脂类代谢

Lipid Metabolism

contents

Introduction of Lipids

catabolism of Fats

biosynthesis of lipids

Lipids Water insoluble compounds Major functions

Energy storage fatty acids, triacylglycerols

Structural elements phospholipids, cholesterol

I. Introduction of Lipids

1. Fatty acids Basic formula: CH3(CH2)nCOOH

Carboxylic acids with hydrocarbon chains of 4-36 carbons

FAs in cells are either: (i) part of a lipid molecule (ii) complex with a carrier protein

(e.g. albumin on blood) Saturated or unsaturated

Saturated fatty acids

Unsaturated fatty acids

Fully saturated fatty acid pack into nearly crystalline arrays, stabilized by hydrophobic interaction

The presence of cis double bonds interferes with the tight packing and results in less stable aggregates

Some Naturally Occurring Fatty acids

#C Common Name

12:0 Lauric Acid

14:0 Myristic Acid

16:0 Palmitic Acid ( 软脂酸 )

16:1 Palmitoleic Acid

18:0 Stearic Acid ( 硬脂酸 )

18:1 Oleic Acid (油酸 )

18:2 Linoleic Acid ( 亚油酸 )

18:3 Linolenic Acid ( 亚麻酸 )

20:0 Arachidic Acid

20:4 Arachidonic acid ( 花生四烯酸 )

24:0 Ligoceric Acid

Essential Fatty acids

2. Triacylglycerol Compose of three fatty acids each in eater

linkage with a single glycerol Most naturally occurring triacylglycerol contain two or more different fatty acids

CH2

C

CH2

CR2

O

HO

O

O C

O

R1

C

O

R3

1

2

3

Fatty acid composition in TAG Plant: more unsaturated fatty acids Animal: largely saturated fatty acids

functions:store fuels and provide energy Yield more energy than protein and carbohydrate

Fat 9 kcal/g

CHO/protein 4 kcal/g

3. Phospholipids

Classes of phospholipids (PL)

Glycerolphospholipids – glycerol backbone Sphingomyelin – spingosine backbone

12

PhospholipidsGlycerolphospholipids

Structure Two fatty acids are attached in ester linkage to the first and second carbon of glycerol A highly polar or charged group is attached by a phosphodiester linkage to the third carbon

13

properties

Amphipathic

Sphingomyelin 鞘氨醇磷酯

Sphingosine

structure

4. Cholesterol

A polar head

A non-polar body

structure

properties Amphipathic

functions

Membrane constituents to modulate membrane fluidity Precursor of steroid hormones and bile acids

Digestionof fats

mobilization and transport of fats Oxidation of Fatty acid

Ketone Bodies

II. catabolism of Fats

Fatty acids have three sources Diet Storage in cells as lipid droplet Cellular biosynthesis

1. Digestion of fats

Processing of dietary lipids

2. Fats mobilization and transport

the levels of glucose will affect the mobilization of fats Low levels of glucose in blood trigger the mobilization of triacyglycerols . Controlled by hormones:

Insulin epinephrine and glucagon

Fatty acids are relased and transported through binding with serum albumin

Glycerol is converted to glyceraldehyde-3-P and enters glycolysis or gluconeogenesis

Glycerol contributes only 5% of the biologically available energy of triacylglycerols

– Saturated fatty acids– CH3-(CH2)n-CH2-CH2-

COOH • Major pathway:

-oxidation

• Minor pathway: -oxidation

-oxidation

3. Oxidation of fatty acids

Stages of fatty acid oxidation

Oxidative phosphorylation

Activation

Mitochondria

membrane

Transport

-oxidation-oxidation

-oxidation

Mitochondria matrix

Dehydrogen

Dehydrogen

Hydration

Acetyl-transfer

Acetyl-CoA

(A) Activation: conversion of fatty acid to fatty acyl-CoA

(B) Transport: via the acyl-carnitine/carnitine transporter

(C) -oxidation : four major steps

脱氢

加水

再脱氢

硫解

-oxidation : four major steps

Question : Complete Oxidation of a Palmitate

4. Ketone bodies

Include acetoacetate, D-β-hydroxybutyrate, and acetone Acetyl-CoA in liver can be converted to keton bodies for exporting to other tissues in conditions of starvation and uncontrolled diabetes.

( 乙酰乙酸 )

( 丙酮 ) (β- 羟丁酸 )

Formation of Ketone bodies

β-Hydroxybutyrate synthesized in the liver passes into the blood and thus to other tissues, and it is converted to acetyl-CoA and then used for energy production

use of Ketone bodies

Ketone body formation and export from the liver

Biosynthesis of fatty acids

Biosynthesis of other lipids Triacyloglycerols

Membrane phopholipids

Cholesterol

III. Lipid Biosynthesis

+

+

H+

H+

Fatty acid synthesis is not simply a reversal of the degradation pathway.

Fatty acid synthesis and degradation pathways again exemplify the principle that synthetic and degradation pathways are almost always distinct.

1. Biosynthesis of fatty acids

柠檬酸

Preparation step one: transfer of acetyl groups from mitochondria to cytosol

Preparation step two: Malonyl-CoA is formed from carboxylation of acetyl-CoA

Acetyl-CoA carboxylase has three functional regions:

biotin carrier protein (gray); biotin carboxylase, which activates CO2 by attaching it to a nitrogen in the biotin ring in an ATP-dependent reaction transcarboxylase, which transfers activated COz from biotin to acetyl-CoA, producing malonyl-CoA.

The acetyl-CoA carboxylase reaction.

The long, flexible biotin arm carries the activated CO2 from the biotin carboxylase region to the transcarboxylase active site

Malonyl-CoA-ACP transacylase

Acetyl-CoA-ACP transacylase

Loading step: transfer of acetyl-CoA and malonyl-CoA to form acetyl-ACP and malonly-ACP

1.缩合

2.加氢还原 4.加氢还原

3.脱水

Four major steps in fatty acids biosynthesis

Acetyl-CoA- ACP transacetylase

Sequence of events during synthesis of a

fatty acid

-Ketoacyl-ACP synthase

-Dedroxyacyl-ACP dehydratase

Enoyl-ACP reductase

Translocation of butyryl group to Cys on KS

Malonyl-CoA -ACP transacylase

-Ketoacyl-ACP reductase

The overall process: 8 Acetyl-CoA + 7ATP + 14NADPH + 14H+

palmitate + 14 NADP+ + 8CoA + 6H2O + 7ADP + 7Pi

1. Seven cycles of condensation and reduction : 1Acetyl-CoA + 7 malonyl-CoA + 14NADPH + 14H+

palmitate + 7CO2 + 14 NADP+ + 8CoA + 6H2O

2. Formation of seven malonyl-CoA molecules: 7 Acetyl-CoA + 7CO2 + 7ATP 7 malonyl-CoA + 7ADP + 7Pi

3. Palmitate-ACP + H2O Palmitate + ACP + H2OPalmitoyl thioesterase

Question:how to synthesize a palmitate ?

2. Biosynthesis of fats

3. Biosynthesis of Phospholipids

Two general strategies for forming the phosphodiester bond of glycerophospholipids

The biosynthesis of sphingolipids

4. Biosynthesis of cholesterol

Summary of cholesterol biosynthesis,

The first stage Formation of mevalonate from acetyl-CoA.

The second stage Conversion of mevalonate into activated isoprene units.

The third stage Formation of squalene (30 carbons) by successive condensation

s of activated isoprene (five-carbon) units

The fourth stage Formation of squalene (30 carbons) by successive condensation

s of activated isoprene (five-carbon) units