professor wu yaosheng 2009-10 biochemistry dept. of biochemistry and molecular biology
TRANSCRIPT
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Professor Wu Yaosheng
2009-10
BiochemistryDept. of Biochemistry and Molecular Biology
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還沒有來得及準備好接受這一地的金黃, 秋天就這樣悄無聲
息的來到了我們的身邊。
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Chapter 9
Regulation of Metabolism
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Main Contents
1. Metabolic Regulation at Cell Level
2. Metabolic Regulation at Hormone Level
3. Regulation of Metabolism at Integral Level
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Key Points and difficulties
◆ Some important metabolism molecules
◆ Mutual relationship of carbohydrate, TG, Pr
◆ Key enzymes and their distribution
◆ Regulation levels and fashion of substance metabolism
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1.Mutual interknit among various metabolism pathways
Sugar
Lipid
Protein
H2O
Salt
Vitamin
各种物质代谢之间互有联系,相互依存。
Digestion Absorption
Middle metabolism
Waste excretion
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Introduction Characteristics of Substance Metabolism
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2. Metabolism processes regulated constant finely
Subtle regulation mechanisms to regulate metabolism intensity, direction, velocity
Inside and outside of circumstances
To influence organism metabolism
To fit in with the change of circumstances
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3. Various tissues and organs have themselves metabolism characters
Different structures
Different enzymes and contents
Different organs
Different metabolism pathways
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4. Each common metabolism pool
For example:
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Sugar digested and absorbed
glycogen degradation
gluconeogensis
Blo
od
sug
ar Va
riou
s tis
su
es
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5. ATP is the common form for energy store and
utilization
Nutriment decomposition
To release energy
ADP+Pi
ATP
Directly supply energy
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6. NADPH can supply the reduction equation for anabolism
For example :
Acetyl CoA
NADPH + H+
Fatty acids, cholesterol
Pentose phosphate pathway
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Questions
1. How to relate carbohydrate metabolism with lipid or protein metabolism by some important interim molecules?
2. What are the important significances of ATP during substance metabolism?
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What are metabolic interrelationships?
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Section One
Metabolic Regulation at C
ell Level
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1.1 Distribution of Enzymes in Cells
•代谢途径有关酶类常常组成多酶体系,分布于细胞的某一区域 。
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Metabolic pathways Distribution Metabolic pathways Distribution
Glycolysis Cytosol Oxidation phosphorylation
Mitochondrion
Citric acid cycle Mitochondrion Protein synthesis ER
Pentose phosphate pathway
Cytosol Urea synthesis Mitochondrion, cytosol
Gluconeogenesis Cytosol DNA synthesis Nucleus
Glycogenesis and glycogenolysis
Cytosol mRNA synthesis Nucleus
Fatty acid β-oxidation Mitochondrion tRNA synthesis Nucleoplasm
Fatty acid synthesis Cytosol rRNA synthesis Nucleus
Respiratory chain Mitochondrion Heme synthesis Cytosol, Mitochon.
Phospholipid synthesis Endoplasmic reticulum
Hydrolytic enzymes Lysosome
Cholesterol synthesis ER, Cytosol Bilirubin synthesis ER, cytosol
Distribution of enzymes in main metabolic pathways
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Distribution of enzymes in main metabolic pathways
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Significances
◆To avoid interference among enzymes in different metabolic pathways
◆ To be benefit to harmonious operation of enzymes
Compartmentalization of enzymes in cells
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1.2 Multienzyme system, Multifunctional Enzymes, and Isoenzymes
1.2.1 Multienzyme System and Multifunctional Enzymes
Multienzyme system is an enzyme complex assembled by several different functional enzymes. For example, pyruvate dehydrogenase complex
Multifunctional enzyme is an enzyme with different enzymatic functions in a single polypeptide. For example, fatty acid synthase system
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The fatty acid synthase complex has 7 active sites:
Acetyl CoA-ACP transacetylase (AT)-ketoacyl-ACP synthase (KS)Malonyl CoA-ACP transferase (MT) -ketoacyl-ACP reductase (KR)-hydroxyacyl-ACP dehydratase (HD)Enoyl-ACP reductase (ER)Acyl carrier protein (ACP)
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1.2.2 Isoenzymes
Enzymes catalyzing the same reaction with different components and different physicochemical properties are named as isoenzymes. For example, LDH
H H
H H
H H
H M
H H
MM
H
MM
M
MM
MM
LDH1
(H4)LDH2
(H3M)
LDH3
(H2M2)LDH4
(HM3)
LDH5
(M4)
lactate dehydrogenase, LDH isoenyzmes19
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Example Two
BB BB BBMM MM MM
CK1(BB) CK2(MB) CK3(MM)
brain cardiac muscle skeleton muscle
肌酸激酶 (creatine kinase, CK) 同工酶
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1.3 Basic Manners of Metabolic Regulation at Cell Level
1.3.1 Rate-Limiting Enzyme and Rated-Limiting Step
Definition for rate-limiting enzyme:
An enzyme with relatively low activity catalyzing the relatively low reaction speed for control the rate of the whole pathway is named rate-limiting enzyme.
A B C D E F GE1 E2 E3 E4 E5 E6
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Rate-limiting enzymes of some metabolism pathways
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Metabolism pathway Rate-limiting enzymes
Glycolysis HK , PFK-1, PK
P.P.P G6PD
Gluconeogenesis Pyr carboxylase, PEP carboxykinse, FBPase, G6Pase
Cictric acid cycle Citrate synthase, Isocitrate DHase, α-KG DHase
Glycogenesis Glycogen synthase
Glycogenolysis Glycogen phosphorylase
Triacylglycerol hydrolysis Triacylglycerol lipase
FA synthesis Acetyl CoA carboxylase
Ketogenesis HMG CoA synthase
Cholesterol synthesis HMG CoA reductase
Urea synthesis Argininosuccinate synthase
Heme synthesis ALA synthase
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1.3.2 Feedback Regulation
The end-products in metabolism pathways often affect the activities of the initial enzymes.
Feedback regulation is one of the finest acting manners of regulatory enzymes.
Positive feedback: F-1,6-BP to 6-FPK-1
Glycogen phosphorylase
Glucogenolysis : Gn G1P G6P G
(—)
(+)Glycogen synthase
UDPG
Negative feedback: most key enzymes
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1.3.3 Substrate Cycle
Substrate cycle is the reversible interconversion between two substrates catalyzed by distinct enzymes for unilateral reactions.
F-1,6-2P
F-6-P
ADP ATP
Pi
FPK-1
Fructose biposphatase-1
AMP F-2,6-2P(+)
(–)
(+)
(–)
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In a chain reaction, when an enzyme is
activated, other enzymes are activated in
turn to bring primal signal amplifying.
1.3.4 Cascade Reactions
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Adenyly cyclase ( inactive )
hormones ( glucagon 、 epinephrine ) + receptor
cAMP
PKA(inactive)
Phosphorylase b kinase
PKA(active)
Phosphorylase b Phosphorylase a-P
Phosphorylase b kinase-P
Adenyly cyclase( active )
ATP
inactive active26
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腺苷环化酶 (无活性)
腺苷环化酶(有活性)
激素(胰高血糖素、肾上腺素等) + 受体
ATP cAMP
PKA( 无活性 )
磷酸化酶 b 激酶
糖原合酶 糖原合酶 -P
PKA( 有活性 )
磷酸化酶 b 磷酸化酶 a-P
磷酸化酶 b 激酶 -P
Pi
磷蛋白磷酸酶 -1
Pi Pi 磷蛋白磷酸酶 -1 磷蛋白磷酸酶 -1
–
–
–磷蛋白磷酸酶抑制剂 -P
磷蛋白磷酸酶抑制剂 PKA (有活性) 27
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1.4 Regulation of Enzymatic Activity in Cells
1.4.1 Allosteric Regulation ( rapid regulation )
when some metabolites combine reversibly to an regulating site of an enzyme and change the conformation of the enzyme, resulting in the change of enzyme activity.
◆◆ allosteric effectors allosteric effectors
◆◆allosteric enzymeallosteric enzyme
◆◆ allosteric siteallosteric siteAllosteric activator
Allosteric inhibitor 28
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Some allosteric enzymes and their effectors in metabolism pathways
Metabolism Allosteric enzymes Activator Inhibitor
GlycolysisHK G-6-P
6-FPK-1 AMP, ADP, F-1,6-BP, F-2,6-BP
Citrate, ATP
Pyruvate kinase F-1,6-BP ATP, alanine
Citric acid cycleCitrate synthase ADP ATP, citrate, NADH
Isocitrate dehydrogenase ADP ATP, Ca2+
Gluconeogenesis Pyruvate carboxylase Acetyl CoA ADP
F-1,6-bisphosphatase Citrate AMP, F-2,6-BP
Glycogenolysis Glycogen phophorylase b
AMP, G-1-P, Pi ATP, G-6-P
Glycogenesis Glycogen sythase G-6-P
FA biosynthesis Acetyl CoA carboxylase Citrate, isocitrate Long-chain fatty acyl-CoA
Cholesterol biosynthesis
HMG-CoA carboxylase Cholesterol
AA metabolism L-glutamate dehydrogenase
ADP, leucine, methionine
ATP, GTP, NADH
Purine synthesis PRPP amidotransferase PRPP AMP, ADP, GMP, GDP,
Pyrimidine synthesis Aspartate transcarbomoylase
CTP
Heme synthesis ALA synthase Heme
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Key points: An allosteric enzyme is regulated by its effectors (activator or inhibitor). Allosteric effectors bind noncovalently to the enzyme. Allosteric enzymes are often multi-subunit proteins. A plot of V0 against [S] for an allosteric enzyme gives a si
gmoidal-shaped curve. The binding of allosteric enzyme with an effector will induce a conformational change Does not consume energy
General Properties of Allosteric Enzymes
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T state R state(high activity) (low activity)
FDP
FDP
FDP
FDPFDP
FDP
FDP
FDP
AMP
AMP
AMP
AMP
(allosteric inhibitor)AMP
Glyceraldehydes-3-phosphateFA –carrier protein
(allosteric activator)
Allosteric effect of fructose-1,6-biphosphatase
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1.4.2 Covalent Modification (rapid regulation )
It means the reversible covalent attachment
of a chemical group.
Types of Covalent Modification:Types of Covalent Modification: phosphorylation / dephosphorylation adenylylation/deadenylylation methylation/demethylation acetylation/deacetylation -- SH / SH / -- SS -- S S , etc
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Protein-OH
Protein-O-P=O
O-
O-
ATP
ADP
Protein kinase
H2O
Pi
Protein phosphatase
The reversible phosphorylation and dephosphorylation of an enzyme
Covalent Modification
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Regulation of covalent modification in enzyme activities
PFK-1 Phosphorylation/dephosphorylation Inactivity/activity
Pyr DHase Phosphorylation/dephosphorylation Inactivity/activity
Pyr decarboxylase Phosphorylation/dephosphorylation Inactivity/activity
Glycogen phosphorylase Phosphorylation/dephosphorylation Activity/inactivity
Phosphorylase b kinase Phosphorylation/dephosphorylation Activity/inactivity
Protein phosphatase Phosphorylation/dephosphorylation Inactivity/activity
Glycogen synthase Phosphorylation/dephosphorylation Inactivity/activity
Triacylglycerol lipase Phosphorylation/dephosphorylation Activity/inactivity
HMG CoA reductase Phosphorylation/dephosphorylation Inactivity/activity
Acetyl CoA carboxylase Phosphorylation/dephosphorylation Inactivity/activity
Enzyme Reactive type Effect
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The activity state of an enzyme modulated can
interconvert reversely
Change of a covalent bond catalyzed by E, and
can be modulated by hormones
The modification is a rapid, reversible and eff
ective and amplified by cascade reaction
The most common is the phosphorylation or
dephosphorylation. Enzymes----protein kinases
or phosphatases
Key points:
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PP
PP
P
P
2ATP 2ADP
2Pi
Phosphorylase b kinase
phosphatase
Phosphorylase b(dimer)
Inactivity
Phosphorylase a(dimer)
High activity
Phosphorylase a(tetramer)
Activity
Covalent modification of phosphorylase
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1.5 Regulation of Enzyme Level in Cells(Genetic Control)
The amount of enzyme present is a balance between the rates of its synthesis and degradation.
The level of induction or repression of the gene encoding the enzyme, and the rate of degradation of its mRNA, will alter the rate of synthesis of the enzyme protein.
Once the enzyme protein has been synthesized, the rate of its breakdown (half-life ) can also be altered as a means of regulating enzyme activity.
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1.5.1 Induction and repression of E Pr Synthesis
Induction: the activation of enzyme synthesis.Repression: the shutdown of enzyme synthesis.
Genetic control of enzyme leverl means to controlling the transcription of mRNA needed for an enzyme’s synthesis.
In prokaryotic cells, it also involves regulatory proteins that induce or repress enzyme’s synthesis.
Regulatory proteins bind to DNA, and then block or enhance the function of RNA polymerase. So, regulatory proteins may function as repressors or activators.
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Repressor
Repressors are regulatory proteins that block transcription of mRNA, by binding to the operator that lies downstream of promoter.
This binding will prevent RNA polymerase from passing the operator and transcribing the coding sequence for the enzyme.------Negative control.
Regulatory proteins are allosteric proteins. Some special molecules can bind to regulatory proteins and alter their conformation, and then affect their ability to bind to DNA.
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Structural geneOperator gene Promotor
repressor gene
I
NH2
For example: lac operon
Z Y
repressor protein
mRNA
A
mRNA
When no lactose:
RNA polymeras
e
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lactose
Structural gene
repressor gene
I
NH2
Z Y
repressor protein
mRNA
A
mRNA
When lactose presents:
P O
RNA polymeras
e
NH2
NH2
ZYA
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Inducers Inducers promote the transcription of mRNA.
OP
Structural gene
RNA polymeras
e
activator-binding site
Activator is an allosteric protein which is unable to bind to promoter to transcribe relative genes directly in eukaryotes.
Activator
When no inducer:
mRNA
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Structural gene
P O
RNA polymeras
e
activator-binding site
activator
When inducer:
mRNA
inducer
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Bacteria also Use Translational Control of Enzyme Synthesis
The bacteria produces antisense RNA that
is complementary to the mRNA coding for the
enzyme.
When the antisense RNA binds to the mR
NA by complementary base paring, the mRNA
cannot be translated into protein.
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1.5.2 Degradation of Enzyme Proteins
Cellular enzyme proteins are in a dynamic state with change of enzyme synthesis and degradation so that ultimately determine enzyme level at any point in time.
In many instances, transcriptional regulation determines the concentrations of specific enzyme, with enzyme proteins degradation playing a minor role.
In other instances, protein synthesis is constitutive, and the amounts of key enzymes and regulatory proteins are controlled via selective protein degradation.
In addition, it also involves the abnormal enzyme proteins ( biosynthetic errors or post-synthetic damage).
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There are two pathways to degrade enzyme protein in cells:
1. Lysosomal pathway
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ATP independent
2. Proteasome pathway
ATP, Ubiquitin dependent
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Questions
1. Which one of the following metabolism pathways is not present in cytoplasm?
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A. Glycolysis B. Phosphate pentose pathway C . Glycogenesis and glycogenolysis D . Fatty acid β-oxidation E . Fatty acid synthesis
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Questions
2. All gluconeogenesis, ketone body biosynthesis and urea synthesis exist in
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A. Heart B . Kidney C . Brain D . Liver E . Muscle
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Can you fill in these blanks?
Substrate cycle is the reversible interconversion between two substrates catalyzed by distinct enzymes for unilateral reactions.
F-1,6-2P
F-6-P
ADP ATP
Pi
FPK-1
Fructose biposphatase-1
AMP F-2,6-2P(+)
(–)
(+)
(–)
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ATP
(+)
Fructose biposphatase-1
(–) (–)
(+)
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Questions
1. Why some persons who are easely drunk can turn to endure alcohol after they have experience to drink wine?
2. Why some persons who need hypnotics ( 安眠药) would become more and more dependent to drugs?
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Section Two
Metabolic Regulation at Ho
rmone Level
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Hormones are generally secreted by endocrine glands, travelled by blood stream to specific target cells.
By these mechanisms, hormones regulate the metabolic processes in various organs and tissues; facilitate and control growth, differentiation, reproductive activities, learning and memory; and help organisms coping with changing conditions and stresses to around environment.
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Hormonal regulation depends upon the transduction of the hormonal signal across the plasma membrane to specific intracellular sites, particularly the nucleus.
Many steps in these signal across the signalling pathway involve phosphorylation of Ser, Thr, and Tyr residues on target proteins.
According to receptor’s location in a cell, hormones are divided into two classes:
Hormones act on cell membrane receptors
Hormones act on intracellular receptors
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Hormones act on cell membrane receptors
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Hormones act on intracellular receptors
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2.1 Regulation of Hormones to Receptors on Cell Membrane
Hormones act on membrane receptors, as the first messenger, to activate various signal transduction pathways that mobilize various second messengers-----cAMP, cGMP, Ca2+, IP3 , DG that activate or inhibit enzymes or cascade o
f enzymes in specific ways.
The first messengers: Peptide or protein hormones: GH, Insulin, etc Amino acid derivatives: epinephrine, norepinephrine
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RR
H
AC
γαβ
GDPαGTP
βγ
Adenylate cyclase
AC
ATP
cAMP
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Hormone receptor
G protein Enzyme
The second messenger
Protein kinase
Enzyme or other protein
Biological effects
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2.2 Regulation of Hormones to Receptors in Cells
Hormones to act on intracellular receptors:
Steroid hormones: Glucocorticoids
Mineralocorticoids
Vit D
Sex hormones
Amino acid derivatives: T3, T4
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Hormone receptor
G protein Enzyme
The second messenger
Protein kinase
Enzyme or other protein
Biological effects
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Can you give some examples?
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Section Three
Regulation of Metabolism
at Integral Level
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Living in a constantly changing environ
ment, human must have the ability to adapt
ing to the environment.
The metabolism of body has to be regul
ated through neurohumoral pathways to sa
tisfy energy needs and to maintain homeos
tasis of the internal environment.
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Why and how?
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3.1 Metabolism Regulation in Starvation
3.1.1 Starvation in Short-term (1-3 days)
Glycogen reserve
Blood Glucose
Insulin
glucagoncorticosteroid
a series of metabolic changes
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(1) Protein Metabolism
Protein
Amino acid gluconeogenesis
deamination
Pyruvatetransamination Alanine
Blood
degradation
Alanine
Pyruvate
Glucose
transamination
Protein degradation ↑, Amino acid Glucose
Muscle
Liver
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(2) Carbohydrate Metabolism
Gluconeogenesis
Liver : 80%
Renocortical : 20%
Lactic acid 30%
Glycerol 10%
Amino acids 40%
Tissue utilize glucose
In brain , glucose is still the main fuel
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(3) Triacylglycerol Metabolism
Fat mobilization
Fatty acid Ketone bodies
Heart Skeletal muscle
Part
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3.1.2 Change of Metabolism in Long-term Starvation ( >7 days)
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Amino acid , but Glu deamination
Starvation in Long-term(1) Protein Metabolism
Muscle protein degradation
Urea
NH3 Acidism( 酸中毒)In urine
( by ketosis 酮症 )
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(2) Carbohydrate Metabolism
( almost equal to that in liver )
In kidney : Gluconeogenesis
Lactic acidPyruvate
The main materials of gluconeogenesis in li
ver:
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(3) Triacylglycerol Metabolism
Fat mobilization
Fatty acidKetone bodies
Skeletal muscle: FA as an energy source to ensure that adequate amounts of ketone bodies are available in brain.
Brain: gradually adapts to using ketone bodies as fuel.
This may reduce utilization of glucose and gluconeogenesis of amino acid, so decrease the breakdown of protein.
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After starvation in Long-term, if the person is given a big meal with a lot of meat and wine in short time, what case would occur?
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3.2 Metabolism Regulation in Stress
injury
pain
frostbite
oxygen deficiency
toxicosis
infection
out-of-control rage
Excitation of sympathetic nerves
Adrenal medullary/cortical hormones
Epinephrine, glucagons, growth hormone
Insulin
Metabolism of carbohydrates
lipids change
proteoins
Effect:Stimulus
Catabolism Anabolism
Stress is a tense state of an organism in response to unusual stimulus.
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(1) Change of Carbohydrate Metabolism
Hyperglycemia catecholamine
glucagon growth hormone corticosteroid
Insulin
GluconeogenesisGlycogenolysis
Blood glucoseIf exceeds renal thre
shold of glucose (8.96 mmol/L)
GlucosuriaStress hyperglycemia Str
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(2) Change of Triacylglycerol Metabolism
AdrenalineNoradrenalineGlucagon
Fatty acidKetone bodies
Fat mobilization
Tissue utilize FA as energy
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(3) Change of Protein Metabolism
Protein hydrolysis
Amino acid: as material for Gluconeogenesis
Urea synthesis
Equilibrium of negative nitrogen
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Stress
Sympathetic excitation
Adrenal cortex/ medulla hormone
TG hydrolysisLipocyte
Liver
Gluconeogenesis
glucose
Glycerophosphate
Glycogenolysis
Ketogenesis Pyruvate Ureogenesis
FA LA Alanine NH3
Urea
Blood vessel
Kidney
Glucosuria
FA LA Glucose
Glycerophosphate
Alanine
Muscle
Muscle glycogenolysis
Protein degradation
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Questions
1. Which one of substance change in blood is incorrect under stress ?
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A. Glucose increase B. Free fatty acid increase C . Amino acid increase D . Ketone body increase E . VLDL increase
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Questions
2. When hungry, the false statement about substance metabolism alternation is
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A . Gluconeogenesis enhancement B. Triglyceride mobilization enhancement C . Ketone body synthesis enhancement
D . Insulin secretion increase E. Glucagon secretion increase
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Questions
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1.How does Ala turn to be glucose in vivo? When does this case occur?
2. How does carbohydrate metabolism and amino acid metabolism be modulated in liver cells to adapt with those in skeleton muscles and in cardiac muscle?
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Questions
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3. How to compare allosteric regulation with chemical modification?
4. Use several examples to explain some diseases involved with abnormal metabolism.
5. What changes of metabolism in body would occur in long-term starvation?