Essential Biochemistrylms.ndmctsgh.edu.tw/sysdata/47/9247/doc/e3262d64f0e7b468/... · 2019-04-24 · Lipoprotein functions 乳糜微粒 • Chylomicrons (CM) • transport fats from

Lecture Notes for

Chapter 17Lipid Metabolism

Essential BiochemistryThird Edition

Charlotte W. Pratt | Kathleen Cornely

Copyright © 2014 John Wiley & Sons, Inc. All rights reserved.

脂質的運送

© 2014 John Wiley & Sons, Inc. All rights reserved.

Lipoproteins transport cholesterol and

other fats.

(缺脂)脂蛋白

Lipoprotein functions

乳糜微粒

• Chylomicrons (CM)

• transport fats from intestines to tissues.

• Very-low-density lipoproteins (VLDL)

• transport triacylglycerols from the liver

to other tissues.

• Low-density lipoproteins (LDL)

• carry cholesterol to the tissues.• LDL levels should be relatively low.

• “Bad cholesterol.”

• High-density lipoproteins (HDL)

• export cholesterol from the tissues to

the liver.• HDL levels should be relatively high.

• “Good cholesterol.”

何者將脂質由週邊組織運往肝臟?

Approximately half of all deaths in

the US are linked to atherosclerosis.

• Atherosclerosis

– A slow progressive

disease

– Characterized by

hardening of the

arteries due to

lipid accumulation

in blood vessel

walls


Atherosclerosis 動脈粥狀硬化

何種脂蛋白在Atherosclerosis的起始扮演重要角色?

脂質的分解


Lipid Metabolism In

Context

• Triacylglycerols contain fatty

acids attached to a glycerol

backbone.

• Fatty acids are broken down

into 2C and 3C intermediates

that feed into the citric acid

cycle.


• Primary source of fatty acid fuel:

dietary triacylglycerols

17-1 Fatty Acid Oxidation

Many free fatty acid are deployed to the liver and muscle cells, especially

heart muscle何種組織主要以Free fatty acid作為能量來源?

Fatty acids are activated before they

are degraded

Acyl-CoA synthetase (ACS)

Fatty acid要分解要先”活化”

“活化” = 預先轉移ATP能量至” CoA”結構

Acyl-CoA synthetases

• 脂肪酸依長鏈數目有不同的類別

– Short (C2-C3)

– Medium (C4-C12)

– Long (≧C12)

– Very long (≧C22)

• 脂肪酸透過滲透作用進細胞，Acyl-CoA synthetase與membrane transport protein協同活化脂肪酸

• 一旦脂肪酸被活化，則無法再滲透出membrane (Acyl-CoA)

• 要繼續分解，則要先將Acyl-CoA運進粒線體

The carnitine shuttle system:

Transport acyl groups into

mitochondria

Fatty acid activated

in cytosol

β-Oxidation

in Mitochondria

何種shuttle system將Acyl group運進粒線體?

Each round of β oxidation has four

reactions

• β oxidation:

Acetyl-CoA進入粒線體後，以2個碳為單位減少的過程稱之

• 因為發生在β position (自Carbonyl carbon起算)，故稱為β-oxidation

Carbonyl carbonC3

C2

Each round of β oxidation has four

reactions

• 每回合4個催化步驟

• 產生一個Acetyl-CoA (2C)

• 原先的長鏈減少2C直到底

The reactions of β oxidation

Step 1 1st β-carbon oxidation (FAD) 氧化

Oxidative

Phosphorylation

Acyl-CoA dehydrogenases:

不同長度的Acyl-CoA由不同的ACDH

作用

中鏈醯輔酶A去氫酶缺乏症Medium-chain acyl-CoA

dehydrogenase (MCAD) deficiency

脂肪酸氧化障礙，會導致能量不足及代謝中毒產生腦病變、心肌病變、及肌肉病變等症狀。

氧化 = 脫氫，產生FADH2

→QH2


Step 2 Hydration 水合


Step 3 2nd β-carbon oxidation (NAD+)

氧化


Step 4 Thiolysis 硫解

每回合β-oxidation後產生何者?

β-Oxidation中，何者非反應產物?

β Oxidation results in ATP

production.


每回合β-oxidation共產生多少 ATP?

Degradation of unsaturated fatty acids

requires isomerization and reduction

當脂肪酸為不飽和脂肪酸，需要額外的步驟加以分解Isomerization and Reduction

由於長鏈脂肪酸以2碳遞減，故不飽和鍵只會有兩種情況：位於奇數 Cis 3,4

位於偶數 Cis 4,5

Enoyl-CoA isomerase converts a cis 3,4

double bond to a trans 2,3 double bond so

that β oxidation can continue.


位於奇數：Cis 3,4轉為Trans 2,3，接續第二步水合

When linoleate is

degraded,

another double

bond blocks β

oxidation.


位於偶數：第一步氧化後，與Cis 4,5形成共振以NADPH還原，形成Cis 3,4

再將Cis 3,4轉化為Trans 2,3，接續第二步水合

Oxidation of odd-chain fatty acids yields

propionyl-CoA

• 大多數Fatty acid為偶數，最後一個亦為Acetyl-CoA

• 有些植物或細菌產生奇數長鏈Fatty acid，最後一個將為3

個碳的Propionyl-CoA

• 解法：消費ATP加一個碳，使其形成Succinyl CoA，進入TCA循環

Breakdown of Propionyl-CoA


Methylmalonyl-CoA

mutase uses an unusual

cofactor.


• Cofactor comes from the vitamin cobalamin.

何種維生素與3碳脂質小分子代謝有關?

Some fatty acid oxidation occurs in

peroxisomes

• The majority of fatty acid oxidation occurs in

mitochondria.

• A small percentage is carried out in organelles known

as peroxisomes.

Some fatty acid oxidation occurs in

peroxisomes

• Different First step Acyl-CoA dehydrogenase

in mitochondria

High affinity for

Very-long chain FA

→ chain-shortening

system

By peroxisomal enzyme catalase

2 H2O2 2 H2O + O2

The function of peroxisomes

1. Very-long-chain fatty acid shortening

system

2. Branched-chain fatty acid (not recognized

by mitochondrial enzymes)

脂肪的合成

17-2 Fatty Acid Synthesis

• As glycolysis and gluconeogenesis, the pathways for

fatty acid synthesis and degradation must differ for

thermodynamic reasons.

β Oxidation Synthesis

Location Mitochondrial matrix Cytosol

Cofactors Coenzyme A Acyl-carrier protein

Energy

Transfer

Generate QH2 and

NADHConsume NADPH

ATP

requirements

2ATP once for acyl

group activation

1 ATP consumed for

each acetyl addition

17-2 Fatty Acid Synthesis

pantothenate (vitamin B5)

The citrate transport system

Fatty acid synthesis

in cytosol

Acetyl-CoA is generated

in mitochondria

(from pyruvate dehydrogenase)

The first step of fatty acid synthesis

Carboxylation of acetyl-CoA

A. CO2 activation

B. Transfers the carboxylate group to acetyl-

CoA

Malonyl-CoA

(C3 intermediate)

the donor of the

two-carbon acetyl units

Fatty acid synthase catalyzes seven

reactions

Fatty acid synthase:

•ACP: acyl-carrier proteinpantothenate arm swings between the

active sites

•6 active siteMAT: transacylase

TE: Thioesterase

KS: 3-ketoacyl-ACP syhthase

KR: 3-ketoacyl-ACP reductase

DH: 3-hydroxyacyl-ACP dehydrase

ER: enoyl-ACP reductase

Fatty acid synthesis begins with two

transacylation reactions.

Then, the two products are condensed…


Condensation in

Fatty Acid Synthesis



Step 3-7 ElongationNADPH generates from

pentose phosphate pathway


Step 8-9 Ending

• Fatty acid synthesis

cycles until a 16-C chain

is formed.

• A thioesterase releases

the acyl-carrier protein.

ATP consumption in Fatty acid

synthesis

• Example: Palmitate (16C)

Derived from Acetyl-CoA (2C)

7 malonyl-CoA required (7ATP)

14 NADPH required (14 × 2.5 = 35ATP)

the total cost = 42ATP

Advantages of multifunctional enzyme

• Allows the enzymes to be synthesized and controlled in

a coordinated fashion.

• The product of one reaction can quickly diffuse to the

next active site.

Other enzymes elongate and desaturate

newly synthesized fatty acids

• In mammals, fatty acid synthase produces mostly the 16-

carbon saturated fatty acid palmitate.

• Some sphingolipids contain C22 and C24 fatty acyl

groups.

• These and other long-chain fatty acids are generated by

enzymes known as elongases.

Other enzymes elongate and desaturate

newly synthesized fatty acids

• Desaturases:

introduce double bonds

into saturated fatty acids.

• Mammals cannot

introduce double bonds at

positions beyond C9 and

therefore cannot

synthesize fatty acids

such as linoleate and

linolenate (essential fatty

acid).

Control of

Fatty Acid

Metabolism

Inhibition

Activation

© 2014 John Wiley & Sons, Inc. All rights

reserved.

Acetyl-CoA can be converted to ketone

bodies

• Prolonged fast

→ glucose is unavailable from the diet

→ liver glycogen has been depleted

• Tissues depend on fatty acids released from stored

triacylglycerols.

• However, the brain does not burn fatty acids because

they pass poorly through the blood–brain barrier.

Ketogenesis

breath a characteristic

sweet smell

During periods of high ketogenic activity,

ketone bodies may be produced

faster than they are consumed.

Liver itself cannot catabolize ketone bodies

because it lacks one of the required enzymes,

3-ketoacyl-CoA transferase.

Catabolism of Ketone bodies

Ketone bodies produced by the liver are

used by other tissues as metabolic fuels

after being converted back to acetyl-CoA.

17-3 Synthesis of Other Lipids

• Other Lipids:

Triacylglycerols

Glycerophospholipids

Sphingolipids

Cholesterols

Triacylglycerols and phospholipids are

built from acyl-CoA groups

• Glycerol backbone from glycolytic intermediates

Synthesis of diacylglycerol and

triacylglycerol

Backbone +R1 +R2

+R3

Synthesis of phosphatidylethanolamine

and phosphatidylcholine

Synthesis of phosphatidylethanolamine

and phosphatidylcholine

Synthesis of phosphatidylserine

Synthesis of phosphatidylinositol

Cholesterol synthesis begins with

acetyl-CoA

• The first steps of

cholesterol synthesis

resemble those of

ketogenesis.

Ketogenesis

→ in mitochondria (liver)

→ Acetoacetate

Cholesterol

→ in cytosol

→ MevalonateRate-determining step

Cholesterol synthesis begins with

acetyl-CoA

• Mevalonate + 2 Pi – CO2

→ Isopentenyl pyrophosphate

Six isoprene units condense to form the

C30 compound squalene

Cholesterol can be used in several ways.

• Embedded into membranes

• Converted into esters for transport


Cholesterol can be used in several ways.

• Cholesterol can be a precursor of:

– Hormones such as testosterone, estrogen

– Bile acids such as cholate


Statins

• Statins have an HMG-like group that acts as

competitive inhibitor of HMG-CoA binding to the

enzyme

Cells can synthesize cholesterol

as well as take it up from

circulating low-density lipoproteins.


reserved.

High-density lipoproteins

remove excess cholesterol from

cells.


reserved.

Summary of

Lipid

Metabolism


reserved.

Documents

Essential Biochemistrylms.ndmctsgh.edu.tw/sysdata/47/9247/doc/e3262d64f0e7b468/... · 2019-04-24 · Lipoprotein functions 乳糜微粒 • Chylomicrons (CM) • transport fats from