Ch21 Lipit Biyosentezi Yonca Duman

Lipid BiosynthesisLipid Biosynthesis

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Lipitlerin Hücresel Rolleri

� Enerji depolayan moleküller ve hücre membranlarının yapısını oluştururlar,

� Özel işlevleri olan lipitler

• Pigmentler ⇒ Retinal, karoten

• Kofaktörler ⇒ Vitamin K

• Deterjanlar ⇒ Safra tuzları• Deterjanlar ⇒ Safra tuzları

• Taşıyıcılar ⇒ Dolichol’ler

• Hormonlar ⇒ Vitamin D1 , seks hormonları

• Hücre içi ve dışı mesaj taşıyıcılar ⇒ eiconasoid’ler, fosfatidil inositol türevleri

• Membran proteinleri için tutunma yerleri ⇒ prenil grupları

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Fatty oxidation and biosynthesis occur:

� by different pathways,

� are catalyzed by different sets of enzymes,

� and take place in different parts of the cell. 3

Acetyl-CoA carboxylase Reaction4

Acetyl-CoA carboxylase Reaction

The formation of malonyl-

CoA from acetyl-CoA is an irreversible process, catalyzed by acetyl-CoA

carboxylase.

� The bacterial enzyme has three separate polypeptide subunits,

� In animal cells, all three activities are part of a single multifunctional

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polypeptide.

� Plant cells contain both types of acetyl-CoA carboxylase.

In all cases, the enzyme contains a biotin prosthetic group covalently bound in amide linkage to the ε-ami-no group of a Lys residue in one of the three polypepti-des or domains of the en-zyme molecule.

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C16

14Harper's Illustrated Biochemistry (Lange, McGraw-Hill Medical, 28th Ed, 2009).

ACPACP: Acyl carier protein

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Fatty Acid Synthase Complex

ACP ACP: Acyl carier protein

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D-

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We can consider the overall reaction for the synthesis of

palmitate from acetyl-CoA in two parts.

First, the formation of seven malonyl-CoA molecules:

7 Acetyl-CoA + 7CO2 + 7ATP → 7 Malonyl-CoA + 7ADP + 7Pi

then seven cycles of condensation and reduction:

Acetyl-CoA + 7 Malonyl-CoA + 14NADPH + 14H+ →Palmitate + 7CO2 + 8 CoA + 14NADP+ + 6H2O

The overall process (the sum of two equations) is:

8 Acetyl-CoA + 7ATP + 14NADPH + 14H+ →Palmitate + 8 CoA + 7ADP + 7Pi + 14NADP+ + 6H2O

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40

Harper's Illustrated Biochemistry (Lange, McGraw-Hill Medical, 28th Ed, 2009).

• [NADH]/[NAD+] very high

• [NADH]/[NAD+] low ≈ 8 × 10-4

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• [NADH]/[NAD+] very high

Sitratın hücre metabolizmasındaki merkezi rolü:

• [Asetil-CoA]mit ve [ATP]mit artarsa sitrat mitokon-driden sitoplazmaya geçerek sitoplazmik asetil-CoA öncülü olur.

• Asetil-CoA karboksilaz aktivasyonu için allosterik modülatör olur.

• PFK-1’i inhibe ederek glikolizi yavaşlatır, glikolize olan karbon akışını düşürür.

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Omurgalılarda

Glukagon ya da Epineprhine ile tetikleme �

[ ] [ ]Protein kinaz

iAktif ĐnaktifProtein fosfatazAsetil-CoA karboksilaz + P Asetil-CoA karboksilaz ��⇀�↽��

Epinephrine

Bitkilerde

Artan stromal pH ve artan stromal [Mg]+2 stromal asetil-CoA karboksilaz’ı aktiveeder (Bunun için bitkinin ışığa gereksinimi vardır).

�

Đnsülin ile tetikleme

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Mitochondrial fatty acid elongation Mitochondrial fatty acid oxidation

Mitochon-

drial elon-

gation (a

process

indepen-

dent of fatty

acid synt-

hase path-

way in cy-

tosol) oc-

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tosol) oc-curs by the successive addition and reduc-tion of ace-tyl units in a reversal of fatty acid oxidation.

Fatty acid elongation in the endoplasmic

reticulum involves the successive

condensations of malonyl-CoA with acyl-

CoA. These reactions are each followed by NADPH-dependent reductions similar to

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NADPH-dependent reductions similar to those catalyzed by fatty acid synthase, the

only difference being that the fatty acid is

elongated as its CoA derivative rather than as its ACP derivative.

Electron transfer in the desaturation of fatty acids in vertebrates

(These reactions take place in the lumenal face of the smooth Endoplasmic Reticulum)

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Electron transfer in the desaturation of fatty acids in bacteria

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Stearoyl-ACP desaturase 9Plant chloroplast stroma

Stearate (18:0) Oleate (18:19), ( )→ ∆(18:1)

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Action of plant desaturases

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In plants, the desaturases that introduce double bonds at the ∆∆∆∆12

and ∆∆∆∆15 positions are located in the ER and the chloroplast. The ER enzymes act not on free fatty acids but on a phospholipid, phospha-tidylcholine, that contains at least one oleate linked to the glycerol.

20:4 (∆5,8,11,14)Precursor for Eicosanoid (prostaglandins,

tromboxanes and leucotrienes) biosynthesis65

Biosynthesis of prostaglandins and thromboxanes in the smooth endoplasmic reticulum of mammalian cells

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Non-Steroidal Anti Inflamatory Drugs (NSAID)

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Non-Steroidal Anti Inflamatory Drugs (NSAID)

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Leukotriene synthesis begins with the action of seve-ral lipoxygenases that catalyze the incorporation ofmolecular oxygen into arachidonate. These enzymes,found in leukocytes and in heart, brain, lung, andspleen, are mixed-function oxidases that use cytoch-rome P-450. The various leukotrienes differ in the po-sition of the peroxide group introduced by the lipoxy-genases. This linear pathway from arachidonate, un-like the cyclic pathway, is not inhibited by aspirin orother NSAIDs.

Plants also derive important signaling molecules from fatty acids. As in animals,a key step in the initiation of signaling involves activation of a specific phos-pholipase. In plants, the fatty acid substrate that is released is αααα-linolenate. A li-poxygenase then catalyzes the first step in a pathway that converts linolenate tojasmonate, a substance known to have signaling roles in insect defense, resistan-ce to fungal pathogens, and pollen maturation. Jasmonate also affects seed ger-mination, root growth, and fruit and seed development.

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Sentezlenen ya da besinlerle alınan yağ asitleri � �

Triaçil gliserollere Membranların fosfolipid Dönüşüm komponentlerine dönüşüm � � Bol gıda alımında ve Hızlı büyüme sırasında aktif büyüme olmadığı sentezlenecek yeni zaman metabolik membranların fosfolipid enerjinin depolanması gereksinimleri için enerjinin depolanması gereksinimleri için için � �

Giserolün yağ açil esterlerinin oluşumu (aynı öncül moleküllerden başlar)

� (Yağ açil-CoA & L-gliserol-3-fosfat)

� Fosfatidik asit

Gliserolün

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Adipose Tissue Generates Glycerol-3-phosphate by Glyceroneogenesis

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Glyceroneogenesis has multiple roles:

� In adipose tissue, glyceroneogenesis coupled with reesterification of free fatty acids controls the rate of fatty acid release to the blood,

� In brown adipose tissue, the same pathway may control the rate at which free fatty acids are

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control the rate at which free fatty acids are delivered to mitochondria for use in thenmogenesis,

� And in fasting humans, glyceroneogenesis in the liver alone supports the synthesis of enough glycerol 3-phosphate to account for up to 65% of fatty acids reesterified to triacylglycerol.

The triacylglycerol cycle

In mammals, triacylgly-cerol molecules are broken down and resynthesized in a triacylglycerol cycle

during starvation. Some of the fatty acids released by lipolysis of triacylglycerol in adipose tissue pass into the bloodstream, and the remainder are used for resynthesis of triacylglyce-rol. Some of the fatty acids released into the blood are

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used for energy (in muscle, for example), and some are taken up by the liver and used in triacylglycerol syn-thesis. The triacylglycerol formed in the liver is trans-ported in the blood back to adipose tissue, where the fatty acid is released by extracellular lipoprotein lipase, taken up by adipo-cytes, and reesterifled into triacylglycerol.

Regulation of glyceroneogenesis

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Flux through the triacylglycerol cycle between liver and adipose tissue is controlled to a large degree bythe activity of PEP carboxykinase, which limits the rate of both gluconeogenesis and glyceroneogenesis.

Glucocorticoid Hormones

Insulin resistance (IR) is a physiological condition where the natural hormone insulinbecomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types such as fat and muscle cells require insulin to absorb glucose. When these cells fail to respond adequately to circulating insulin, blood glucose levels rise. The liver helps regulate glucose levels by reducing its secretion of glucose in the presence of insulin. This normal reduction in the liver’s glucose production may not occur in people with insulin resistance.

Insulin resistance in muscle and fat cells reduces glucose uptake (and also local storage of glucose as glycogen and triglycerides, respectively), whereas insulin resistance in liver cells results in reduced glycogen synthesis and storage and a failure to suppress glucose production

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results in reduced glycogen synthesis and storage and a failure to suppress glucose production and release into the blood. Insulin resistance normally refers to reduced glucose-lowering effects of insulin. However, other functions of insulin can also be affected. For example, insulin resistance in fat cells reduces the normal effects of insulin on lipids and results in reduced uptake of circulating lipids and increased hydrolysis of stored triglycerides. Increased mobilization of stored lipids in these cells elevates free fatty acids in the blood plasma. Elevated blood fatty-acid concentrations (associated with insulin resistance and diabetes mellitus Type 2), reduced muscle glucose uptake, and increased liver glucose production all contribute to elevated blood glucose levels. High plasma levels of insulin and glucose due to insulin resistance are a major component of the metabolic syndrome. If insulin resistance exists, more insulin needs to be secreted by the pancreas. If this compensatory increase does not occur, blood glucose concentrations increase and type 2 diabetes occurs.

Membrane Lipids

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Basit öncüllerinden fosfolipid moleküllerinin

oluşması için:

1. Omurga molekülün (gliserin ya da sfingosin) sentezi,

2. Ester ya da amid bağlarıyla yağ asitlerinin omurgaya

takılması,

3. Bazı hallerde hidrofilik başlık grubunun omurgaya bir

fosfodiester bağı ile bağlanması,

4. Son fosfolipid molekülünü oluşturmak üzere başlık

grubunun değiştirilmesi

gerekir.

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In eukaryotic cells, phospholipid

synthesis occurs primarily on the surfaces of the smooth endoplasmic

reticulum and the mitochondrial

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inner membrane. Some newly formed phospholipids remain at the site of synthesis, but most are destined for other cellular locations.

Phospholipid synthesis in bacteria

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Phospholipid synthesis in bacteria

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Anionic phospholipid synthesis in eukaryotes

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Yeast Cells

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Yeast Cells

Mammalian Cells

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Phosphatidylcholine synthesis from choline in mammalians

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Summary of

the pathways to

phosphatidyl-

choline and

phosphatidyl-

ethanolamine. Conversion of

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Conversion of phosphatidyl-ethanolamine to phosphatidyl-choline in mammals takes place only in the liver.

Vertebrate heart tissue is uniquely enriched in ether lipids; about half of the heartphospholipids are plasmalogens. The membranes of halophilic bacteria, ciliatedprotists, and certain invertebrates also contain high proportions of ether lipids. Thefunctional significance of ether lipids in these membranes is unknown; perhapstheir resistance to the phospholipases that cleave ester-linked fatty acids frommembrane lipids is important in some roles.

Platelet-activating factor, is a potent molecular signal. It is released from leukocytescalled basophils and stimulates platelet aggregation and the release of serotonin (avasoconstrictor) from platelets. It also exerts a variety of effects on liver, smoothmuscle, heart, uterine, and lung tissues and plays an important role in inflammationand the allergic response.

Peroxisomes

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Plasmalogen synthesis in

peroxisomes

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Biosynthesis of sphingolipids in smooth endoplasmic reticulum

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Polar Lipids Are Targeted to

Specific Cellular

Membranes.

After synthesis on the smooth ER, the polar lipids, inclu-ding the glycerophospho-

lipids, sphingolipids, and glycolipids, are inserted into specific cellular membranes in specific proportions, by mec-hanisms not yet understood.

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hanisms not yet understood.

Membrane lipids are insoluble in water, so they cannot simply diffuse from their point of synthesis (the ER) to their point of insertion. Instead, they are delivered in membrane vesicles that bud from the Golgi complex then move to and fuse with the target membrane.

Summary of cholesterol biosynthesis

Biosynthesis of cholesterol takes place in four stages:

1. Condensation of three acetate units to form a six-carbon intermediate, mevalonate,

2. Conversion of mevalonate to activated isoprene units,

3. Polymerization of six 5-

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3. Polymerization of six 5-carbon isoprene units to form the 30-carbon linear squalene,

4. Cyclization of squalene to form the four rings of the steroid nucleus, with a further series of changes (oxidations, removal or migration of methyl groups) to produce cholesterol.

1. Mevolanate formation from 3 acetate

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The third reaction is the committed and rate-limiting step and HMG-CoA reductase, anintegral membrane protein of the smooth ER,is the major point of regulation on the path-way to cholesterol biosynthesis.

1. Mevolanate formation from 3 acetate

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The third reaction is the committed and

rate-limiting step and HMG-CoA reductase,

an integral membrane protein of the

smooth ER, is the major point of regulation

on the pathway to cholesterol biosynthesis.

2. Transformation of mevalonate activated isoprene units

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3. Polimerization of 6 activated isoprene units having 5 carbons to squalene having 30 carbons

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4. Formation of the rings of the

steroid nucleus from squalene

and the other reactions for the

synthesis of cholestrol as end

product

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Bile acids and their salts are relatively hydrophilic cholesterolderivatives that are synthesized in the liver and aid in lipiddigestion.

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Lipoproteins. (a) Structure of a low-density lipoprotein (LDL). Apolipoprotein B-100 (apoB-100) is one of the largest single

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of the largest single polypeptide chains known, with 4,636 amino acid residues (Mr 513,000).

(b) Lipoproteins. Four classes of lipoproteins, visualized in the electron microscopeafter negative staining. Clockwise from top left: chylomicrons, 50 to 200 nm indiameter; VLDL, 28 to 70 nm; HDL, 8 to 11 nm; and LDL, 20 to 25 nm.

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(stimulates dephosphorylation)

(stimulates phosphorylation)

Phosphorylated form is

inactive

Dephosphorylated form

is active

The third reaction is the committed and rate-limiting step and HMG-CoA reductase, anintegral membrane protein of the smooth ER,is the major point of regulation on the path-way to cholesterol biosynthesis.

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A high cellular cholesterol level diminishestranscription of the gene that encodes theLDL receptor, reducing production of thereceptor and thus the uptake of cholesterolfrom the blood (hypercholesterolemia).

Pathological accumulations of cholesterol in blood vessels (atherosclerotic

plaques) can develop, resulting in obstruction of blood vessels (atherosclerosis).

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These compounds, and several synthetic analogs, resemble mevalonate are competitive inhibitorsof HMG-CoA reductase, thus inhibiting cholesterol synthesis. Lovastatin treatment lowers serumcholesterol by as much as 30%. When combined with an edible resin that binds bile acids andprevents their reabsorption from the intestine, the drug is even more effective.

Ch21 Lipit Biyosentezi Yonca Duman

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