in the ER of intestinal cells• contain 85 % of TGs (it is the main transport form of dietary TGs).• apoprotein B-48 (apo B-48) is the main protein component • deliver TGs from the intestine (via lymph and blood) to tissues (muscle

for energy, adipose for storage).• bind to membrane-bound lipoprotein lipase (at adipose tissue and

muscle), where the triacylglycerols are again degraded into free fatty acids and monoacylglycerol for transport into the tissue

• are present in blood only after feeding

Chylomicrons

exocytosisLymphatic

vessel

VLDL• are formed in the liver• contain 50 % of TGs and 22 % of cholesterol • two lipoproteins — apo B-100 and apo E • the main transport form of TGs synthesized in the organism (liver)• deliver the TGs from liver to peripheral tissue (muscle for energy, adipose for storage)

• bind to membrane-bound lipoprotein lipases (triacylglycerols are again degraded into free fatty acids and monoacylglycerol)

Apo BApo E

triacylglycerol

cholesteryl esters

phospholipidscholesterol

Lipoproteinlipase – enzyme which is located within capillaries of muscles and adipose tissue

Function: hydrolyses of TGs of chylomicrons and VLDL. Formed free fatty acids and glycerol pass into the cells

Chylomicrons and VLDL which gave up TGs are called remnants of chylomicrons and remnants of VLDL

Remnants are rich in cholesterol esters

Remnants of chylomicrons are captured by liver

Remnants of VLDL are also called intermediate density lipoproteins (IDL)

Fate of the IDL: - some are taken by the liver - others are degraded to the low density lipoproteins (LDL) (by the removal of more triacylglycerol)

LDLLDL are formed in the blood from IDL and in liver from IDL (enzyme – liver lipase)

LDL are enriched in cholesterol and cholesteryl esters (contain about 50 % of cholesterol)

Protein component - apo B-100

LDL is the major carrier of cholesterol (transport cholesterol to peripheral tissue)

Cells of all organs have LDL receptors

Receptors for LDL are localized in specialized regions called coated pits, which contain a specialized protein called clathrin

Apo B-100 on the surface of an LDL binds to the receptor

Receptor-LDL complex enters the cell by endocytosis.

Endocytic vesicle is formed

LDL uptake by receptor-mediated endocytosis

congenital disease when LDL receptor are not synthesized (mutation at a single autosomal locus) the concentration of cholesterol in blood markedly increases severe atherosclerosis is developed (deposition of cholesterol in arteries) nodules of cholesterol called xanthomas are prominent in skin and tendons most homozygotes die of coronary artery disease in childhood the disease in heterozygotes (1 in 500 people) has a milder and more variable clinical course

Familial hypercholesterolemia

atherosclerosis

xanthomas

HDL are formed in the liver and partially in small intestine contain the great amount of proteins (about 40 %)

pick up the cholesterol from peripheral tissue, chylomicrons and VLDL enzyme acyltransferase in HDL esterifies cholesterols, convert it to cholesterol esters and transport to the liver

High serum levels of cholesterol cause disease and death by contributing to development of atherosclerosis

Cholesterol which is present in the form of the LDL is so-called "bad cholesterol."

Cholesterol in the form of HDL is referred to as "good cholesterol”

HDL functions as a shuttle that moves cholesterol throughout the body

The ratio of cholesterol in the form of LDL to that in the form of HDL can be used to evaluate susceptibility to the development of atherosclerosis

LDL/HDL Ratio

For a healthy person, the LDL/HDL ratio is 3.5

Transport Forms of Lipids

LIPID METABOLISM: LIPID METABOLISM:

MOBILIZATION OF MOBILIZATION OF TRIACYLGLYCEROLS; TRIACYLGLYCEROLS;

OXIDATION OF OXIDATION OF GLYCEROLGLYCEROL

• TGs are delivered to adipose tissue in the form of chylomicrones and VLDL, hydrolyzed by lipoprotein lipase into fatty acids and glycerol, which are taken up by adipocytes.

• Then fatty acids are reesterified to TGs.

• TGs are stored in adipocytes.• To supply energy demands

fatty acids and glycerol are released – mobilisation of TGs.

Storage and Mobilization of Fatty Acids (FA)

adipocyte

TG hydro-lysis is inhibited by insulin in fed state

At low carbohydrate and insulin concentrations (during fasting), TG hydrolysis is stimulated by epinephrine, norepinephrine, glucagon, and adrenocorticotropic hormone.

•Lipolysis - hydrolysis of triacylglycerols by lipases. •A hormone-sensitive lipase converts TGs to free fatty acids and monoacylglycerol•Monoacylglycerol is hydrolyzed to fatty acid and glycerol or by a hormone-sensitive lipase or by more specific and more active monoacylglycerol lipase

• Fatty acids and glycerol diffuse through the adipocyte membrane and enter bloodstream.• Glycerol is transported via the blood in free state and oxidized or converted to glucose in liver.• Fatty acids are traveled bound to albumin. • In heart, skeletal muscles and liver they are oxidized with energy release.

Transport of Fatty Acids and Glycerol

Oxidation of Glycerol

Glycerol is absorbed by the liver.

Steps: phosphorylation, oxidation and isomerisation.

Glyceraldehyde 3-phosphate is an intermediate in: glycolytic pathway gluconeogenic pathways

Isomerase

LIPID LIPID METABOLISM: METABOLISM:

FATTY FATTY ACID ACID

OXIDATIONOXIDATION

(1) Activation of fatty acids takes place on the outer mitochondrial membrane

(2) Transport into the mitochondria

(3) Degradation to two-carbon fragments (as acetyl CoA) in the mitochondrial matrix (β-oxidation pathway)

Stages of fatty acid oxidation

(1) Activation of Fatty Acids • Fatty acids are converted to CoA thioesters by acyl-CoA synthetase (ATP dependent)

• The PPi released is hydrolyzed by a pyrophosphatase to 2 Pi

• Two phosphoanhydride bonds (two ATP equivalents) are consumed to activate one fatty acid to a thioester

• The carnitine shuttle system.

• Fatty acyl CoA is first converted to acylcarnitine (enzyme carnitine acyltransferase I (bound to the outer mitochondrial membrane).

• Acylcarnitine enters the mitochondria by a translocase.

• The acyl group is transferred back to CoA (enzyme - carnitine acyltransferase II).

(2) Transport of Fatty Acyl CoA into Mitochondria

• The β-oxidation pathway (β-carbon atom (C3) is oxidized) degrades fatty acids two carbons at a time

βα

(3) The Reactions of β oxidation

1. Oxidation of acyl CoA by an acyl CoA dehydrogenase to give an enoyl CoA

Coenzyme - FAD

2. Hydration of the double bond between C-2 and C-3 by enoyl CoA hydratase with the 3-hydroxyacyl CoA (β-hydroxyacyl CoA) formation

3. Oxidation of 3-hydroxyacyl CoA to 3-ketoacyl CoA by 3-hydroxyacyl CoA dehydrogenase

Coenzyme – NAD+

4. Cleavage of 3-ketoacyl CoA by the thiol group of a second molecule of CoA with the formation of acetyl CoA and an acyl CoA shortened by two carbon atoms.

Enzyme - β-ketothiolase.

The shortened acyl CoA then undergoes another cycle of oxidation

The number of cycles: n/2-1, where n – the number of carbon atoms

Fatty acyl CoAβ-Oxidation of saturated fatty

acids

• One round of β oxidation: 4 enzyme steps produce acetyl CoA from fatty acyl CoA

• Each round generates one molecule each of: FADH2

NADHAcetyl CoA Fatty acyl CoA (2 carbons shorter each round)

Fates of the products of β-oxidation: - NADH and FADH2 - are used in ETC - acetyl CoA - enters the citric acid cycle - acyl CoA – undergoes the next cycle of oxidation

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ENERGI β-OKSIDASI :

ENERGI YANG DIHASILKAN dari β-OKSIDASI BILA DIKAIT- KAN dengan OKSIDASI BIOLOGI dan S.A.S adalah :

- TAHAP OKSIDASI I ( FAD ) = 2 ATP

- TAHAP OKSIDASI II ( NAD ) = 3 ATP +

SETIAP SIKLUS β-OKSIDASI = 5 ATP

- DARI S.A.S. PER MOL. ASETIL-KoA = 12 ATP

- PADA TAHAP AKTIVASI, HUTANG = 2 ATP

KALAU JUMLAH ATOM C dari ASAM LEMAK =N MAKA TERDAPAT ½ N MOL. ASETIL-KoA dan ( N/2 – 1 ) SIKLUS OKSIDASI

ENERGI : ½ N X 12 + (½ N – 1 ) X 5 - 2 MOL.ATP

MISAL : ASAM PALMITAT ( 16 ATOM C )

16/2 x 12 + ( 16/2 -1 ) X 5 - 2 = 129 MOL. ATP

LIPID METABOLISM: LIPID METABOLISM: FATTY ACID FATTY ACID OXIDATIONOXIDATION

• Odd-chain fatty acids occur in bacteria and microorganisms

• Final cleavage product is propionyl CoA rather than acetyl CoA

• Three enzymes convert propionyl CoA to succinyl CoA (citric acid cycle intermediate)

β-OXIDATION OF ODD-CHAIN FATTY ACIDS

Propionyl CoA Is Converted into Succinyl CoA

1. Propionyl CoA is carboxylated to yield the D isomer of methylmalonyl CoA. The hydrolysis of an ATP is required.Enzyme: propionyl CoA carboxylaseCoenzyme: biotin

2. The D isomer of methylmalonyl CoA is racemized to the L isomer Enzyme: methylmalonyl-CoA racemase

3. L isomer of methylmalonyl CoA is converted into succinyl CoA by an intramolecular rearrangementEnzyme: methylmalonyl CoA mutaseCoenzyme: vitamin B12 (cobalamin)

Ke siklus Asam sitrat

OXIDATION OF FATTY ACIDS IN PEROXISOMES

Peroxisomes - organelles containing enzyme catalase, which catalyzes the dismutation of hydrogen peroxide into water and molecular oxygen Acyl CoA

dehydrogenase transfers electrons to O2 to yield H2O2 instead of capturing the high-energy electrons by ETC, as occurs in mitochondrial β-oxidation.

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KETOGENESIS & KETOLISIS

PADA KEADAAN TERTENTU ( KELAPARAN; DIABETES M.) MOBILISASI AS. LEMAK ↑ OKSIDASI-β ↑ ENERGI

KETOGENESIS

KETOGENESIS = SINTESIS BENDA KETON KETOLISIS = KATABOLISME BENDA KETON

KETOGENESIS terjadi di HEPAR, dengan TUJUAN UNTUK PENGHEMATAN ENERGI ( TIDAK SEMUA AS.LEMAK DI OK- SIDASI + SAS, TAPI DIBENTUK MENJADI BENDA KETON )

BENDA KETON : β-HIDROKSI BUTIRAT, ASETOASETAT dan

ASETON.

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HEPAR (BENDA KETON)

DARAH

OTOT SKELET

ENERGI

OTAK

ENERGI ( sebagai peng- ganti glukosa, melalui : glucose-fatty acids-keton bodies cycle ) BENDA KETON bersifat ASAM

GANGGUAN ASAM BASA DARAH ( KETOASIDOSIS )

terutama pada - DIABETES MELLITUS

- KELAPARAN masih dapat diatasi

oleh tubuh dengan SISTEM BUFFER

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F F A ( MOBILISASI dari ADIPOSA )

ASIL-KoAGLISEROL-P TG

FOSFOLIPID

Membran Mitokondria

ASIL-KoA

H3C-CO-CH2-CO~SKoA ASETOASETIL-KoA

CH3-CO-SKoA ASETIL-KoA

( ASETIL-KoA )n

KoA-SH

OKSIDASI - β

H2O

CH2-COO-

H3C-COH-CH2-CO-SKoA

HMG-KoA

ASETOASETAT

3β-HIDROKSI BUTIRAT ( paling dominan )

CH3-CO-SKoA

HMG-KoA Liase

NADH + H+ NAD+

SAS

KOLESTEROL

KETOGENESIS

ASIL-KoA

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KETOGENESIS HANYA TERJADI DI HEPAR, KATABOLISME NYA TERJADI DI LUAR HEPAR SEBAGIAN BESAR DI OTOT SKELET

3-HIDROKSI BUTIRAT

ASETO ASETAT

ASETO ASETIL-KoA

ASETIL-KoA

NAD

NADH + H+

SUKSINIL-KoA SITRAT

SUKSINAT OKSALO ASETAT

SIKLUS ASAM SITRATKoA-Transferase

Tiolase

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BAHAN BAKU : ASETIL-KoA

PRINSIPNYA : PENGGANDENGAN ASETIL-KoA

ASETIL-KoA BERASAL DARI - KH glikolisis

- PROTEIN / AS.AMINO

CARA SINTESIS :1. SISTEM MITOKONDRIA

2. SISTEM EKSTRA MITOKONDRIA

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SINTESIS ASAM LEMAK SISTEM MITOKONDRIA :

►MERUPAKAN SISTEM UNTUK MEMPERPANJANG ASAM LEMAK YANG SUDAH ADA atau UNTUK KONVERSI SATU ASAM LEMAK KE JENIS ASAM LEMAK YANG LAIN ► LEBIH SERING DIPAKAI UNTUK SINTESIS ASAM LEMAK TIDAK JENUH = UNSATURATED FATTY ACIDS = UFA

► BAHAN BAKU : ASAM PALMITAT ( 16 C )

atau ASAM LEMAK TIDAK JENUH YANG

ADA DALAM TUBUH.

► PRINSIP REAKSINYA merupakan KEBALIKAN DARI OKSIDA-SI β ( ENZIMNYA SAMA, KECUALI ENZ. TIOLASE DIGANTI DENGAN ENZ. ENOIL-KoA REDUKTASE.

►BERLANGSUNG DALAM SUASANA ANAEROB

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SINTESIS ASAM LEMAK SISTEM MITOKONDRIA

CH3-(CH2)n-CH2-CO-S-KoA

CH3-(CH2)n-1-CH=CH-CO-S-KoA

CH3-(CH2)n-1-CH-CH2-CO-S-KoA

CH3-(CH2)n-1-C-CH2-CO-S-KoA

CH3-(CH2)n-1- C-S-KoA +

FAD+

FADH + H+

H2O

NAD+

NADH + H+

KoA-SH

CH2-CO-S-KoA

O

O

OH

ASETIL-KoA

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SINTESIS ASAM LEMAK SISTEM EKSTRA MITOKONDRIA :

★ SINTESIS ASAM LEMAK “DE NOVO” DENGAN BAHAN DASARNYA : ASETIL-KoA + CO2

★ SISTEM INI SERING DIGUNAKAN dan AKTIF DI JARINGAN- JARINGAN HEPAR, ADIPOSA dan KELENJAR MAMMAE YANG SEDANG LAKTASI

★ DIKATALISA OLEH KOMPLEKS ENZIM : “ FATTY ACID SINTHASE COMPLEX “ YANG MENGANDUNG GUGUS PROTEIN PENGEMBAN ASIL ( ACYL CARRIER PROTEIN = ACP )

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SINTESA ASAM LEMAK SISTEM EXTRA MITOKONDRIA

CH3-CO-SKoA ASETIL-KoA

-OOC-CH2-CO-SKoA MALONIL-KoA

CO2

HS-PAN- -Cys-HS

HS-Cys- -PAN-HS

-- -Cys-S-C-CH3

-- -PAN-S-C-CH2-COO

-ENZ-ASIL ( ASETIL MALONIL )

O

O

=

KoA KoA

- -CyS-SH

- -PAN-S-C-CH2-C-CH3 ENZ-3-KETOASIL ( ENZ ASETOASETIL )

CO23-KETOASIL SINTASE

- -CyS-SH

- -PAN-S-C-CH2-CH-CH3 ENZ.-3-HIDROKSI ASIL

O O

O O

NADPH + H+NADP+

- -Cys-SH

- -PAN-S-C-CH=CH-CH3 ENZ.-2,3-ASIL TAK JENUH

3-KETO ASIL REDUKTASE

HIDRATASEH2O

- -Cys-SH

- -PAN-S-C-CH2-CH2-CH3

NADPH + H+

NADP+

PENGHASIL NADPH :

- JALUR HMP - ISOSITRAT DEHIDRO GENASE - ENZIM MALAT

ENZIM-ASILPALMITAT

7 X

( Cn )

BIOTIN

ENZIM

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SINTESIS ASAM LEMAK SISTEM MIKROSOM

☺ JARANG DILAKUKAN

☺ FUNGSI : SEPERTI SISTEM MITOKONDRIA :

MEMPERPANJANG RANTAI AS. LEMAK

☺ REAKSINYA MIRIP DENGAN SISTEM EKSTRA MITOKON

DRIA, YAITU MEMERLUKAN ADANYA MALONIL-KoA