Download Protein Metabolism

Protein Metabolism
Amino Acids: Building blocks of proteins
A.As
Structural
Functional
Hormones
Etc.
P.P.C.
Excess
C – Skeleton
N
NH+4
NH3
Energy
Production
Urea
Routes of supply:
Dietary Protein
~ 100g / day
Amino Acid Pool:
2
Body
1
Protein
~ 400g / day
A. A.
Pool
100g
I
300~400g / day
Body Protein
Glucose,
glycogen
Synthesis of non-essential
a.as.
3
Routes of utilization:
30g / day
Synthesis of N-compounds
e.g. porphyrins
III
II
K.B.
F.As.
steroids.
CO2 + H2O + E
(1/5 th of Energy is provided
by dietary protein)
1
Notes:
 Definition of A.A. pool: The total amount of free
A.As found in both the extra-/intra- cellular
compartments.
 Over 50% of A.A. pool is found in skeletal muscle.
Protein Turnover:
Proteins (synthesis)
proteins (degradation)
 Body proteins are maintained constant.
(300 ~ 400g / day)
Rate of turnover: e.g. digestive enzymes / plasma
proteins: rapid (hrs/days).
Structural proteins: slow (months /
years)
 Proteins rich in sequences containing pro, glu, ser
and thr are rapidly degraded. Chemically altered
proteins
(e.g.
due
to
oxidation)
are
also
preferentially degraded.
2
Role of Dietary Protein in P.M.
1˚
Dietary Protein
2˚
A.As.
Synthesis of tissue proteins
Energy (~
1
th
5 )
Recommended daily allowance (RDA) of dietary
protein:
Excess A.As cannot be stored as storage protein.
30 – 50 g (protein) equiv. are lost per day due to:
A.As. catabolism
 Must be compensated by diet
(RDA: 0.8 x body weight)
 This is to prevent usage of body protein (- ve NBalance)
Diet low in protein
deficiency in essential A.As
Wasting
mobilization
(Hydrolysis)
of body protein
Diet high in protein: excess a.as
Urea
deficiency in body
protein synthesis
NH3
glucose
glycogen
fat
3
Digestion of Dietary Proteins (D.P.):
large
- Dietary Protein M.W.
small
A.As. M.W
Proteolytic
(absorbable)
enzymes
(Stomach, pancreas, intestine)
A. Gastric digestion:
Gastric juice (HCl + pepsinogen)
- HCl:
stomach acid too dilute (PH 2-3) to
hydrolyze D.P. (secreted by parietal cells)
 HCl:
1. P. Denaturation
2. Antiseptic
- Pepsin: acid–stable endopeptidase (secreted as
pepsinogen by serous cells).
chief cells
Pepsinogen (A.As.)
HC1
Pepsin
autocatalysis
Pepsin has similar action
to Renin in adult human
4
optimal PH 1.5-2.2
D.P. pepsin
few A.As
(Trp / phe / Tyr) + Leu-Glu
Glu-Asn, Leu-Val
Val-Cys
B. Pancreatic digestion:
Large p.p.c.
Pancreatic
enzymes
Oligopeptides + A.As.
pro- Zymogens including: (Trypsinogen) – (6A.A.)
⊕
⊕
autoEnteropeptidase
catalysis
secretin
cholecystokinin
(secreted by I.M. cells
found on brush border
membrane)
Produced by M.C. of jujenum
Trypsin
and lower duodenum
pancreas
Oligopeptides + Free AAs.
cleaves
c=o of peptide
bonds of lys/Arg
Inhibited by a low
M.W. peptide
(trypsin inhibitor)
secreted in
pancreatic juice.
5
C. Intestinal digestion:
Luminal surface of intestine (Aminopeptidase)
“exopeptidase”
N-term. residue
Smaller peptides + A.As.
from oligopeptides
Luminal
Dipeptides Dipetidases free A.As.
(I.mucosa)
Absorption:
I.M.C
Free
A.As.
Dipeptides
A.As.
Hydrolysis
A.As
(Dipeptidase)
Portal
circulation
A.As.
Transport of A.As. into cells: Active transport / ATP
Notes:
 Absorption much more complex (20 different A.As.,
compare with monosaccharides).
 Absorption of A.As. follow M-M kinetics.
 A.As. are absorbed at different rates (Gly is the
fastest).
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 L-A.As. are absorbed much quicker than D-A.As.
 Absorption of A.As. into mucosal cells require Na+ dependent transport systems in which ATP is
required as a source of energy.
 Competition of some A.As. for absorption:
 Five different systems for A.As. absorption may
exist for:
a) Neutral A.As. (e.g. Ala, val, phe).
b) Basic A.As. (Lys, arg) and cys.
c) Glycine and imino acids (pro, OH-pro)
d) Acidic A.As. (Asp, Glu)
e) Other A.As. (e.g. taurine)
 γ-glutamyl cycle mechanism, may exist for A.As.
absorption similar to A.As. reabsorption from renal
tubule.
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 Disorder of Digestion: Celiac disease: abnormal
mucosa due to glutin sensitivity (N-glutamyl peptides
are not digested because of absence of digestive
enzyme, causing immune reaction of mucosa).
 Disorder of Absorption: Protein sensitivity, due to
absorption of undigested protein by mucosa.
Activation of pancreatic proteolytic enzymes
Trypsinogen
enterokinase
Trypsin
Pro-Carboxypeptidase A+B
Carboxypeptidase A + B
Proelastase
Chymotrypsinogen
elastase
Chymo
trypsin
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Collagen
collagenase
Smaller P.P.C. + free A.As.
Responsible for tissue necrosis in pancreatitis.
Elastin
Elastase
+
Other proteins
Smaller P.P.C. + free A.As.
Hormonal Control of A.A. Metabolism:
 Insulin and somatomedins promote active transport
of A.As. across cell membranes.
 Insulin inhibits gluconeogenesis from A.As., and
promotes protein synthesis.
 GH,
somatomedins,
androgens,
and
thyroid
hormones promote positive nitrogen balance by
stimulating protein synthesis.
 Glucocorticoids enhance gluconeogenesis from A.As.
In high-dose chronic glucocorticoid therapy negative
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nitrogen balance results causing thinning of skin and
osteoporosis.
 During fast, glucocorticoids predominate, leading to
increased break down of muscle proteins to provide
glucose.
 100g of dietary carbohydrate daily for adults prevents
protein break down for gluconeogenesis.
Catobolism of A.As:
1. Removal of α – amino group in A.As.:
A. Transamination: is the funneling of NH2 to glu
or the process by which the amino group of one
A.A. is transferred to an α-keto acid (mainly
αKG). All A.As. undergo transamination except:
Lys / Pro / OH-Pro / Thr
10
A.A.
α KG
A.A.
Aminotransferase
Keto
acid
Glutamate
Oxidative
Deamination
NH2 for Synthesis of non-essential a.as.
donor
Most important aminotransferases: ALT/AST
NH2
Asp + α KG
- Oxaloacetate + Glu
AST
used as “N” source
in urea cycle
All (ATs) require: Pyridoxal-p: (vit. B6 deriv.)
Mechanism: see diagram
Physiological importance of transamination
1.
Synthesis of non-essential amino acids from
amination of their keto acids, e.g. Ala from
pyruvate, Asp from oxaloacetate, if they are in short
supply from the diet.
2.
Synthesis of glucose from glucogenic A.As.
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3.
The C-skeleton can be used as a source of energy.
Clinical importance of aminotransferases
Two
important
aminotransferases
of
diagnostic
importance: AST/ALT. ALT (cytosolic), AST (cytosolic,
mitochondrial). Plasma ALT and AST may be elevated
in acute liver conditions and myocardial infarction.
Note:
Aminotransferase reactions do not always involve αKG;
amino groups may be transferred directly to other keto
acids.
B. Oxidative deamination: results in the liberation of
(NH2) group as (NH3)
 Stie: 1˚ liver / kidney (mitochondria)
 Glu
Glu
DH
(rapid)
α KG + NH3
+
NADH+H
NAD
A.A.
Glu
Glu DH (NADPH)
+
Urea cycle
TCA
(Energy production)
cycle
12
 How (NH2) groups of a.as are released as (NH3)?
 Coenzyme of Glu – DH: NAD+ / NADP +
 Notes: Direction of reaction depends on:
[Glu], [α KG], [NH3], NAD+ / NADH
Allosteric regulators:
ATP, GTP
⊖
ADP, GDP
⊕
 NADH+H+ will be oxidized in the oxidative
phosphorylation pathway. Hence the name oxidative
deamination.
 αKG used in transamination reaction is generated by
oxidative deamination.
The Urea Cycle
 The major route for disposing of (NH2) of a.as
H2N
C = O Urea
H2N
1 N (from NH2)
1 N (from Asp)
Glu is the
source of
both “N”
C = O : from CO2
Site: Liver
13
STEPS OF REACTIONS:
In the mitochondria:
1. Formation of carbomyl phosphate:
CO2 + NH+4 + 2ATP Carbomyl
Carbomyl-℗ (high
energy
Phosphate Synthetase I
phospate,
from liver oxidative
ΔG= -14.0
metabolism
2ADP +
Kcal/mole)
N-acetyl
Pi + 3H+ 3H2O
glu ⊕
Notes:
 CO2 incorporation into carbomyl-p contributes to
acid reduction in tissue involved.
 Arginine in the urea cycle stimulates the activity of
N-acetyl glutamate synthase, thus:
CoA
Acetyl CoA + glu
N-acetyl-glu
N-acetyl-glu synthase
Arg ⊕
2. Formation of L-Citrulline: (Energy in carbomyl-p
drives the reaction in the forward direction)
14
Orn.
TranscarboCarbomyl-℗ + L-Ornithine mylase
L-Citrulline
L-Citrulline leaves the mitochondria to the cytosol:
ATP
AMP
+
PPi
3. L-Citrulline + L-Asp
Arginosuccinate
4. Arginosuccinate Arginosucc. Lyase
L-Arginine
Fumarate
5. L-Arginine Arginase Urea + L-Ornithine
Fate of fumarate:
1. Fumarate fumarase Malate
Malate
(Hydration)
(cytosol)
mito. TCA cycle
2. Malate
oxaloacetate
PEP
Asp
urea cycle
Glucose
15
Fate of urea:
1- Liver (urea)
2- Intestine
Bacterial
Urea
Urease
Blood Circulation
(Urea)
Kidney
(urea)
NH3 + CO2
feces
In renal failure: Hyperammonemia is due to
increased
intestinal
urea
due
to
its
increased
concentration in the blood circulation. Hence, high NH3
will be formed in the intestine, which is a major source
of blood ammonia.
Overall “urea” reaction:
Asp + NH3 + CO2 + 3ATP
Urea + fumarate +
2ADP + 2Pi + AMP +
PPi + 3H2O
4ATP – equiv. are used.
16
Regulation of the urea cycle:
 Rate-limiting step: carbomyl-p-synthetase I, activated
by N-acetyl-glu (synthesized greatly after ingestion of
a protein-rich meal: AcetylCoA + Glu
N-Acetyl-
glu).
 The role of urea cycle “arg” has been discussed.
 A high protein diet increases the rate of synthesis of
arginase in liver. Therefore, up-regulates the urea
cycle.
Notes:
 About 80% of nitrogen in human is excreted as urea,
small amounts of ammonia, A.As., urate, creatinine
and other nitrogenous compounds.
 Normal adult plasma concentration: 3.3-6.6 mmol.
 The kidney produces some urea.
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 Many tissues possess all but one urea-cycle enzyme,
arginase. Therefore, they use this pathway to
synthesize arginine.
 In acidosis urea synthesis is decreased and glutamine
synthesis is increased in the liver. Glutamine is then
transported from liver to kidney where it is deaminated
by glutaminase to release NH3+glu. NH3 binds to H+ in
renal tubule and excreted as NH4+ in urine.
Hyperammonemia
 High
blood
ammonia
leads
to
“ammonia
intoxication”: flapping tremor, slurring of speech,
blurring of vision, and in severe cases coma and death.
Types: A – Acquired: impaired liver function (major).
Other causes: include urinary tract infections,
leukemia.
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B – Hereditary: Genetic defects in each of the
five urea cycle enzymes have been reported.
Rare,
but
fatal
in
infancy.
The
urea
concentration is extremely low.
Mechanism of ammonia intoxication
Source of brain ammonia:
A. Arterial blood supply.
B. Catabolism of brain cell protein.
C. Deamination of γ-aminobutyric acid (GABA)
(inactivation) (Major source):
GABA GABA deaminase Butyraldehyde
Succinate
NH3
Reactions of ammonia detoxication:
(1) α KG + NH4+
GDH
NADH+H+
or
NADPH+H+
Glutamate
NAD+
or
NADP+
19
(2) Glutamate + NH4+ Gln synthetase
ATP
Therefore,
depletion
Glutamine
ADP+Pi
of
αKG
due
to
increase
concentration of ammonia, results in a decrease cellular
oxidation and ATP production. The brain depends on
TCA for its energy requirement.
(A) Sources of Ammonia:
*1- Transamination of a.as and oxidative deamination
of Glu.
*2- Glutamine: Gln
Glutaminase
 Kidneys NH3
NH4+ (important in acid-base
formed in renal tubule and
trapped (Ion trapping)
 Intestine:
Glu + NH3
balance)
dietary
or
glutamine
blood
20
*3- Intestinal urease:
Urea/dietary protein
urease
CO2 + NH3
4- Amines: dietary or body monomine by the action of
amine oxidase, NH3 is generated.
5- Purines/Pyrimidines: Catabolism of Pu./Py., NH2
attached to the rings is released as NH3.
6- Non-Oxidative deamination of A.As.: Asn, Cys,
Gln, His, Ser and Thr. The reaction starts with
removal of H2O (dehydration) by dehydrase or
“H2S” (from Cys) followed by deamination.
7- Amino acid oxidases: oxidatively deaminate α –
A.As., requiring FMN/FAD as cofactors. Liver and
kidney rich in those oxidases removing NH2 from
D-/L-A.As.
A.A. + FMN + H2O
Ketoacid + NH3 + FMNH2
FMNH2+O2
FMN+H2O2
H2O2 catalase
H2O+½ O2
* : Major routes
21
The Transport of Ammonia:
Liver
Sk. Muscle
 NH3 is transported in blood as: Urea/Glutamine/
Brain
Alanine
Sk. Muscle
Glu + NH
Glu
3
- Glutamine Glnase Glu + NH3
(Kidney)
Notes:
 During severe muscular exercise: AMP concentration
increases in muscle:
AMP
IMP + NH3
or: During stravation muscle protein is degrades to
A.As. The A.As. are transaminated:
A.As.
Ketoacid + NH3
The accumulated ammonia or NH4+ will react with
α KG:
α KG + NH3
Glutamate
Aminotransferase
22
 Glutamate can be further amidated to form
glutamine:
Glu + NH4
Gln
ATP
ADP+Pi
Alternatively:
 NH2 of glutamate can be transferred to pyruvate:
Pyruvate + Glu
ALT
Ala + α-KG
Ala leaves the muscle to the liver:
 Ala + ketoacid
ALT
Pyruvate + A.A.
 Pyruvate serves as a substrate for gluconeogenesis
 Glucose leaves the liver to muscle for glycolysis
forming pyruvte. This is know as the Alanine Cycle.
23
Metabolism of C-Skeleton:
Products of C-skeleton catabolism:
2- α KG
3- Pyruvate
1- Oxaloacetate
4- Fumarate
6- aceltoacetylCoA
5- acetylCoA
7- Succinyl CoA
 Fate: 1- Synthesis of glucose/lipid, 2-Energy
production.
 Site: TCA cycle.
Catabolism of Certain A.As
H2O
- Gly:
H2O2
Gly Gly-oxidase
O2
TCA cycle
Glyoxylate.
NH3
Malate
“Urine”
CO2 + formaldehyde
Oxalate
Synthesis of Ser from Gly:
5
10
N
,
N
– CH2 THF4 Ser
Gly
Ser-OH-CH3 transferase
Thr
Gly
Acetaldehyde
AcetylcoA?
(makes24Thr a
ketogenic )
 Gly: is non-essential so is Ser.
 Ser:
Ser
Ser dehydrase
[X]
or deaminase
 Thr Thr dehydrase [X]
or deaminase
Pyruvate
NH3
α-Ketobutyrate
NH3
succinylCoA
Ser can be also synthesised from:
NAD+
NADH+H+
3- Phosphoglycerate
3- phosphohydroxypyruvate
Glu
αKG
Pi
Ser
Phospho-L-Ser
αKG
Glu
HydroxyPyruvate
2 phosphoglycerate
glycerate
Pi
25
Arginine & Histidine
 essential for growing infants, non-essential for
maintenance during adulthood life.
Trans.
Glu
α KG
Oxidase
Ornithine
Glu – Semialdehyde + A.A.
+
A.A. keto acid
H2O
Comes from urea cycle
from Arg “cleavage”
– pyrroline – 5 – carboxylate
1
2H
Arg
urea + Ornithine
Proline
 Ornithine synthesised by Trans. Of Glu-semi
aldehyde can be used to synthesise “Arg”
sufficient for maintenance. Thus in extrahepatic
tissues, ornithine condenses with carbomyl-p,
until the formation of Arg. Arginase is lacking
in these tissues.
His: ATP + 5 – phosphoribosyl – PPi
H2O
L-Histidine
NH3
PPi
NAD+
H2O
26
L-Histidine
This reaction is a slow-rate:
 Not adequate for growth.
His
Histadase
Urocanic acid
N-Formiminoglutamate
THF
Glu
5-formiminoTHF
 Deficiency of histidase leads to “histidinemia”.
 Biochemical changes: elevated levels of histidine in
blood and urine.
 Mental retardation is common.
27
Methionine and Cysteine
 Met: essential A.A., diet usually deficient in meth.
Met
Mg
ATP
S-adenosylmethionine
2+
Pi + PPi
(SAM)
Methyl donor in many
reactions e.g P-Choline
synthesis, catechol, creatine
S-adenosylhomocysteine
adenosine
*Cystathionine
synthase
H2O
Pyruvate
Homocysteine
Ser pyridoxal-p
H2O
Cystathionine
Succinyl CoA
(extra CH2)
Methylmalonyl CoA
desulfuration
Cysteine
+
α ketobutyrate
+ NH4+
propinyl CoA
Notes:
 C-skeleton of cysteine is provided by ser, SH-group
by met.
 When cysteine is absent from the diet, Methionine
requirement icreases by 30%.
* : deficiency leads to homocystinuria
28
**: deficiency leads to cystathioninuria
Phenylalanine and Tyrosine
Phe-
 phe
hydroxylase
deficiency
Tyr
Tyrosinosis
p-hydroxyhpenyl-pyruvate
tyr-amino
transferase
phe-aminotransferase
p-OHPhelactate
phenylpyruvate
PhenylCO2
phenyllactate
acetate
+
Gln
(excreted in urnie) Phenylacetyl
glutamine
2,5-di-oH
phenylacetate
(homogentisate)
O2, Fe2+, Glutathione
Fumarylacetoacetate
acetoacetate
Fumarate
deficiency: Alcaptonuria
Tyrosinemia: deficiency in p-OH-phe-pyruvate oxidase.
Increase blood/urine p-OH-Phe-pyruvate &
increase in blood: Tyr. Hepatic failure &
death in the first 6 months of life.
29
Tyrosinosis:
plasma tyr, excretion of large quantity
of p-OH-phe-pyruvate in urine.
Tryptophan:
Trp Trp-dioxygenase
(pyrrolase)
Formylkynurenine
3-OH-Kynurenine
Kynurenine
Ala
3-OH-Anthranilic acid 3 steps
7 steps
Nicotinic acid
Acetoacetyl CoA
NAD+
NADP+
2 Acetyl CoA
NH3
Trp
CO2
Indolepyruvate
O2
Indoxyl
Indoleacetic acid
CO2
O2
Indole
skatoxyl
skatol
CO2
Indole and skaltol are responsible for characteristic odor
of feces.
 Hartnup disease: deficiency of Trp dioxygenase or
impaired intestinal absorption of Trp.
30
Clinical
manifestation:
pellagra,
dermatitis
with
neurological degeneration.
Pellarga may arise from a diet deficient in Trp as found
in poor peasants who subsit on maize (niacin is in the
bound form, unavailable for consumption). 60 mg Trp
yields 1.0 mg nicotinamide.
Gluconeogenic / Ketogenic Amino Acids
Ala, Cys
Gly, Ser
Thr
Pyruvate
(Asn, Asp)
Phe/Tyr
Trp
Acetyl CoA
OX.A.A
Malate
Ala
Leu, Lys
Citrate
“TCA”
Cycle
Isocitrate
Fumarate
Acetoacetate
α KG
Succinate
Succinyl
CoA
K.B.
F.A.
Met
Thr
Val
Arg, Gln
Glu, His
Pro
31
Ileu
 Leu / Lys – Pure ketogenic
 Ileu / Phe / Tyr / Trp – Ketogenic and Gluconeogenic
 Ala / Arg / Asn / Asp / Cys / Glu / Gln / Gly / His / Met
/ Pro / Ser / Thr / Val – Pure Gluconeogenic
Essential Amino Acids:
P
V T
T
Phe Val Trp
I
M
H
A L
L
Thr Ileu Met His Arg Leu Lys
Synthesis of non-essential amino acids
1. Tyr:
BH4 + O2
BH2 + H2O
Phe
Tyr
Phenylalanine hydroxylase
2. Synthesis by transamination: Ala, Asp, Glu
- Pyruvate
ALT
Glu/A.A.
- Oxaloacetate
Ala
Keto acid
AST
Asp
32
A.A./(Glu)
Keto acid
A.A.
keto acid
- α KG (ketoglutarate)
Glu Amino-transferase
Glu
3.Synthesis by amidation: Asn/Gln
- Asp Asnsynthetase
Gln
+ATP
- Glu
Asn Asparaginase Asp + NH3
Glu+AMP
+PPi+H+
GlutamineSynthetase
ATP+NH3
Gln
Pi+ADP+H
INBORN ERRORS OF A.A. METABOLISM
 Mutant genes
Abnormal Proteins/Enzymes
Partial/total loss of enzymes activity
Accumulation
of metabolites which interfere with normal development
mental retardation.
 Rare occurrence (1:50,000).
 More than 40 disorders have been described.
Most Common:
Alcaptonuria: deficiency: Homogentisate Oxidase (phecatabolism).
33
effect: accumulation of homogentisate
polymers
dark urine
Maple Syrup Urine Disease: Deficiency: branded-chain
ketoacid DH.
NH3
Ox.Decarb-
Val/Leu/Ileu
keto acid
B.c.a.aoxylation
aminotransferase
( -Ketoacid DH)
effect:
accumulation of b.c.a.as and keto acids in
plasma and urine.
 high mortality rate, and neurologic problems.
Homocystinuria: deficieny: Cystathionine Synthetase
effect: accumulation of homocysteine
in urine. Met/its metabolites are
increase in blood.
 Mental retardation, osteoporosis, dislocation of lens
 In some patients, administration of very large doses
of pyridoxal-p alleviate the symptoms.
Phenylketonuria (PKU): Most important (1:11,000)
Deficiency: Phe-hydroxylase (multi-allels 6-10 mutation
effect: Hyperphenylalaninemia (may be caused by
34
deficiency in BH2 reductase/ BH2 synthetase).
in tissues, Plasma and Urine.

Phe
Phenyl pyruvate
Phenyllactate
Phenylacetate
 Mental retardation by the age of 1 year. (I.Q.< 50)
 Hypopigmentation (fair hair, light skin color, blue eyes).
 Detection: ferric cholride test/ Bacterial assay
(Guthrie test). Usually 48 hrs after
ingesting breast: milk / formula.
 Treatment: feeding synthetic A.As. preparation low
in phe / natural food low in Phe. Early
treatment prevents neurologic damage.
Tyr must be supplemented.
Synthesis of N-Containing Compounds:
1- Porphyrins: Site: liver/ bone marrow (stem cells).
Gly + succinyl CoA
protoporphyrin IX
35
Heme
Fe2+
2- Creatine phosphate:
* Site: muscle
 high-energy compound donates its ~ to ADP
ATP.
CK
Creatine ~ + ADP
ATP+ creatine
(maintenance of [ATP] during first few mins.
of intense muscular contraction).
Gly + Arg
Creative
3- Histamine: produced by mast cells as allergic
reaction/trauma. It is a potent vasodilator, and stimulates acid and pepsin
from gastric mucosa (ranitidine inhibits
its secretion).
His
CO2
Histamine
Decarboxylase
 Antihistamines block the action of His-decarboxylase.
36
4- *Catecholamines:
( Dopamine, nor-epinephrine,
epinephrine) biologically active amines.
Dopamine/nor-ep: Neurotranmitters in
brain/autsonomous. N.S.
Nor-ep/ep.: also produced in adrenal medulla.
Synthesis:
Phe-
- Phe
Tyr
hydroxylase
Tyrosine hydroxylase
3,4 -dihydroxyphenylalanine
Tyr
(Dopa)
BH4
BH2+H2O
+
O2
BH2reductase
NADP+
NADPH+H+
NADP+-reductase
CO2
Dopa
Dopamine
Dopadecarboxylase
(pyridoxal-p)
Dopamine Dopamine hydroxylase
Nor-epinephrine
37
Ascorbate
Dehydro-ascorbate
+
+H2
O2
Nor-eprinephrine
Epinephrine
N-methyl transferase
SAM
S-ad-homo-cys
Inactivation of Catecholamines
Epinephrine
Nor-epinephrine
NH3
Di-OH-Mandelic acid
Metanephrine
Normetanephrine
NH3
NH3
3-mehoxy-4-hydroxy
mandelic acid
or Vanillyl mandelic acid (VMA)
Dopamine
NH3
Di-OH-phenylacetate
3-methoxytyramine
NH3
Homovanillic
38
Acid
Serotonin (Vasocontrictor): I.M. Cells (largest
amount), platelets, CNS
(smaller amount).
Function: pain perception, behaviors
regulation of temp, sleep, blood pressure.
(pyridoxal-p)
Trp Trp-hydroxylase 5-OH-trp decarboxylase Serotonin
CO2
BH4
BH2
+O2
5-hydroxyindole acetic acid (5HIAA)
39