METABOLISME ENERGI DAN ZAT GIZI MAKRO PERTEMUAN 8 HENDRA WIJAYA-DUDUNG ANGKASA PROGRAM STUDI ILMU GIZI-FIKES

VISI DAN MISI UNIVERSITAS ESA UNGGUL

KEMAMPUAN AKHIR YANG DIHARAPKAN Mahasiswa dapat menjelaskan biosintesis asam lemak, trigliserida, kolesterol dan lipoprotein

BIOSYNTHESIS OF FATTY ACIDS Hendra Wijaya Esa unggul University

TRANSPORT OF ACETYL-COA INTO THE CYTOSOL

TRANSPORT OF ACETYL-COA INTO THE CYTOSOL Acetyl-CoA generated in the mitochondrion Mitochondrial membrane is impermeable to acetyl-CoA Acetyl-CoA enters the cytosol in the form of citrate Processing of malate to pyruvate generates NADPH for fatty acid biosynthesis

OVERVIEW OF FATTY ACID SYNTHESIS

SYNTHESIS OF FATTY ACID MOVIE

Acetyl-CoA Carboxylase reaction

Acetyl-CoA Carboxylase reaction Irreversible reaction that is the committed step in fatty acid synthesis Biotin-dependent Mechanism similar to that of pyruvate carboxylase Subject to allosteric and hormonal control Stimulated by citrate, inhibited by long-chain fatty acids Phosphorylation, which inhibits enzyme activity, is promoted by glucagon and reversed by insulin

Intermediates in Fatty Acid Synthesis are Linked to Acyl Carrier Protein (ACP)

REACTION SEQUENCE FOR FATTY ACID BIOSYNTHESIS Intermediates attached to the sulfhydryl terminus of a phosphopantetheine group Phosphopantetheine linked to Ser hydroxyl of ACP, while attached to AMP in CoA ACP can be considered a big CoA molecule Individual enzymes in bacteria, enzyme complex in eukaryotes Condensation of malonyl-CoA and acetyl-CoA driven by decarboxylation Stereochemistry and reducing agent are different between synthesis and degradation In subsequent round of elongation, butyryl thioester condenses with malonyl-ACP after transfer to condensing enzyme Elongation cycles continue until palmitoyl(C16)-ACP is formed, which is hydrolyzed to give palmitate and ACP

STOICHIOMETRY OF FATTY ACID BIOSYNTHESIS Stoichiometry of palmitate synthesis: Acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14H+ palmitate + 7CO2 + 14NADP+ + 8CoA + 6H2O Malonyl-CoA synthesis: 7 Acetyl-CoA + 7CO2 + 7ATP 7 malonyl-CoA + 7ADP + 7Pi + 7H+ Overall stoichiometry of palmitate synthesis: 8 Acetyl-CoA + 14 NADPH + 7ATP + 7H+ palmitate + 14NADP+ + 8CoA + 6H2O + 7ADP + 7Pi

FATTY ACID ELONGATION In eukaryotes, elongation occurs in both mitochondria and the endoplasmic reticulum (ER), but the ER system has much higher activity Reactions occur on separate enzymes rather than in a complex Fatty acid is elongated as its CoA derivative Two carbon units are added sequentially the carboxyl end of both saturated and unsaturated fatty acids Malonyl-CoA is again the two-carbon donor

FATTY ACID DESATURATION Double bonds are introduced into long-chain acyl-CoAs through an electron-transfer process coupled to the reduction of molecular oxygen Reaction catalyzed by a complex of membrane-bound enzymes Double bonds inserted such that the new double bond is three carbons closer to the CoA group, and never beyond the C9 position

ESSENTIAL FATTY ACID The formation of D12 and D15 double bonds is not possible in animals Animals cannot synthesize linoleic acid (18:2D9,12), linolenic acid (18:3D9,12,15), or arachidonic acid (20:4 D5,8,11,14), which are used in the synthesis of eicosanoid hormones Prostaglandins Leukotrienes These are called essential fatty acids because they are essential lipid components that must be provided in the diet

BIOSYNTHESIS OF TRIACYLGLYCEROL

TRIACYLGLYCEROL (TG) SYNTHESIS Generally synthesized from glycerol 3-phosphate, which is produced by the reduction of dihydroxyacetone phosphate (DHAP) Acylations performed with acyl-CoA and acyltransferases Fatty acyl chain at C1 is usually saturated, fatty acyl chain at C2 is usually unsaturated TG and phospholipid pathways generally diverge at phosphatidic acid and diacylglycerol Diacylglycerol formed by phosphatase Acyltransferase forms TG

CONFORMATIONAL MODEL OF (A) PHOSPHOLIPID PHOSPHATIDYLCHOLINE AND (B) TRIACYLGLYCEROL

GLYCEROPHOSPHOLIPID

GLYCEROPHOSPHOLIPIDS: Membrane Lesitin C1 substituents mostly saturated fatty acids, C2 substituents mostly unsaturated fatty acids PE, PG, and CL found in bacteria, eukaryotes contain all six Phospholipases serve as digestive enzymes and as generators of signal molecules

CTP: Citidene Tryphosphate

Biosynthesis Of PhospatidylserineI: CDP-Diacylglycerol Pathway Sytosin CTP: Citidene Tryphosphate

Biosynthesis Of Phospatidylcholine: CDP-Choline & CDP-ethanolamine

PHOSPHOLIPID SYNTHESIS

KETON BODIES

9/15/2018 Metabolisme Lipida

KETONE BODIES Acetyl-CoA from fatty acid oxidation enters the citric acid cycle when fat and carbohydrate breakdown are balanced Entry depends on oxaloacetate Oxaloacetate consumed to form glucose by gluconeogenesis in fasting, diabetes, and starvation In the absence of oxaloacetate, acetyl-CoA is converted to acetoacetate or D-b-hydroxybutyrate through ketogenesis Acetone is formed by the non-enzymatic decarboxylation of acetoacetate Ketone bodies are important fuel molecules OVERVIEW

Formation of keton bodies from acytil-CoA Initial condensation Ester condensation to form HMG-CoA (also precursor in cholesterol biosynthesis) Acetoacetate and acetyl-CoA formed in a mechanism similar to the reverse of the citrate synthase reaction

Metabolic Conversion of Ketone Bodies to Acetyl-CoA S Acetoacetate reduced to hydroxybutyrate in an NADH-dependent reaction Acetoacetyl-CoA can be cleaved by thiolase to give 2 acyl-CoA The liver can supply acetoacetate to other tissues

Cholesterol

SPHINGOLIPIDS

SPHINGOLIPIDS

SPHINGOLIPIDS

SPHINGOLIPIDS Backbone is ceramide rather than glycerol Most sphingolipids contain carbohydrates as their head group Sphingolipids play important roles in nervous tissue Sphingomyelin is an important component of the myelin sheath Gangliosides constitute 6% of the lipids in gray matter

SYNTHESIS OF CERAMIDA

Toy-Sachs Disease: A Disorder of Ganglioside Breakdown Gangliosides are degraded inside lysosomes by the sequential removal of terminal sugars In Tay-Sachs disease, ganglioside GM2 accumulates because hexosaminidase activity is absent This ganglioside interferes with neuronal function Genetic recessive disease

MEMBRANE LIPIDS Have a hydrophilic and hydrophobic component 1,2-diacylglycerol or N-acetylsphingosine (ceramide) linked to a polar head group Hydrophobic acyl chains Form bilayered membranes in aqueous media Membranes are noncovalent, fluid assemblies Membrane lipids synthesized predominantly on the cytoplasmic face of the ER, then transported in vesicles to their destinations

β -OXIDATION vs BIOSYNTHESIS

FATTY ACID BIOSYNTHESIS VS β-OXIDATION

Hendra Wijaya Esa unggul university Atherosclerosis Hendra Wijaya Esa unggul university 9/15/2018 Metabolisme Lipida

ATHEROSCLEROSIS Aterosklerosis : proses patologis yang menyerang pembuluh darah arteri berukuran sedang dan besar Atherosclerosis (bahasa Yunani) => athero = subur; scleros = keras  bertalian erat dengan penyimpangan metabolisme lemak dan kolesterol  merupakan penyebab timbulnya penyakit kardiovaskuler DISLIPIDEMIA :  kolesterol total (> 200 mg/dl)  LDL (> 130 mg/dl)  trigliserida (> 200 mg/dl)  HDL (< 35 mg/dl) 9/15/2018 Metabolisme Lipida

ARTERI TREE AND ATHEROSCLEROSIS

ATHEROSCLEROSIS A : pembentukan fatty streak B : Progresi lesi lebih lanjut C : Lesi lanjutan berupa pembentukan plaque dan thrombus 9/15/2018 Metabolisme Lipida

ATHEROSCLEROSIS 1 2 3 4 9/15/2018 Metabolisme Lipida

ATHEROSCLEROSIS

MEKANISME MOLEKULAR

FAKTOR RESIKO Makan & Minum Berlebihan Obesitas Gaya Hidup Santai Diabetes Aterosklerosis Merokok Konsumsi Garam Dapur Tinggi Hipertensi Penyakit Kardio- Konsumsi Lemak Total Tinggi vaskuler Konsumsi Lemak Jenuh Tinggi Rasio Konsumsi Lemak Tidak Jenuh/Jenuh Rendah Konsumsi Kolesterol Tinggi Kadar Kolesterol Darah Meningkat 9/15/2018 Metabolisme Lipida

EFFECTS OF DIETARY INTAKE Cholesterol that accumulates in arteries is manufactured largely from fragments derived from saturated fat. Saturated fatty acids elevate blood cholesterol and are the main determinants of blood cholesterol Saturated fatty acids elevated LDL PUFA and MUFA lower blood cholesterol Dietary cholesterol elevates cholesterol Very low fat diets  lower all types of lipoproteins, may raise triglycerides High sugar diet, High alcohol intake may raise triglycerides 9/15/2018 Metabolisme Lipida

Penyakit Jantung Koroner   Telah lama diketahui bahwa konsumsi asam lemak tidak jenuh yang tinggi cenderung menurunkan kadar kolesterol plasma. Konsumsi minyak kedelai yang cukup (10,6 % dari total energi) menurunkan kadar kolesterol total dan kolesterol-LDL pada manusia (Pakpaenkitvatana et al, 1989) Efek merendahkan kadar kolesterol darah oleh asam lemak tidak jenuh (ALTJ) disebabkan oleh mekanisme produksi VLDL. Hipotesis: ALTJ menurunkan sintesis VLDL, dan sebagai akibatnya produksi LDL juga berkurang. Selanjutnya ALTJ yang tidak membentuk formasi trigliserida pada VLDL akan dioksidasi sebagai sumber energi dan ketone bodies yang terbentuk akhirnya akan dikeluarkan melalui urine dan saluran pernafasan, atau dikonversi menjadi glukosa (Beynen dan Katan (1985) . 9/15/2018 Metabolisme Lipida

REKOMENDASI THE AMERICAN HEART ASSOCIATION :  Total calories intake : adjusted to maintain a healthy body weight  Total fat intake : max. 30 % of total calories  Saturated fat : 7-10 % of total calories  Polyunsaturated fat : up to 10 % of total calories  Monounsaturated fat : up to 15 % of total calories  Cholesterol intake : less than 200 mg per day  Sodium intake : less than 2400 mg per day  Carbohydrate intake : 55-60 % of total calories (CHO complex) 9/15/2018 Metabolisme Lipida

Prostaglandin : ● platelet membentuk thromboxane A2 (TXA2)  agregasi platelet, saluran darah mengecil ● saluran darah dan sel-sel lain membentuk prostacyclin (PGI2)  mencegah agregasi platelet, saluran darah melebar ASAM LEMAK OMEGA-3 dapat mencegah terbentuknya TXA2 dan menstimulir pembentukan PGI2 9/15/2018 Metabolisme Lipida

Eicosapentaenoic Acid (EPA) Docosahexaenoic Acid (DHA) Linolenic Acid omega-3 Linoleic Acid omega-6 Eicosapentaenoic Acid (EPA) Docosahexaenoic Acid (DHA) Arachidonic Acid Eicosanoids Regulate BP Regulate Blood Clotting (Linoleic-Increases Clotting) (Linolenic Decreases Clotting) Regulate Inflammatory Reactions 9/15/2018 Metabolisme Lipida

TERIMA KASIH