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INTERRELASI METABOLISME DAN

PENGATURANNYA
 
1,2
Marhaen Hardjo
1
Head of Biochemistry Department, Medical Faculty of Hasanuddin University
2
Director of Stem Cell Center Hasanuddin University Hospital

DEPARTMENT OF BIOCHEMISTRYY
MEDICAL FACULTI OF
HASANUDDIN UNIVERSITY
KERANGKA SLIDE

• PENGERTIAN INTERELASI METABOLISME


• PROSES YANG TERJADI DALAM INTERELASI METABOLISME
• HASIL INTERELASI METABOLISME
• HORMON-HORMONE ENDOKRIN DAN REGULASINYA
PENDAHULUAN

kegiatan organisme memerlukan


perubahan energi dan reaksi kimia.

Metabolisme

ANABOLISME KATABOLISME
Glukosa  Glikogen

ANABOLISME As.lemak & Gliserol  Trigliserida

As. Amino  Protein

Glikogen  Glukosa

KATABOLISME Trigliserida  gliserol & As.lemak

Protein  As. amino


Reaksi Anabolisme dan Katabolisme
berlangsung secara cepat. Terjadi karena
adanya katalisator yaitu enzim (molekul
protein), berfungsi secara cepat karena
adanya : ko enzim yaitu beberapa vitamin B
Complex dan kofaktor yaitu beberapa
mineral serta adanya media air
carbohyd
rates

The main
source of
energy

Fats Protein
Pengertian interelasi
metabolisme

Interelasi Metabolisme adalah


proses metabolisme karbohidrat,
lemak, protein yang pada mulanya
berproses masing-masing tetapi
pada akhirnya akan saling
berinteraksi pada suatu siklus yang
dinamakan siklus kreb.
• PROSES DAN HASIL DARI INTERELASI METABOLISME
TERUTAMA ENERGI POTENSIAL ADALAH PROSES
TERJADINYA METABOLISME ENERGI YANG BERSUMBER
DARI MOLEKUL KARBOHIDRAT, LEMAK, DAN PROTEIN,
TERJADI DIDALAM MITOKONDRIA DAN AKAN
MENGHASILKAN SEJUMLAH ENERGI.
OUTPUT/HASIL AKHIR
INTERELASI METABOLISME

Penguraian 1 gram glukosa (karbohidrat) menjadi CO2, H2O


 Energi 4 Kkal

Penguraian 1 gram as.lemak (lemak) menjadi CO2, H2O 


Energi 9 Kkal

Penguraian 1 gram as.amino (protein) menjadi CO2, H2O dan


NH3  Energi 4 Kkal
Fase /Jalur katabolisme

Karbohidrat Lemak Protein

1. Fase khusus masing-masing (oksidatif)


2. Fase bersama (siklus krebs)
Fungsi Energi dari penguraian ATP

UNTUK SEL
 M’bntuk molekul baru
 Mngganti struktur sel yg rusak
 Mengeluarkan dan memasukkan zat-zat dari dan kedalam sel
 Membentuk molekul cadangan energi

UNTUK PERGERAKAN OTOT


 Aaktif maupun istirahat
 Diperintah otak maupun tidak ada perintah dari otak

UNTUK KEPERLUAN SEL


 Proses pencernaan, penyerapan, dan mengangkut zat gizi
penghasil energi hingga masuk kedalam sel
SECARA KESELURUHAN ENERGI (KALORI) YG
DIHASILKAN DARI PENGURAIAN ATP AKAN
DIGUNAKAN UNTUK :

1. AKTIFITAS SAAT TUBUH ISTIRAHAT BASAL (BASAL ENERGY EXPENDITURE /BEE)


2. AKTIFITAS FISIK (AF)
3. PENGARUH TERMIS DARI MAKANAN (THERMIC EFFECT OF FOOD/ TEF)

Seluruh energi yang digunakan tubuh adalah Penjumlahan


dari BEE + AF + TEF = Energi (kalori ) total.
Aktifitas saat tubuh istirahat basal (Basal
1 Energy Expenditure /BEE)
• Proses metabolisme dlm
sel
• Denyut jantung
• Grakan peristaltik usus
• Tonus otot, etc
Rumus BEE :
Rumus Du Bois
• BEE Pria = 66 + (13,7 x BB kg) + (5xTB cm) – (6,8 x U. Thn)
• BEE wnt = 655 +(9,6 x BB kg) + (1,8 x TB cm) –(4,7 x U. Thn)

Cara cepat/ cara lain :


• BEE Pria = 30 kkal x kg BB
Faktor-faktor yang mempengaruhi
• BEE nilaikkal
Wanita = 25 BEEx kg BB
• Umur
• JK
• Suhu tubuh dan lingkungan

• Tidur
2 Aktifitas fisik (AF)

• Aktifitas sangat ringan dan ringan = 30 – 50 % BEE


• Aktifitas sedang 50-75% BEE
• Aktifitas berat 75% BEE

RUMUS Menghitung Nilai AF


Jenis AF x Jumlah BEE
3 Thermic Effect of Food (TEF)

 Nilai TEF biasa disebut juga dengan Specifik Dinamik Action= SDA. Nilai TEF
untuk protein adalah tertinggi 30 %, lalu karbohidrat, kemudian lemak. SDA
bekerja  mulai dari TEF tertinggi kemudian yang terendah. Karena menu
makanan merupakan gabungan protein,  karbohidrat dan lemak, maka nilai TEF
adalah 10 % dari ( BEE + AF )
• CONTOH PERHITUNGAN ENERGI UNTUK PA’ RAHMAT YANG BERUMUR 30 TAHUN, BB=60
KG DAN TB=160  CM, AKTIFITAS SEHARI-HARINYA DIKATEGORIKAN SEDANG (50%). BEE
(CARA DU BOIS) BEE PRIA   = 66 + (13.7 X BB KG ) + ( 5 X TB CM ) – ( 6,8 X  U.THN ) =
1450 KKAL

• AKTIFITAS FISIK SEDANG ( 50 % ) = 50 % X 1450 KKAL = 725 KKAL


• TEF = 10 % X (BEE + AF ) = 10 % X (1450+725)  = 217.5 
• MAKA TOTAL KESELURUHAN PENGGUNAAN ENERGI ( TOTAL ENERGI EXPENDITURE = TEE )
ADALAH PENJUMLAHAN DARI :             = BEE + AF + TEF TEE = 1450 +  725 + 217.5 = 2392.5
KKAL
Metabolic
Interrelationships
Liver­ #1 metabolic player
•Responds quickly to dietary conditions because of 
rapid turnover of its enzymes
•Processes most incoming nutrients

•Maintains  constant  concentrations  of  nutrients 


in  blood  (e.g.,  via  gluconeogenesis),  smoothing 
out fluctuations due to the Starve­Feed Cycle
•Processes toxins and wastes (e.g., through urea 
cycle)
•Synthesizes and secretes plasma proteins
Liver­ #1 metabolic player

•Primarily depends 
on b­oxidation of 
fatty acids for its 
own energy needs.
Liver
•Amino acids go directly 
to the liver through the 
portal vein after 
absorption.
•Uses them to make 
proteins, for 
gluconeogenesis, for 
biosynthesis of nitrogen­
containing molecules, or 
for fuel.
Adipose Tissue­ maintainer #2
•Stores triglycerides and releases FA’s 
and glycerol as signaled by glucagon/ 
epinephrine
•Turnover is 50­60 g/day.
cAMP­activated
triglycerides fatty acids + glycerol
lipases

transport in blood
Albumin

muscle      heart    liver


•Two distinct 
types: white 
adipose tissue and 
brown adipose 
tissue.
•Brown fat has 
high levels of 
thermogenin, 
which are 
metabolically 
activated by cold 
exposure.
Huffington Post
Skeletal Muscle (big consumer)
Case Study: Paul J. cramps up
Less than two weeks after
finishing the 2010 Boston
Marathon in 4:10, disaster
struck for Paul J. in the
Pittsburgh Marathon. He ran
the first half in 2:04 and the
second half in 2:40. Severe
leg cramps set in at around
mile 20, and he ended up on
the ground screaming in pain.
The day was cool, and he took
in lots of electrolytes.
Case Study: Paul J. cramps up
Less than two weeks after What probably went
wrong for Paul?
finishing the 2010 Boston
Marathon in 4:10, disaster a) Lactic acid!
struck for Paul J. in the
Pittsburgh Marathon. He ran b) His fat stores ran
the first half in 2:04 and the out.
second half in 2:40. Severe
c) His blood sugar
leg cramps set in at around dropped.
mile 20, and he ended up on
the ground screaming in pain. d) Carnitine
The day was cool, and he took deficiency!
in lots of electrolytes.
e) Hyponatremia!
Energy Systems of Skeletal Muscle

(Phosphagen system)
Match the photo to the energy system!
a) 1= lactate; 2= phosphagen; 3= aerobic
b) 1= phosphagen; 2= aerobic; 3= lactate
c) 1= aerobic; 2= lactate; 3= phosphagen
d) 1= aerobic; 2= phosphagen; 3= lactate

1. 2. 3.
Anaerobic Conditions- bursts
of heavy activity
• ATP exhausted rapidly (1 or 2 sec); replenished by:

Phosphagen System
Anaerobic Conditions- bursts
of heavy activity
•phosphocreatine lasts ~10 seconds

•next 1 to 2 minutes
glycogen ­> G­6P ­> pyruvate ­> lactate
Fate of Lactate
•Cooperation 
between muscle and 
liver (Cori cycle) to 
regenerate glucose 
from lactate.
•Heart also burns 
lactate.
Lactate Threshold

• WITH LOW INTENSITY WORK, LACTATE IS CLEARED FROM THE 
BLOODSTREAM AS FAST AS IT IS MADE. 

• AS WORK INCREASES, THERE IS A POINT WHEN LACTATE IS 
PRODUCED TOO FAST FOR THE BODY TO CLEAR IT. 
Exercise cannot be
sustained for more
than a minute or two
after lactate threshold
because of PFK-1
inhibition
work
Aerobic Conditions- rest,
slow runs, light activity
1. glycogen ­> G­6P ­> pyruvate ­> CO2 + H2O
•1­ 2 hour supply, moderately fast
•Limited by entry of pyruvate into mitochondria 
and/or O2 supply

2. fatty acids ­> acetyl­CoA ­> CO2 + H2O
•Many hours supply, slow
•Limited by diffusion of FA’s from blood, carnitine
Cross Country Collapse

Emily, the #2 ranked female high


school cross country runner in the
state, is competing in the Western
Maine championship. She goes into the
woods just before the mile mark but
doesn’t come out.
She had been struggling the entire
season, feeling weak and tired, and
had dropped out of three races prior to
this meet. What type of testing would
you do on Emily?
Cross Country Collapse

Emily, the #2 ranked female high


school cross country runner in the A. Test for a
state, is competing in the Western glycogen
Maine championship. She goes into the storage disease
woods just before the mile mark but B. Test for
doesn’t come out. cardiomyopathy
She had been struggling the entire
season, feeling weak and tired, and C. Test for diabetes
had dropped out of three races prior to D. Test for anemia
this meet. What type of tests would you
do on Emily? E. Test for
pregnancy
Aerobic training effects
Increased number of mitochondria

Increased hemoglobin and


hematocrit (percentage of red cells in
blood; normally 36-49%)

Increased heart efficiency

Result is increased O2 uptake and use by


tissues: VO2 max: normally ~35 mL O2/kg/
min
VO2 MAX OF ELITE
AEROBIC ATHLETES

JOAN BENOIT BJORN DAEHLIE LANCE ARMSTRONG


79 ML/KG/MIN 90 ML/KG/MIN 84 ML/KG/MIN
VO2 MAX OF ELITE ANIMAL
ATHLETES

PRONGHORN ANTELOPE
300 ML/KG/MIN
10K- UNDER 10 MINUTES!
Changes in metabolism
over time
During endurance exercise, the
respiratory quotient (CO2 exhaled/O2
consumed) falls, indicating increased use
of fatty acids.

RQ =1.0 for carbohydrates


RQ= 0.70 for fats (more
highly reduced)
Changes in metabolism
over time
During endurance exercise, the
respiratory quotient (CO2 exhaled/O2
consumed) falls, indicating increased use
of fatty acids.
Increased [acetyl CoA]
from b oxidation slows
bridging reaction
Effect is decreased
funneling of sugar into
TCA.
Changes in metabolism
over time
During endurance exercise, the
respiratory quotient (CO2 exhaled/O2
consumed) falls, indicating increased use
of fatty acids.
Case Study: Paul W. is confused
Paul W. turned the corner for
the last 200 yards of the 1990
Boston Marathon. He was well
ahead of me, having passed
me in Wellesley. In the last few
minutes of the race, however,
he became confused. As he
passed by “The Pru,” he
started walking in circles. He
ended up finishing 15 minutes
behind me. What went wrong
for Paul W.?
Case Study: Paul W. is confused
Paul W. turned the corner for What probably went
wrong for Paul?
the last 200 yards of the 1990
Boston Marathon. He was well a) Lactic acid!
ahead of me, having passed
me in Wellesley. In the last few b) His fat stores ran
minutes of the race, however, out.
he became confused. As he
c) His blood sugar
passed by “The Pru,” he dropped.
started walking in circles. He
ended up finishing 15 minutes d) Carnitine
behind me. What went wrong deficiency!
for Paul W.?
e) Hyponatremia!
Brain
•No significant energy reserves.

•Dependent on blood glucose at ~4.5 mM to 
maintain ion gradients.

•Uses 20% of the total O2 consumed by a resting 
human (only 2% of the body mass)
•After  several  days  of  low  glucose,  switches  to 
use  of  ketone  bodies,  which  are  degraded  via 
TCA. Conserves body’s proteins.
Heart
Cardiac muscle is
aerobic only with
circulating fats the
preferred fuel.

Lack of O2 leads to
tissue death (myocardial
infarction).
Hormones
WHICH OF THE FOLLOWING PATHWAYS IS
INHIBITED BY THE
A. GLYCOLYSISACTION OF INSULIN?

B. KREB’S CYCLE

C. GLUCONEOGENESIS

D. GLYCOGEN SYNTHESIS

E. FATTY ACID SYNTHESIS


1. Insulin (high blood sugar)
•Insulin deficiency or resistance can lead to 
hyperglycemia, metabolic syndrome, and diabetes.
The insulin receptor is a receptor 
tyrosine kinase (RTK).
Insulin binding triggers auto­ 
phosphorylation at Tyr.
2. Epinephrine (fight or flight)
Epinephrine receptors act through G 
proteins.
3. Glucagon (low 
blood sugar)
Glucagon receptor also acts through 
G proteins.
INTERMEDIARY
METABOLISM
INTERMEDIARY METABOLISM
RELATIONSHIPS
(SACCHARIDES, LIPIDS,
PROTEINS)
1.AFTER FEEDING (ENERGY INTAKE IN A
DIET)

 OXIDATION → CO2, H2O, UREA + ATP


 FORMATION OF STORES → GLYCOGEN, TAG

Urea
Glycogen

nonreducing reducing
end end
The figures were found (May 2007) at http://www.wellesley.edu/Chemistry/chem227/sugars/oligo/glycogen.jpg 
http://students.ou.edu/R/Ben.A.Rodriguez­1/glycogen.gif, http://fig.cox.miami.edu/~cmallery/255/255chem/mcb2.10.triacylglycerol.jpg 
INTERMEDIARY METABOLISM
RELATIONSHIPS
(SACCHARIDES, LIPIDS,
2. DURING FASTING
PROTEINS)
 USE OF ENERGY STORES
• GLYCOGEN → GLUCOSE
• TAG → FATTY ACIDS

 FORMATION OF NEW ENERGY


SUBSTRATES
• GLUCONEOGENESIS (GLYCEROL, MUSCLE
PROTEINS)
• KETOGENESIS (STORAGE TAG → FFA → KETONE
BODIES)
The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. 
Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2
The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. 
Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2
PRINCIPAL METABOLIC PATHWAYS
OF THE INTERMEDIARY
METABOLISM:

• GLYCOGENESIS • GLYCOGENOLYSIS
• GLUCONEOGENESIS • GLYCOLYSIS
• LIPOGENESIS • LIPOLYSIS
• SYNTHESIS OF FA • b-OXIDATION
• KETOGENESIS • KETONE BODIES DEGR.
• PROTEOSYNTHESIS • PROTEOLYSIS
• UREA SYNTHESIS • DEGRADATION OF AA

CITRATE CYCLE, RESPIRATORY CHAIN


MAJOR INTERMEDIATES

ACETYL-CO A

PYRUVATE

NADH
PYRUVATE (PDH) – I.E. FROM GLUCOSE
AMINO ACIDS (DEGRAD.) – FROM PROTEINS
FATTY ACIDS (b-OXIDATION) – FROM TAG
KETONE BODIES (DEGRAD.) – FROM FA

ACETYL-COA

CITRATE CYCLE, RCH → CO2, H2O, ATP


SYNTHESIS OF FA
SYNTHESIS OF KETONE BODIES
SYNTHESIS OF CHOLESTEROL
SYNTHESIS OF GLUCOSE !!!
AEROBIC GLYCOLYSIS
OXIDATION OF LACTATE (LD)
DEGRADATION OF SOME AMINO ACIDS

PYRUVATE

ACETYL-COA (PDH)
LACTATE (LACTATE DEHYDROGENASE)
ALANINE (ALANINE AMINOTRANSFERASE)
OXALOACETATE (PYRUVATE CARBOXYLASE)
GLUCOSE (GLUCONEOGENESIS)
AEROBIC GLYCOLYSIS
PDH REACTION
b-OXIDATION
CITRATE CYCLE
OXIDATION OF ETHANOL

NADH

RESPIRATORY CHAIN → REOXIDATION TO


NAD+

ENERGY STORAGE IN ATP


! OXYGEN SUPPLY IS NECESSARY!
AEROBIC GLYCOLYSIS
PDH REACTION
b-OXIDATION
CITRATE CYCLE
OXIDATION OF ETHANOL

NADH PYRUVATE → LACTATE

RESPIRATORY CHAIN → REOXIDATION TO


NAD+

ENERGY STORAGE IN ATP


THE MOST IMPORTANT IS TO
ANSWER THE QUESTIONS:

WHERE?
WHEN?
HOW?

COMPARTMENTALIZATION OF THE
PATHWAYS
STARVE-FEED CYCLE
REGULATION OF THE PROCESSES
COMPARTMENTALIZATION OF MTB
PATHWAYS

The figure is found at http://fig.cox.miami.edu/~cmallery/150/proceuc/c7x7metazoan.jpg (May 2007)
• GLYCOLYSIS
• GLUCONEOGENESIS (FROM OXALOACETATE
OR GLYCEROL)

• METABOLISM OF GLYCOGEN
• PENTOSE CYCLE
• SYNTHESIS OF FATTY ACIDS
• SYNTHESIS OF NONESSENTIAL AMINO
ACIDS
• TRANSAMINATION REACTIONS
• SYNTHESIS OF UREA (A PART; ONLY IN THE
LIVER!)

• SYNTHESIS OF HEME (A PART)


MITOCHONDRION

• PYRUVATE DEHYDROGENASE COMPLEX (PDH)


• INITIATION OF GLUCONEOGENESIS
• b-OXIDATION OF FATTY ACIDS
• SYNTHESIS OF KETONE BODIES (ONLY IN THE
LIVER!)
• OXIDATION DEAMINATION OF GLUTAMATE
• TRANSAMINATION REACTIONS
• CITRATE CYCLE
• RESPIRATORY
MEMBRANE)
CHAIN (INNER MITOCHONDRIAL

• AEROBIC PHOSPHORYLATION (INNER MITOCH.


MEMBRANE)
• SYNTHESIS OF HEME (A PART)
SMOOTH ER
• SYNTHESIS OF TRIACYLGLYCEROLS AND
PHOSPHOLIPIDS
• ELONGATION AND DESATURATION OF FATTY
ACIDS
• SYNTHESIS OF STEROIDS
• BIOTRANSFORMATION OF XENOBIOTICS
• GLUCOSE-6-PHOSPHATASE

ROUGH ER
• PROTEOSYNTHESIS
• POSTTRANSLATIONAL MODIFICATION OF
PROTEINS
• PROTEIN SORTING
• EXPORT OF PROTEINS (FORMATION OF
VESICULES)

RIBOSOMES

• PROTEOSYNTHESIS
NUCLEUS

• REPLICATION AND TRANSCRIPTION OF


LYSOSOMES

• HYDROLYSIS OF PROTEINS,
SACCHARIDES, LIPIDS AND NUCLEIC
ACIDS

PEROXISOMES

• OXIDATIVE REACTIONS INVOLVING O 2

• USE OF HYDROGEN PEROXIDE


• DEGRADATION OF LONG CHAIN FA (FROM
STARVE-FEED CYCLE

• RELATIONSHIPS OF THE METABOLIC


PATHWAYS
UNDER VARIOUS CONDITIONS
• COOPERATION OF VARIOUS TISSUES
• SEE ALSO
HTTP://WWW2.EUR.NL/FGG/OW/COO/BIOC
H/#ENGLISH
(METABOLIC INTERRELATIONSHIPS)
1) Well-fed
state

The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. 
Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2
2) Early
fasting state

The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. 
Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2
3) Fasting
state 

The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. 
Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2
4) Early
refed state 

The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. 
Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2
The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. 
Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2
CHANGES OF LIVER GLYCOGEN
CONTENT

The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. 
Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2
FASTING
WELL-FED STATE
STATE

 glucagon,
hormones  insulin
adrenaline, cortisol

 glycemia
 glycemia
response of  lipolysis
 lipogenesis
the body  ketogenesis
 proteosynthesis
 proteolysis
FASTING
WELL-FED STATE
STATE
 glucagon,
hormones  insulin
adrenaline, cortisol
 glycemia
 glycemia
response of  lipolysis
 lipogenesis
the body  ketogenesis
 proteosynthesis
 proteolysis
from stores
source of
from food (glycogen)
glucose
gluconeogenesis
fate of glycolysis
glycolysis
glucose formation of stores
FASTING
WELL-FED STATE
STATE

source of
from food TAG from storage TAG
fatty acids

fate of b-oxidation  b-oxidation


fatty acids synthesis of TAG ketogenesis
FASTING
WELL-FED STATE
STATE

source of
from food TAG from storage TAG
fatty acids

fate of b-oxidation  b-oxidation


fatty acids synthesis of TAG ketogenesis

source of from muscle


from food
amino acids proteins

proteosynthesis
fate of
oxidation gluconeogenesis
amino acids
lipogenesis
METABOLISM OF AMMONIA
•-SYNTHESIS
THE IMPORTANCE OF
OF NUCLEOTIDES ( NUCLEIC
GLUTAMINE
ACIDS) -
• DETOXIFICATION OF AMINO N (-NH 2
TRANSPORT)
• SYNTHESIS OF CITRULLINE (USED IN UREA
CYCLE):

 INTAKE OF PROTEINS IN A DIET (FED


STATE) OR
 DEGRADATION OF BODY PROTEINS
(STARVATION)
• ENTEROCYTE: GLN  CITRULLINE  BLOOD
 KIDNEYS
• KIDNEYS: CITRULLINE  ARG  BLOOD 
LIVER
• LIVER: ARG  UREA + ORNITHINE

ORNITHINE → INCREASED VELOCITY OF THE


UREA CYCLE
=  DETOXIFICATION OF NH3 FROM DEGRAD.
GENERAL PRINCIPLES OF
REGULATION
• CATABOLIC / ANABOLIC PROCESSES
• LAST STEP OF EACH REGULATION
MECHANISM: CHANGE OF A
CONCENTRATION OF AN ACTIVE
ENZYME (= REGULATORY OR KEY ENZYME)
• REGULATORY ENZYMES
 OFTEN ALLOSTERIC ENZYMES
 CATALYZE HIGLY EXERGONIC
REACTIONS (IRREVERZIBLE)
 LOW CONCENTRATION WITHIN A CELL
I. REGULATION ON THE
ORGANISM LEVEL
1. SIGNAL TRANSMISSION AMONG CELLS
(SIGNAL SUBSTANCES)

2. SIGNAL TRANSSDUCTION THROUGH THE


CELL MEMBRANE

3. INFLUENCE OF ENZYME ACTIVITY:


 INDUCTION OF A GENE EXPRESSION
 INTERCONVERSION OF EXISTING ENZYMES
(PHOSPHORYLATION / DEPHOSPHORYLATION)
II. REGULATION ON THE CELL
1. COMPARTMENTALIZATION OF MTB
LEVEL
PATHWAYS
2. CHANGE OF ENZYME
CONCENTRATION
(ON THE LEVEL OF SYNTHESIS OF
NEW ENZYME )
3. CHANGE OF ENZYME ACTIVITY
(AN EXISTING ENZYME IS
ACTIVATED OR INACTIVATED)
1. COMPARTMENTALIZATION OF MTB
PATWAYS
• TRANSPORT PROCESSES BETWEEN
COMPARTMENTS
• VARIOUS ENZYME DISTRIBUTION
• VARIOUS DISTRIBUTION OF
SUBSTRATES AND PRODUCTS (
TRANSPORT)
• TRANSPORT OF COENZYMES
• SUBSEQUENT PROCESSES ARE CLOSE TO
EACH OTHER
2. SYNTHESIS OF NEW ENZYME
MOLECULES:
• INDUCTION BY SUBSTRATE OR REPRESSION
BY PRODUCT
(ON THE LEVEL OF TRANSCRIPTION)

EXAMPLES:
XENOBIOTICS  INDUCTION OF CYT P450
HEME  REPRESSION OF DELTA-
AMINOLEVULATE SYNTHASE
3. CHANGE OF ACTIVITY OF AN
EXISTING ENZYME

a) IN RELATION TO AN ENZYME KINETICS


 CONCENTRATION OF SUBSTRATES ( KM)

 AVAILABILITY OF COENZYMES
 CONSUMPTION OF PRODUCTS
 PH CHANGES

 SUBSTRATE SPECIFICITY - DIFFERENT KM


3.b)CHANGE OF ACTIVITY
ACTIVATION OF AN OF THE
OR INACTIVATION
EXISTING ENZYME
ENZYME
• COVALENT MODIFICATION OF THE
ENZYMES
 INTERCONVERSION:
PHOSPHORYLATION/DEPHOSPHORYLATION)
 CLEAVAGE OF AN PRECURSORE (PROENZYME,
ZYMOGEN)

• MODULATION OF ACTIVITY BY
MODULATORS (LIGANDS):
 FEED BACK INHIBITION
PHOSPHORYLATION /
DEPHOSPHORYLATION

• SOME ENZYMES ARE ACTIVE IN A


PHOSPHORYLATED FORM, SOME ARE
INACTIVE
• PHOSPHORYLATION:
PROTEIN KINASES
MACROERGIC PHOSPHATE AS A DONOR OF
THE PHOSPHATE (ATP!)

• DEPHOSPHORYLATION
PROTEIN PHOSPHATASE
INORGANIC PHOSPHATE IS THE PRODUCT!
Reversible covalent
modification:

A)
• phosphorylation by
a protein kinase
• dephosphorylation by
a protein phosphatase
B)
• phosphorylated enzyme
is either active or
inactive
(different enzymes are
influenced differently)
The figure is found at: http://stallion.abac.peachnet.edu/sm/kmccrae/BIOL2050/Ch1­13/JpegArt1­13/05jpeg/05_jpeg_HTML/index.htm 
(December 2006)
MODULATORS OF ENZYME ACTIVITY
(ACTIVATORS, INHIBITORS)

• ISOSTERIC MODULATION: COMPETITIVE


INHIBITION
• ALLOSTERIC MODULATION:
CHANGE OF K OR V
M MAX

T-FORM (LESS ACTIVE) OR R-FORM (MORE


ACTIVE)

• IMPORTANT MODULATORS: ATP / ADP