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Chapter 9
Regulation of Metabolism
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Metabolism:
Catabolism: to generate energy
Anabolism: to use eneragy
Metabolism in the living organism contains many
pathways.
Cells maintain a dynamic homeostasis, the living organism modulates various metabolisms in intensity, direction and velocity, in order to adapt changes of enviroment inside and outside the body.
Metabolism regulation is an important character of life, being an adaptation formed in evolution over a long –term.
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There are three hierarchies in metabolism
regulations:
1) Metabolism regulation in the cell level
2) Hormone regulation of metabolism
3) Regulation of metabolism in level of the
whole
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Section 1
Metabolism Regulation in Cell Level
1. Basic manner of metabolism regulation in cells
1) Integration and orientation of metabolism enzymes and pathways
ⅰ. Regional distribution of enzymes in cells
Eukaryote cells have many inner-membrane systems, so enzyme distribution presents compartmentation, which not only avoids interference among enzymes in different metabolism pathways but also benefits harmonious operation of enzymes.
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Table 1 Compartment distribution of main metabolism pathways (enzymes in eukarote cell)
Metabolism pathways distribution Metabolism pathways distribution
Cictric acid cycle Mitochondrion Oxidative phosphrylation Mitochondrion
Urea synthesis Mit, Cytosol Protein synthesis ER, Cytosol
Glycolysis Cytosol DNA synthesis Nucleus
P.P.P Cytosol mRNA synthesis Nucleus
Glycogenolysis Cytosol tRNA synthesis Nucleoplasma
Glycogenesis Cytosol rRNA synthesis Nucleus
Gluconeogenesis Cytosol Ch synthesis ER, Cytosol
FA β-oxidation Mitochondrion PL synthesis ER
FA synthesis Cytosol Heme synthesis Cytosol, Mit
Respiratory chain Mitochondrion Hydrolytic enzymes Lysosome
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ⅱ. Multienzyme System and Multifunctional Enzyme
Monomeric enzyme
Oligameric enzyme
Multienzyme System:
Pyruvate dehydrogenase complex
Multifunctional Enzyme:
FA synthase system
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ⅲ. IsoenzymeIsoenzymes (isozymes ) : are different forms of an enzyme which catalyze the same reaction, but which exhibit different physical or kinetic properties, such as isoelectric point, pH optimum, substrate affinity or effect of inhibitors.Examples:LDH (lactate dehydrogenase ) H4 H3M H2M2 HM3 M4
Heart Muscle
Different tissues express different isoenzyme forms (by regulating tissues express different isoenzyme forms) , as appropriate to their particular metabolic needs.
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2) Basic manner of metabolism regulation
Metabolism speed or direction often lies up on activities of some key enzymes.
The enzyme that catalyzes the reaction at the slowest speed, whose activities is modulated by substrates, metabolites(products or effectors), is called regulatory enzyme, key enzyme or rate-limiting enzyme.
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Table 2 Rate-limiting enzymes of some important metabolism pathways
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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ⅰ. Feedback Regulation
The substrates or products in metabolism pathways often affect the initial enzymes in the pathway.
Feedback regulation is one of the finest acting manners of regulatory enzymes.
Negative feedback:
Positive feedback:Glycogen phos
phorylaseGlucogenolysis : Gn G1P G6P G
(—)
(+)Glycogen synthase
UDPG
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ⅱ. Substrate Cycle
In a metabolism pathway, the direction of reversible reaction is controlled by different enzyme.
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.
ⅲ. Cascade Reaction
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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 active
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2. Regulation of Enzymatic Activity in Cells
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 enzymeallosteric enzyme
• allosteric siteallosteric site Allosteric activator
Allosteric inhibitor
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Table 3 Some allosteric enzymes and effectors in enzyme systems of metabolism pathways
Metabolism Allosteric Activator Inhibitor pathway enzymes Glycolysis HK AMP, ADP, FBP, Pi G6P PFK-1 FBP Citrate PK FBP ATP, Acetyl CoA Cictric acid cycle Citrate synthase AMP ATP, long-chain fatty acyl CoA Isocitrate DHase AMP, ADP ATP Gluconeogenesis Pyr carboxylase Acetyl CoA, ATP FBPase Citrate AMP Glycogenolysis Glycogen phosphorylase AMP, G1P, Pi ATP, G6P Glycogenesis Glycogen synthase G6P FA synthesis Acetyl CoA carboxylase Citrate, Isocitrate long-chain Cholesterol synthesis HMG CoA reductase CholesterolAmino acid metabolism GLDH ADP, Leu, Met ATP, GTP, NADH
fatty acyl CoA
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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
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-phosphate
Fatty acid –carrier proteinCitrate(allosteric activator)
Allosteric effect of fructose-1,6-biphosphatase
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2). Covalent Modification(rapid regulation )
It means the reversible covalent attachment of a chemical.
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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Table 4 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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Change of a covalent bond
The most common is the phosphorylation or dephos
phorylation. Enzymes----protein kinases or phosphata
ses
The activity of an enzyme after the modification ca
n increase or decrease.
The modification is a rapid, reversible and effective
process.
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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3. Regulation of Enzyme Content 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) Induction and repression of Enzyme Protein Synthesis
Induction: the activation of enzyme synthesis.Repression: the shutdown of enzyme synthesis.
Genetic control of enzyme activity 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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ⅰ. Repressor Repressors are regulatory proteins that block transcription of mRNA, by binding to the operator that lies downstream of promoter.
This biding will prevent RNA polymerase from passing the operator the and transcribing the coding sequence for the enzymes.------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. They work by two ways:
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Structural geneOperator gene Promotor
repressor gene
I
NH2
Some repressor readily bind to the operator and block transcription: 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 there is lactose:
P O
RNA polymeras
e
NH2
NH2
ZYA
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mRNA
OPtrpR
Some repressor can not bind to the operator directly : Trp operon
Structural geneWhen Trp
RNA polymeras
e
repressor protein
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mRNA
OPtrpR
Structural gene
When Trp
Trp ( corepressor )
RNA polymeras
e
repressor protein
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ⅱ. ActivatorsActivators promote the transcription of mRNA.
OP
Structural gene
RNA polymeras
e
activator-binding site
Activator is an allosteric protein which can not bind to the activator-binding site normally.
activator
When no inducer:
mRNA
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OP
Structural gene
RNA polymeras
e
activator-binding site
activator
When inducer:
mRNA
inducer
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ⅲ. Bacteria also Use Translational
Control of Enzyme Synthesis The bacteric produces antisense RNA tha
t is complementary to the mRNA coding for t
he enzyme.
When the antisense RNA binds to the m
RNA by complementary base paring, the mR
NA cannot be translated into protein.
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2) Regulation on Enzyme Protein Degradation
Cellular enzyme proteins are in a dynamic state of turn over, with the relative rates of enzyme synthesis and degradation ultimately determining the amount of enzymes.
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:
ⅰ. Lysosomal pathway
ATP independent
ⅱ. Proteasome pathway
ATP, Ubiquitin dependent
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Section 2
Hormone Regulation of Metabolism
Hormones are secreted by certain cells, usually located in glands, either by simple diffusion or circulation in the blood stream, to specific target cells.
By these mechanisms, hormones regulate the metabolic processes of various organs and tissues; facilitate and control growth, differentiation, reproductive activities, learning and memory; and help the organism cope with changing conditions and stress in its environment.
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Hormonal regularion 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 associating transmembrane receptorsHormones associating intracellular receptors
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1. Regulation Hormones Associating Transmembrane Receptors
Hormones associating transmembrane receptors, as the first messenger, which act by binding to membrane receptors, activate various signal transduction pathways that mobilize various second messengers-----cAMP, cGMP, Ca2+, IP3 , DG that activate or inhibit enzymes or cascade
of enzymes in specific ways.
The first messenger: Peptide or protein hormones: GH, Insulin, etc Amino acid derivatives: epinephrine, norepinephrine
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RR
H
AC
γαβ
GDPαGTP
βγ
腺苷酸环化酶
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. Regulation Hormones Associating
Intracellular Receptor
Hormones associating intracellular receptor:
Steroid hormones: Glucocorticoids
Mineralococorticoids
Vit D
Sex hormones
Amino acid derivatives: T3, T4
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Section 3 Regulation of Metabolism in Relation to the Whole
Living in an ever-changing environment,
human must have the ability to adapting to th
e environment, the body regulates metabolism
through neurohumoral pathways to satisfy ene
rgy needs and maintain homeostasis of the inte
rnal environment.
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1. 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, wrowth 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 MetabolismHyperglycemi
a catecholamine glucagon growth hormone corticosteroid
Insulin
GluconeogenesisGlycogenolysis
Blood glucoseIf exceeds renal thre
shold of glucose (8.96 mmol/L)
GlucosuriaStress hyperglycemia Str
ess glucosuria
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In the beginning phase of stress:
Liver
Muscle
Glycogens
Gluconeogenesis
Glycogens
Most tissue utilizes glucose
In brain, it utilizes glucose normally.
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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
TAG 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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2. Change of Metabolism in Starvation1) Starvation in Short-term (1-3 days)
Glycogen reserve
Blood Glucose
Insulin
glucagoncorticosteroid
a series of metabolic changes
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ⅰ. 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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ⅱ. 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 source.
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Renal cortex
ⅲ. Triacylglycerol Metabolism
Fat mobilization
Fatty acidGKetone bodies
Heart Skeletal muscle
Part
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Amino acid , but Glu deamination
2) Starvation in Long-term
ⅰ. Protein Metabolism
Muscle protein degradation
Urea
NH3 AcidismIn urine
( by ketosis )
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ⅱ. Carbohydrate Metabolism
( almost equal to that in liver )
In kidney :
Gluconeogenesis
Lactic acidPyruvate
The main materials of gluconeogenesis in liver:
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ⅲ. Triacylglycerol Metabolism
Fat mobilization
Fatty acidGKetone 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.