K1,Structures and roles of fatty acids
K2,Fatty acid breakdown
K3,Fatty acid synthesis
K4,Metabolism of triacylglycerols
K5,Cholesterol metabolism
K6,Lipoproteins
Section K Lipid metabolism
? 1.Structure and properties
? 2,Nomenclature
? 3,Roles
? 4.Prostaglandins
Structures and roles of fatty acids
Structure and properties
Structure of fatty acid
saturated fatty acid unsaturated fatty acid
structure
Fatty acids structure and names
Fatty acid
? A fatty acid consists of a hydrocarbon chain
and a terminal carboxylic acid group,
? Most fatty acids have an even number carbon
atoms in an unbranched chain,
? Fatty acids can divided into saturated and
unsaturated fatty acids according to with or
without double bond,
? The properties of a fatty acid depend on the
chain length and the number of double bonds,
Nomenclature
? Fatty acid are named according to
the number of carbon atoms in the
chain and the number and position
of any double bonds,
Table fatty acids structure and names
Roles
? Essential components of
biological membranes,
? Covalently modifying proteins,
? Energy stores and fuel molecules,
? Fatty acid derivatives serve as
hormones and intracellular second
messengers,
Lipid
hormone
Prostaglandins
? Prostaglandins 前列腺素 and the other
eicosanoids 类二十烷酸 (prostacylins
前列环素,thromboxanes 凝血恶烷 and
leukotrienes 白三烯 ) are derived from
arachidonate 花生四烯酸, These
compounds all act as local hormones,
Arachidonic acid and some of its
eicosanoid derivatives
? Thromboxane A2
eicosanoid
PG
? 1,Overview
? 2,Activation
? 3,Transport into mitochondria
? 4,β-Oxidation pathway
? 5,Oxidation of unsaturated fatty
acids
? 6,Oxidation of odd-chain fatty
acids
? 7,Regulation
? 8,Energy yield
? 9,Ketone bodies
K2,Fatty acid breakdown
Overview
? Fatty acid breakdown brings about the
oxidation of long-chain fatty acids with
the production of energy in the form of
ATP,
? Fatty acid breakdown include β-oxidation
(fatty acid degrade into acetyl CoA);
citric acid cycle and oxidative
phosphorylation,
Stages of fatty acid oxidation
Activation
? Fatty acid breakdown occurs in the
cytosol of prokaryotes and in the
mitochondrial matrix of eukaryotes,
? The fatty acid is activated by forming
a thioester link with CoA before
entering the mitochondria,
Fatty Acid Activation
? Fatty acid + HSCoA + ATP fatty acyl-CoA +
AMP + PPi
? Catalyzed enzyme is acyl CoA synthase (also
called fatty acid thiokinase)
Fatty acid activation
Transport into mitochondria
? Small- and medium-chain acyl CoA
molecules (up to 10 carbon atoms) are
readily able to cross the inner
mitochondrial membrane by diffusion,
? The long acyl CoA is transported into
the mitochondria as carnitine 肉碱
derivatives by carnitine / acyl carnitine
translocase 移位酶,
Structure of carnitine
Fatty acid entry into mitochondria via
the acyl-carntine/carntine transporter
β-Oxidation pathway
? Oxidation
? Hydration 水化
? Oxidation
? Cleavage,or thiolysis 硫解
? Cleavage of the β-bond of fatty acyl
chain gives fatty acid breakdown its
alternative name,β-oxidation,
The fatty acid oxidation pathway
Oxidation
Hydration
Oxidation
Cleavage or thiolysis
summary
C16
Fatty acid synthesis
Reaction of palmitoyl CoA
? Palmitoyl-CoA + 7CoA + 7FAD + 7NAD+ +
7H2O 8 acetyl-CoA + 7FADH2 +
7NADH + 7H+
Oxidation of unsaturated fatty acids
Unsaturated fatty acid
Oxidation of odd-chain fatty acids
? It is similar in oven-chain fatty acid but in
the last step of oxidation pathway the
five carbon acyl CoA intermediate is
cleaved into one molecule of the C3
propionyl 丙酰 CoA and one molecule of
C2 acetyl CoA
Propionyl-CoA transform
H oxidation during fatty acid breakdown
Regulation
Energy yield
? Palmitoyl-CoA + 7CoA + 7O2 + 28Pi + 28ADP
8 acetyl-CoA + 28ATP + 42H2O
? 7 NADH + H+ 2.5 X 7 = 17.5 ATP
? 7 H2O
? 7 FADH2 1.5 X 7 = 10.5 ATP
? 7 H2O
? ADP + Pi ATP + H2O
Energy yield(2)
? 8 Acetyl-CoA + 16O2 + 80Pi + 80ADP 8CoA +
80ATP + 104H2O + 16CO2
? Acetyl-CoA 3 NADH + H+
? 10 ATP 1 FADH2 GTP ATP
? 32 H2O + 80 H2O - 8 H2O = 104 H2O
Energy yield(3)
? Palmitoyl-CoA + 23O2 + 108Pi + 108ADP
CoA + 108ATP + l6CO2 + 146H2O
? 108 – 2 = 106 ATP
Ketone bodies
? Acetoacetate
? 乙酰乙酸,
? D-3-hydroxybutyrate
? 羟丁酸 and acetone
? 丙酮 are collectively
termed ketone bodies 酮
体,
Ketone bodies (1)
Acetoacetyl-CoA
乙酰乙酰 CoA
HMG-CoA
β-羟 -β-甲戊二酰 CoA
Ketone bodies(2)
Ketone bodies degrade
FATTY ACID SYNTHESIS
content
? 1,Overview
? 2,Transport into the cytosol
? 3,The pathway
? 4,Formation of double bonds
? 5,Regulation
? Substance,Acetyl CoA
? Reductant,NADPH
? Acyl carrier,ACP
? Site,Cytosol
? Enzyme,Fatty acid synthase
Overview
Transport into the cytosol
? Since fatty acid synthesis takes place in
the cytosol (细胞浆 ),the acetyl CoA(乙酰
辅酶 A) produced from pyruvate(丙酮酸 )
has to be transported out of the
mitochondria(线粒体 ),
? However,the inner mitochondrial
membrane is not permeable to this
compound,so it is first combined with
oxaloacetate (草酰乙酸 ) to form
citrate(柠檬酸 ) which readily crosses
the membrane,In the cytosol the
citrate is cleaved to regenerate the
acetyl CoA,
Transport(2)
Transport(3)
The pathway
? The first committed step(关键步骤 ) in
fatty acid biosynthesis(生物合成 ) is the
carboxylation(羧化 ) of acetyl CoA to
form malonyl CoA(丙二酸单酰辅酶 A)
which is catalyzed by the biotin-
containing enzyme acetyl CoA
carboxylase (羧化酶 ),
Pathway (1)
Pathway (2)
O
? Acetyl ACP H3C—C—ACP
? Malconyl ACP
O O
C—CH2—C—ACP
O
Acetyl CoA and malonyl CoA are then
converted into their ACP derivatives,
Pathway (3)
? (1) Condensation of acetyl-ACP and
malonyl-ACP to form acetoacetyl-ACP,
(乙酰乙酰 -ACP) releasing free ACP and
CO2 (catalyzed by acyl-malonyl-ACP
condensing enzyme酰基 -丙二酸单酰 -ACP
合酶,β-酮酰 ACP合酶 ),
The elongation cycle in fatty acid synthesis involves four reactions
Pathway(4 )
? (2) Reduction of acetoacetyl-ACP to form
D-3-hydroxybutyryl-ACP (D-3-羟丁酰 -
ACP) using NADPH as reductant
(catalyzed by β –ketoacyl-ACP reductase
β-酮酰 ACP还原酶 ),
Reaction 2
Reaction 2
? (3) Dehydration of D-3-hydroxybutyryl-
ACP to produce crotonyl-ACP (丁烯酰 -
ACP,catalyzed by 3-hydroxyacyl-ACP
dehydratase β-羟酰 ACP脱水酶 ),
Reaction 3
Reaction 3
? (4) Reduction of crotonyl-ACP by a
second NADPH molecule to give butyryl-
ACP (丁酰 -ACP,catalyzed by enoyl-ACP
reductase 烯酰 -ACP还原酶 ),
Reaction 4
Reaction 4
Whole reaction
Associated proteins
? 1,Acetyl transacylase (AT)
? 2,Malonyl transacylase (MT)
? 3.Acyl-malonyl-ACP condensing enzyme
(β-
Ketoacyl-ACP synthase KS)
? 4.β-Ketoacyl-ACP reductase (KR)
? 5,3-Hydroxyacyl-ACP dehydratase (HD)
? 6,Enoyl-ACP reductase (ER)
? 7,Thioesterase
? 8,ACP
mode
synthase
? Further rounds of elongation add
more two-carbon units from malonyl-
ACP on to the growing hydrocarbon
chain,until the C16 palmitate (棕榈酸 )
is formed, Then it is hydrolyzed by a
thioesterase to give plamitate and
ACP,
fate
软脂酸分解与合成代谢的区别
? 区别点 ? 脂酸合成 ? 脂酸氧化
? 1.细胞中部位
? 2.酰基载体
? 3.二碳片断参加
或断裂的形式
? 4.电子供体或受
体
? 5.对 HCO3-和柠
檬
? 酸的需求
? 6.酶系
? 7.能量变化
? 细胞质
? ACP
? 丙二酸单酰 CoA
? NADPH
? 要求
? 7种酶,蛋白组成复
合体
? 消耗 7个 ATP及 14个
NADPH
? 线粒体
? CoA
? 乙酰 CoA
? FAD,NAD
? 不要求
? 4种酶
? 产生 106个
ATP
The overall stoichiometry (化学计量学 ) for
the synthesis of palmitate
? 8 acetyl CoA + 7ATP + 14 NADPH + 6 H+
? palmitate + 14 NADPH+ + 8 CoA +
6 H2O +7 ADP + 7 Pi
Fatty acid enlongation
? Further elongation of fatty acids takes place
on the cytosolic surface of the smooth
endoplasmic reticulum (SER滑面内质网 )
? Two carbon donor---malonyl CoA
? Acyl carrier----CoA
FORMATION OF DOUBLE BONDS
? In eukaryotes the SER has enzymes able to
introduce double bonds into fatty acyl CoA
molecules in an oxidation reaction that uses
molecular oxygen,
? Saturated fatty acyl CoA + NADH + H+ +O2
Mono-unsaturated acyl CoA + NAD+ + 2H2O
desaturation
Desaturation(2)
? Mammals lack the enzymes to insert
double bonds at carbon atoms beyond
C-9 in the fatty acid chain,
? Fatty acid can divide into essential and
nonessential fatty acid in the dietary
fat,
Essential fatty acid
Regulation
Phosphorylation
The key control point of fatty acid
synthesis is acetyl CoA carboxylase
which catalyzes the formation of
malonyl CoA,
? phosphorylation (磷酸化 )by an AMP-
activated protein kinase,Thus when
the energy charge of the cell is low
(high AMP,low ATP ) acetyl CoA
carboxylase is inactive,It is
reactivated by dephosphorylation by
protein phosphatase (磷酸酶 ) 2A,
Acetyl CoA carboxylase is inactivated by
Hormone
? Glucagon and epinephrine inhibit fatty
acid synthesis by inhibiting protein
phosphatase 2A,whereas insulin (胰岛
素 ) stimulates fatty acid synthesis by
activating the phosphatase,
Allosterical regulation
? Acetyl CoA carboxylase is also
allosterically regulated,citrate activates
the enzyme,whereas palmitoyl CoA
inhibits it,
Allosterical regulation
1,Structure and function
2,Synthesis
3,Breakdown
4,Regulation
METABOLISM OF TRIACYLGLYEROLS
Stucture and function
? Triacylglycerols (fats or triglycerides)
consist of three fatty acid chains esterified
to a glycerol backbone,Simple
triacylglycerols (三脂酰甘油 ) have three
identical fatty acids,mixed triacylglycerols
have two or three different fatty acids,
structure
Structure (2)
Triacylglycerols
Triacylglycerols are the major energy store
and the major dietary lipid in humans,
They are insoluble in water and are stored
in specialized adipose (fat) cells,
Synthesis
Triacylglycerols(甘油三脂 ) are synthesized
from glycerol 3-phosphate,which is
derived from the glycolytic intermediate
dihydroxyacetone phosphate (磷酸二羟丙
酮 ),and fatty acyl CoAs,
synthesis 1
Synthesis 2
The phosphate group is then removed
to form diacylglycerol (DAG 二脂酰甘
油 ),which is further acylated to
triacylglycerol,The energy for the
synthesis of triacylglycerols comes
from the hydrolysis of the high-
energy thioester bond (硫酯键 ) in acyl
CoA,
Synthesis 3
Synthesis 3
Breakdown
The fatty acids in triacylglycerols are
released from glycerol backbone by the
action of lipases (脂酶 ),The free fatty
acids can be degraded by β –oxidation to
produce energy,The glycerol is
converted into dihydroxyacetone
phasphate (磷酸二羟丙酮 ) which enters
glycolysis (糖酵解 ),
Breakdown 1
Breakdown 2
4.Regulation
The concentration of free fatty acids in the blood is controlled
by the rate at which hormone–sensitive triacylglycerol lipase
hydrolyzes the triacylglycerols stored in adipose tissue,
Glucagon (胰高血糖素 ),epinephrine (肾上腺素 ) and
norepinephrine (去甲肾上腺素 ) cause an increase in the
intracellular level of cAMP which allosterically activates cAMP-
dependent protein kinase,
The kinase in turn phosphorylates hormone-sensitive lipase,
activating it,and leading to the release of fatty acids into the
blood,Insulin has the opposite effect; it decrease the level of
cAMP which leads to the dephosphorylation and inactivation of
hormone-sensitive lipase,
regulation
summary
1.Functions of cholesterol
2,Biosynthesis of cholesterol
3,Regulation of cholesterol biosynthesis
4,Bile salts
5,Vitamin D
6,Steroid hormones
CHOLESTEROL ETABOLESM
1.Functions of cholesterol
? I,Cell membranes
? II,Precursor of steroid hormones
? III,Vitamin D
? IV,Bile salts
2.Biosynthesis of cholesterol
? (1) Synthesis of Mevalonate 甲羟戊酸 from Acetyl
CoA
? (2) Conversion 转化 of Mevalonate to Two
Activated Isoprenes 异戊二烯
? (3) Condensation of Six Activated Isoprene Units
to Form Squalene 鲨烯
? (4) Conversion of Squalene to the Four-Ring
Steroid Nucleus
cholesterol
Cholesterol structure
Synthesis 1
? All 27 carbon atoms of cholesterol (胆固
醇 ) are derived from acetyl CoA,First
acetyl CoA and acetoacetyl CoA
combine to form HMG CoA which,in
turn,is reduced to mevalonate(甲羟戊酸 )
by HMG CoA reductase (还原酶 ),
Synthesis 1
Synthesis 2
? Mevalonate is converted into the five-
carbon isoprene(异戊烯 ) compounds 3-
isopentenyl pyrophosphate (异戊烯焦磷
酸 ) and its isomer dimethylallyl
pyrophosphate (二甲（基）烯丙基焦磷
酸 ),
Synthesis 2
二甲烯丙基焦磷酸
Synthesis 3
Synthesis 3
? These two compounds condense to form the
C10 geranyl pyrophosphate (香叶焦磷酸 ),which
is elongated to the C15 farnesyl pyrophosphate
(法尼焦磷酸 ) by the addition of another molecule
of isopentenyl pyrophosphate,
? Two molecules of farnesyl pyrophosphare
condense to form the C30 squalene (鲨烯 ),
which is then converted via squalene epoxide
(环氧 ) and lanosterol (羊毛固醇 ) to cholesterol,
Synthesis 4
Synthesis 5
豆固醇 麦角固醇
羊毛固醇
Synthesis 6
synthesis 7
Regulation of cholesterol
biosynthesis
? Feedback-inhibiting the activity of HMG CoA
reductase,the enzyme which catalyzes the
committed step in cholesterol biosynthesis
? Decreasing the amount of HMG CoA reducing
the synthesis and translation of its mRNA;
? Decreasing the amount of HMG CoA reductase
by increasing its rate of degradation,
regulation
application
Bile salts
? Bile salts (bile acids) are the major excretory
form of cholesterol.These polar compounds
are formed in the liver by converting
cholesterol into the activated intermediate
cholyl CoA (胆酰 CoA) and then combining
this compound with either glycine,to form
glycocholate(甘氨酰胆酸 ),or taurine 牛磺酸,
to form taurocholate (牛磺胆酸 ),
Bile salt
Bile salt
? The detergent-like bile salts are secreted
into the intestine where they aid the
digestion and uptake of dietary lipids,
? The intestinal absorption of the lipid-
soluble vitamins A,D,E and K also
requires the action of the bile salts,
Vitamin D
? Vitamin D is derived from cholesterol in a
series of reactions,one of which requires
the action of UV light to break the bond
between two carbon atoms.Deficiency of
vitamin D causes rickets (佝偻病 ) in
children and osteomalacia (骨软化症 ) in
adults,
Vitamin D
Steroid hormones
? The steroid hormones are derived from
cholesterol by a series of reactions that
involve the heme-containing cytochrome
P450 enzymes,These mono-oxygenases
require both O2 and NADPH to function,
five classes of steroid hormones
? (1) the progestagens (e.g,progesterone孕酮 );
? (2)the androgens (雄激素 e.g,testosterone 睾
丸酮 );
? (3) the estrogens (雌激素 e.g,estrone 雌酮 );
? (4) the glucocorticoids (糖皮质激素
e.g.cortisol 皮质醇 );
? (5) the mineralocorticoids (盐皮质激素
e.g,aldosterone 醛固酮 ),
transform
1.Structure and function
2,Chylomicrons 乳糜微粒
3,VLDLs,IDLs and LDLs
4,HDLs
5,Atherosclerosis 动脉粥样硬化
6,Familial hypercholesterolemia
家族性高胆固醇血症
K6 LIPOPROTEINS
Structure and function
structure
major function of lipoproteins
? The major function of lipoproteins is
to transport triacylglycerols,
cholesterol and phospholipids around
the body,
Chylomicrons
? Chylomicrons (乳糜微粒 ) are
synthesized in the intestine and
transport dietary triacylglycerols to
skeletal muscle and adipose tissue,and
dietary cholesterol to the liver,
transport
? At these target tissues the triacylglycerols are
hydrolyzed by lipoprotein lipase on the surface
of the cells and the released fatty acids are
taken up either for metabolism to generate
energy or for storage,The resulting
cholesterol-rich chylomicron remnants are
transported in the blood to the liver where they
are taken up by receptor-mediated endocytosis
(内吞作用 ),
Transport
structure
VLDLS,IDLS and LDLS
? VLDLS,are synthesized in the liver and
transport triacylglycerols,cholesterol
and phospholipids to other tissues,
where lipoprotein lipase hydrolyzes
the triacylglycerols and releases the
fatty acids for uptake,
VLDL remnants
? The VLDL remnants are transformed
first to IDLS and then to LDLS as all of
their apoproteins other than apoB-100
are removed and their cholesterol
esterified,The LDLS bind to the LDL
receptor protein on the surface of target
cells and are internalized by receptor-
mediated endocytosis,
cholesterol
? The cholesterol,which is released from the
lipoproteins by the action of lysosomal
lipases,is either incorporated into the cell
membrane or re-esterified for storage,High
levels of intracellular cholesterol decrease
the syntheses of the LDL receptor,
reducing the rate of uptake of cholesterol,
and inhibit HMG CoA reductase,preventing
the cellular syntheses of cholesterol,
structure
endocytosis
HDLs
? HDLs are synthesized in the blood and
extract cholesterol from cell membranes,
converting it into cholesterol esters,
Some of the cholesterol esters are then
transferred to VLDLS and all of the HDLs
are taken up into the liver cells by
receptor-mediated endocytosis and the
cholesterol disposed of in the form of bile
salts,
synthesis
Synthesis 2
Atherosclerosis
? Atherosclerosis (动脉硬化症 ) is
characterized by cholesterol-rich
arterial thickenings (atheromas 动脉粥
样硬化 ) that narrow the arteries and
cause blood clots to form,If these
blood clots block the coronary
arteries supplying the heart,the result
is a myocardial infarction (心肌梗塞 ),or
heart attack,
Familial hypercholesterolemia
家族性高胆固醇血症
? This is a inherited disorder in which
individuals have a lack of functional
LDL receptors preventing cholesterol
from being taken up by the tissues,
? High blood cholesterol
? Atheromas 动脉粥样硬化
? Xanthomas 黄瘤病
? Myocardial infarction 心肌梗塞
transform
K2,Fatty acid breakdown
K3,Fatty acid synthesis
K4,Metabolism of triacylglycerols
K5,Cholesterol metabolism
K6,Lipoproteins
Section K Lipid metabolism
? 1.Structure and properties
? 2,Nomenclature
? 3,Roles
? 4.Prostaglandins
Structures and roles of fatty acids
Structure and properties
Structure of fatty acid
saturated fatty acid unsaturated fatty acid
structure
Fatty acids structure and names
Fatty acid
? A fatty acid consists of a hydrocarbon chain
and a terminal carboxylic acid group,
? Most fatty acids have an even number carbon
atoms in an unbranched chain,
? Fatty acids can divided into saturated and
unsaturated fatty acids according to with or
without double bond,
? The properties of a fatty acid depend on the
chain length and the number of double bonds,
Nomenclature
? Fatty acid are named according to
the number of carbon atoms in the
chain and the number and position
of any double bonds,
Table fatty acids structure and names
Roles
? Essential components of
biological membranes,
? Covalently modifying proteins,
? Energy stores and fuel molecules,
? Fatty acid derivatives serve as
hormones and intracellular second
messengers,
Lipid
hormone
Prostaglandins
? Prostaglandins 前列腺素 and the other
eicosanoids 类二十烷酸 (prostacylins
前列环素,thromboxanes 凝血恶烷 and
leukotrienes 白三烯 ) are derived from
arachidonate 花生四烯酸, These
compounds all act as local hormones,
Arachidonic acid and some of its
eicosanoid derivatives
? Thromboxane A2
eicosanoid
PG
? 1,Overview
? 2,Activation
? 3,Transport into mitochondria
? 4,β-Oxidation pathway
? 5,Oxidation of unsaturated fatty
acids
? 6,Oxidation of odd-chain fatty
acids
? 7,Regulation
? 8,Energy yield
? 9,Ketone bodies
K2,Fatty acid breakdown
Overview
? Fatty acid breakdown brings about the
oxidation of long-chain fatty acids with
the production of energy in the form of
ATP,
? Fatty acid breakdown include β-oxidation
(fatty acid degrade into acetyl CoA);
citric acid cycle and oxidative
phosphorylation,
Stages of fatty acid oxidation
Activation
? Fatty acid breakdown occurs in the
cytosol of prokaryotes and in the
mitochondrial matrix of eukaryotes,
? The fatty acid is activated by forming
a thioester link with CoA before
entering the mitochondria,
Fatty Acid Activation
? Fatty acid + HSCoA + ATP fatty acyl-CoA +
AMP + PPi
? Catalyzed enzyme is acyl CoA synthase (also
called fatty acid thiokinase)
Fatty acid activation
Transport into mitochondria
? Small- and medium-chain acyl CoA
molecules (up to 10 carbon atoms) are
readily able to cross the inner
mitochondrial membrane by diffusion,
? The long acyl CoA is transported into
the mitochondria as carnitine 肉碱
derivatives by carnitine / acyl carnitine
translocase 移位酶,
Structure of carnitine
Fatty acid entry into mitochondria via
the acyl-carntine/carntine transporter
β-Oxidation pathway
? Oxidation
? Hydration 水化
? Oxidation
? Cleavage,or thiolysis 硫解
? Cleavage of the β-bond of fatty acyl
chain gives fatty acid breakdown its
alternative name,β-oxidation,
The fatty acid oxidation pathway
Oxidation
Hydration
Oxidation
Cleavage or thiolysis
summary
C16
Fatty acid synthesis
Reaction of palmitoyl CoA
? Palmitoyl-CoA + 7CoA + 7FAD + 7NAD+ +
7H2O 8 acetyl-CoA + 7FADH2 +
7NADH + 7H+
Oxidation of unsaturated fatty acids
Unsaturated fatty acid
Oxidation of odd-chain fatty acids
? It is similar in oven-chain fatty acid but in
the last step of oxidation pathway the
five carbon acyl CoA intermediate is
cleaved into one molecule of the C3
propionyl 丙酰 CoA and one molecule of
C2 acetyl CoA
Propionyl-CoA transform
H oxidation during fatty acid breakdown
Regulation
Energy yield
? Palmitoyl-CoA + 7CoA + 7O2 + 28Pi + 28ADP
8 acetyl-CoA + 28ATP + 42H2O
? 7 NADH + H+ 2.5 X 7 = 17.5 ATP
? 7 H2O
? 7 FADH2 1.5 X 7 = 10.5 ATP
? 7 H2O
? ADP + Pi ATP + H2O
Energy yield(2)
? 8 Acetyl-CoA + 16O2 + 80Pi + 80ADP 8CoA +
80ATP + 104H2O + 16CO2
? Acetyl-CoA 3 NADH + H+
? 10 ATP 1 FADH2 GTP ATP
? 32 H2O + 80 H2O - 8 H2O = 104 H2O
Energy yield(3)
? Palmitoyl-CoA + 23O2 + 108Pi + 108ADP
CoA + 108ATP + l6CO2 + 146H2O
? 108 – 2 = 106 ATP
Ketone bodies
? Acetoacetate
? 乙酰乙酸,
? D-3-hydroxybutyrate
? 羟丁酸 and acetone
? 丙酮 are collectively
termed ketone bodies 酮
体,
Ketone bodies (1)
Acetoacetyl-CoA
乙酰乙酰 CoA
HMG-CoA
β-羟 -β-甲戊二酰 CoA
Ketone bodies(2)
Ketone bodies degrade
FATTY ACID SYNTHESIS
content
? 1,Overview
? 2,Transport into the cytosol
? 3,The pathway
? 4,Formation of double bonds
? 5,Regulation
? Substance,Acetyl CoA
? Reductant,NADPH
? Acyl carrier,ACP
? Site,Cytosol
? Enzyme,Fatty acid synthase
Overview
Transport into the cytosol
? Since fatty acid synthesis takes place in
the cytosol (细胞浆 ),the acetyl CoA(乙酰
辅酶 A) produced from pyruvate(丙酮酸 )
has to be transported out of the
mitochondria(线粒体 ),
? However,the inner mitochondrial
membrane is not permeable to this
compound,so it is first combined with
oxaloacetate (草酰乙酸 ) to form
citrate(柠檬酸 ) which readily crosses
the membrane,In the cytosol the
citrate is cleaved to regenerate the
acetyl CoA,
Transport(2)
Transport(3)
The pathway
? The first committed step(关键步骤 ) in
fatty acid biosynthesis(生物合成 ) is the
carboxylation(羧化 ) of acetyl CoA to
form malonyl CoA(丙二酸单酰辅酶 A)
which is catalyzed by the biotin-
containing enzyme acetyl CoA
carboxylase (羧化酶 ),
Pathway (1)
Pathway (2)
O
? Acetyl ACP H3C—C—ACP
? Malconyl ACP
O O
C—CH2—C—ACP
O
Acetyl CoA and malonyl CoA are then
converted into their ACP derivatives,
Pathway (3)
? (1) Condensation of acetyl-ACP and
malonyl-ACP to form acetoacetyl-ACP,
(乙酰乙酰 -ACP) releasing free ACP and
CO2 (catalyzed by acyl-malonyl-ACP
condensing enzyme酰基 -丙二酸单酰 -ACP
合酶,β-酮酰 ACP合酶 ),
The elongation cycle in fatty acid synthesis involves four reactions
Pathway(4 )
? (2) Reduction of acetoacetyl-ACP to form
D-3-hydroxybutyryl-ACP (D-3-羟丁酰 -
ACP) using NADPH as reductant
(catalyzed by β –ketoacyl-ACP reductase
β-酮酰 ACP还原酶 ),
Reaction 2
Reaction 2
? (3) Dehydration of D-3-hydroxybutyryl-
ACP to produce crotonyl-ACP (丁烯酰 -
ACP,catalyzed by 3-hydroxyacyl-ACP
dehydratase β-羟酰 ACP脱水酶 ),
Reaction 3
Reaction 3
? (4) Reduction of crotonyl-ACP by a
second NADPH molecule to give butyryl-
ACP (丁酰 -ACP,catalyzed by enoyl-ACP
reductase 烯酰 -ACP还原酶 ),
Reaction 4
Reaction 4
Whole reaction
Associated proteins
? 1,Acetyl transacylase (AT)
? 2,Malonyl transacylase (MT)
? 3.Acyl-malonyl-ACP condensing enzyme
(β-
Ketoacyl-ACP synthase KS)
? 4.β-Ketoacyl-ACP reductase (KR)
? 5,3-Hydroxyacyl-ACP dehydratase (HD)
? 6,Enoyl-ACP reductase (ER)
? 7,Thioesterase
? 8,ACP
mode
synthase
? Further rounds of elongation add
more two-carbon units from malonyl-
ACP on to the growing hydrocarbon
chain,until the C16 palmitate (棕榈酸 )
is formed, Then it is hydrolyzed by a
thioesterase to give plamitate and
ACP,
fate
软脂酸分解与合成代谢的区别
? 区别点 ? 脂酸合成 ? 脂酸氧化
? 1.细胞中部位
? 2.酰基载体
? 3.二碳片断参加
或断裂的形式
? 4.电子供体或受
体
? 5.对 HCO3-和柠
檬
? 酸的需求
? 6.酶系
? 7.能量变化
? 细胞质
? ACP
? 丙二酸单酰 CoA
? NADPH
? 要求
? 7种酶,蛋白组成复
合体
? 消耗 7个 ATP及 14个
NADPH
? 线粒体
? CoA
? 乙酰 CoA
? FAD,NAD
? 不要求
? 4种酶
? 产生 106个
ATP
The overall stoichiometry (化学计量学 ) for
the synthesis of palmitate
? 8 acetyl CoA + 7ATP + 14 NADPH + 6 H+
? palmitate + 14 NADPH+ + 8 CoA +
6 H2O +7 ADP + 7 Pi
Fatty acid enlongation
? Further elongation of fatty acids takes place
on the cytosolic surface of the smooth
endoplasmic reticulum (SER滑面内质网 )
? Two carbon donor---malonyl CoA
? Acyl carrier----CoA
FORMATION OF DOUBLE BONDS
? In eukaryotes the SER has enzymes able to
introduce double bonds into fatty acyl CoA
molecules in an oxidation reaction that uses
molecular oxygen,
? Saturated fatty acyl CoA + NADH + H+ +O2
Mono-unsaturated acyl CoA + NAD+ + 2H2O
desaturation
Desaturation(2)
? Mammals lack the enzymes to insert
double bonds at carbon atoms beyond
C-9 in the fatty acid chain,
? Fatty acid can divide into essential and
nonessential fatty acid in the dietary
fat,
Essential fatty acid
Regulation
Phosphorylation
The key control point of fatty acid
synthesis is acetyl CoA carboxylase
which catalyzes the formation of
malonyl CoA,
? phosphorylation (磷酸化 )by an AMP-
activated protein kinase,Thus when
the energy charge of the cell is low
(high AMP,low ATP ) acetyl CoA
carboxylase is inactive,It is
reactivated by dephosphorylation by
protein phosphatase (磷酸酶 ) 2A,
Acetyl CoA carboxylase is inactivated by
Hormone
? Glucagon and epinephrine inhibit fatty
acid synthesis by inhibiting protein
phosphatase 2A,whereas insulin (胰岛
素 ) stimulates fatty acid synthesis by
activating the phosphatase,
Allosterical regulation
? Acetyl CoA carboxylase is also
allosterically regulated,citrate activates
the enzyme,whereas palmitoyl CoA
inhibits it,
Allosterical regulation
1,Structure and function
2,Synthesis
3,Breakdown
4,Regulation
METABOLISM OF TRIACYLGLYEROLS
Stucture and function
? Triacylglycerols (fats or triglycerides)
consist of three fatty acid chains esterified
to a glycerol backbone,Simple
triacylglycerols (三脂酰甘油 ) have three
identical fatty acids,mixed triacylglycerols
have two or three different fatty acids,
structure
Structure (2)
Triacylglycerols
Triacylglycerols are the major energy store
and the major dietary lipid in humans,
They are insoluble in water and are stored
in specialized adipose (fat) cells,
Synthesis
Triacylglycerols(甘油三脂 ) are synthesized
from glycerol 3-phosphate,which is
derived from the glycolytic intermediate
dihydroxyacetone phosphate (磷酸二羟丙
酮 ),and fatty acyl CoAs,
synthesis 1
Synthesis 2
The phosphate group is then removed
to form diacylglycerol (DAG 二脂酰甘
油 ),which is further acylated to
triacylglycerol,The energy for the
synthesis of triacylglycerols comes
from the hydrolysis of the high-
energy thioester bond (硫酯键 ) in acyl
CoA,
Synthesis 3
Synthesis 3
Breakdown
The fatty acids in triacylglycerols are
released from glycerol backbone by the
action of lipases (脂酶 ),The free fatty
acids can be degraded by β –oxidation to
produce energy,The glycerol is
converted into dihydroxyacetone
phasphate (磷酸二羟丙酮 ) which enters
glycolysis (糖酵解 ),
Breakdown 1
Breakdown 2
4.Regulation
The concentration of free fatty acids in the blood is controlled
by the rate at which hormone–sensitive triacylglycerol lipase
hydrolyzes the triacylglycerols stored in adipose tissue,
Glucagon (胰高血糖素 ),epinephrine (肾上腺素 ) and
norepinephrine (去甲肾上腺素 ) cause an increase in the
intracellular level of cAMP which allosterically activates cAMP-
dependent protein kinase,
The kinase in turn phosphorylates hormone-sensitive lipase,
activating it,and leading to the release of fatty acids into the
blood,Insulin has the opposite effect; it decrease the level of
cAMP which leads to the dephosphorylation and inactivation of
hormone-sensitive lipase,
regulation
summary
1.Functions of cholesterol
2,Biosynthesis of cholesterol
3,Regulation of cholesterol biosynthesis
4,Bile salts
5,Vitamin D
6,Steroid hormones
CHOLESTEROL ETABOLESM
1.Functions of cholesterol
? I,Cell membranes
? II,Precursor of steroid hormones
? III,Vitamin D
? IV,Bile salts
2.Biosynthesis of cholesterol
? (1) Synthesis of Mevalonate 甲羟戊酸 from Acetyl
CoA
? (2) Conversion 转化 of Mevalonate to Two
Activated Isoprenes 异戊二烯
? (3) Condensation of Six Activated Isoprene Units
to Form Squalene 鲨烯
? (4) Conversion of Squalene to the Four-Ring
Steroid Nucleus
cholesterol
Cholesterol structure
Synthesis 1
? All 27 carbon atoms of cholesterol (胆固
醇 ) are derived from acetyl CoA,First
acetyl CoA and acetoacetyl CoA
combine to form HMG CoA which,in
turn,is reduced to mevalonate(甲羟戊酸 )
by HMG CoA reductase (还原酶 ),
Synthesis 1
Synthesis 2
? Mevalonate is converted into the five-
carbon isoprene(异戊烯 ) compounds 3-
isopentenyl pyrophosphate (异戊烯焦磷
酸 ) and its isomer dimethylallyl
pyrophosphate (二甲（基）烯丙基焦磷
酸 ),
Synthesis 2
二甲烯丙基焦磷酸
Synthesis 3
Synthesis 3
? These two compounds condense to form the
C10 geranyl pyrophosphate (香叶焦磷酸 ),which
is elongated to the C15 farnesyl pyrophosphate
(法尼焦磷酸 ) by the addition of another molecule
of isopentenyl pyrophosphate,
? Two molecules of farnesyl pyrophosphare
condense to form the C30 squalene (鲨烯 ),
which is then converted via squalene epoxide
(环氧 ) and lanosterol (羊毛固醇 ) to cholesterol,
Synthesis 4
Synthesis 5
豆固醇 麦角固醇
羊毛固醇
Synthesis 6
synthesis 7
Regulation of cholesterol
biosynthesis
? Feedback-inhibiting the activity of HMG CoA
reductase,the enzyme which catalyzes the
committed step in cholesterol biosynthesis
? Decreasing the amount of HMG CoA reducing
the synthesis and translation of its mRNA;
? Decreasing the amount of HMG CoA reductase
by increasing its rate of degradation,
regulation
application
Bile salts
? Bile salts (bile acids) are the major excretory
form of cholesterol.These polar compounds
are formed in the liver by converting
cholesterol into the activated intermediate
cholyl CoA (胆酰 CoA) and then combining
this compound with either glycine,to form
glycocholate(甘氨酰胆酸 ),or taurine 牛磺酸,
to form taurocholate (牛磺胆酸 ),
Bile salt
Bile salt
? The detergent-like bile salts are secreted
into the intestine where they aid the
digestion and uptake of dietary lipids,
? The intestinal absorption of the lipid-
soluble vitamins A,D,E and K also
requires the action of the bile salts,
Vitamin D
? Vitamin D is derived from cholesterol in a
series of reactions,one of which requires
the action of UV light to break the bond
between two carbon atoms.Deficiency of
vitamin D causes rickets (佝偻病 ) in
children and osteomalacia (骨软化症 ) in
adults,
Vitamin D
Steroid hormones
? The steroid hormones are derived from
cholesterol by a series of reactions that
involve the heme-containing cytochrome
P450 enzymes,These mono-oxygenases
require both O2 and NADPH to function,
five classes of steroid hormones
? (1) the progestagens (e.g,progesterone孕酮 );
? (2)the androgens (雄激素 e.g,testosterone 睾
丸酮 );
? (3) the estrogens (雌激素 e.g,estrone 雌酮 );
? (4) the glucocorticoids (糖皮质激素
e.g.cortisol 皮质醇 );
? (5) the mineralocorticoids (盐皮质激素
e.g,aldosterone 醛固酮 ),
transform
1.Structure and function
2,Chylomicrons 乳糜微粒
3,VLDLs,IDLs and LDLs
4,HDLs
5,Atherosclerosis 动脉粥样硬化
6,Familial hypercholesterolemia
家族性高胆固醇血症
K6 LIPOPROTEINS
Structure and function
structure
major function of lipoproteins
? The major function of lipoproteins is
to transport triacylglycerols,
cholesterol and phospholipids around
the body,
Chylomicrons
? Chylomicrons (乳糜微粒 ) are
synthesized in the intestine and
transport dietary triacylglycerols to
skeletal muscle and adipose tissue,and
dietary cholesterol to the liver,
transport
? At these target tissues the triacylglycerols are
hydrolyzed by lipoprotein lipase on the surface
of the cells and the released fatty acids are
taken up either for metabolism to generate
energy or for storage,The resulting
cholesterol-rich chylomicron remnants are
transported in the blood to the liver where they
are taken up by receptor-mediated endocytosis
(内吞作用 ),
Transport
structure
VLDLS,IDLS and LDLS
? VLDLS,are synthesized in the liver and
transport triacylglycerols,cholesterol
and phospholipids to other tissues,
where lipoprotein lipase hydrolyzes
the triacylglycerols and releases the
fatty acids for uptake,
VLDL remnants
? The VLDL remnants are transformed
first to IDLS and then to LDLS as all of
their apoproteins other than apoB-100
are removed and their cholesterol
esterified,The LDLS bind to the LDL
receptor protein on the surface of target
cells and are internalized by receptor-
mediated endocytosis,
cholesterol
? The cholesterol,which is released from the
lipoproteins by the action of lysosomal
lipases,is either incorporated into the cell
membrane or re-esterified for storage,High
levels of intracellular cholesterol decrease
the syntheses of the LDL receptor,
reducing the rate of uptake of cholesterol,
and inhibit HMG CoA reductase,preventing
the cellular syntheses of cholesterol,
structure
endocytosis
HDLs
? HDLs are synthesized in the blood and
extract cholesterol from cell membranes,
converting it into cholesterol esters,
Some of the cholesterol esters are then
transferred to VLDLS and all of the HDLs
are taken up into the liver cells by
receptor-mediated endocytosis and the
cholesterol disposed of in the form of bile
salts,
synthesis
Synthesis 2
Atherosclerosis
? Atherosclerosis (动脉硬化症 ) is
characterized by cholesterol-rich
arterial thickenings (atheromas 动脉粥
样硬化 ) that narrow the arteries and
cause blood clots to form,If these
blood clots block the coronary
arteries supplying the heart,the result
is a myocardial infarction (心肌梗塞 ),or
heart attack,
Familial hypercholesterolemia
家族性高胆固醇血症
? This is a inherited disorder in which
individuals have a lack of functional
LDL receptors preventing cholesterol
from being taken up by the tissues,
? High blood cholesterol
? Atheromas 动脉粥样硬化
? Xanthomas 黄瘤病
? Myocardial infarction 心肌梗塞
transform
