an introduction to protein metabolism

1. METABOLISM
OF
AMINO ACIDS
assistant professor Dr.
Abdulhussien M. Aljebory
College of pharmacy
Babylon University

2. 1. Introduction
2. Amino acid classification
3. Some definitions:
- nitrogen balance (NB)
- protein requirement
- biological value (BV)
4. Digestion of protein
5. Absorption of protein
6. Metabolic fate of protein
7. Metabolism of amino acids:
- removal of ammonia: by deamination, transamination
and transdeamination
- fate of carbon skeletons of amino acid
- metabolism of ammonia

3. Metabolism
• Total of all chemical changes that occur in
body. Includes:
– Anabolism: energy-requiring process where small
molecules joined to form larger molecules
• E.g. Glucose + Glucose
– Catabolism: energy-releasing process where
large molecules broken down to smaller
• Energy in carbohydrates, lipids, proteins is
used to produce ATP through oxidation-
reduction reactions

4. Metabolic Pathways
• The enzymatic reactions of
metabolism form a network of
interconnected chemical reactions,
or pathways.
• The molecules of the pathway are
called intermediates because the
products of one reaction become the
substrates of the next.
• Enzymes control the flow of energy
through a pathway.
Intermediary Metabolism

5. Oxidation-Reduction Reactions
• Oxidation occurs via the loss of hydrogen or the
gain of oxygen
• Whenever one substance is oxidized, another
substance is reduced
• Oxidized substances lose energy
• Reduced substances gain energy
• Coenzymes act as hydrogen (or electron)
acceptors
• Two important coenzymes are nicotinamide
adenine dinucleotide (NAD+
)and flavin adenine
dinucleotide (FAD)

6. Stages of Metabolism
Figure 24.3
• Energy-containing nutrients are processed in
three major stages:
1. Digestion – breakdown of food; nutrients
are transported to tissues
2. Anabolism and formation of catabolic
intermediates where nutrients are:
• Built into lipids, proteins, and glycogen
or
• Broken down by catabolic pathways to
pyruvic acid and acetyl CoA.
3. Oxidative breakdown – nutrients are
catabolized to carbon dioxide, water, and ATP

7. Protein Metabolism
• Non-essential amino acids can be formed by
transamination, transfer of an amine group
to keto acid. Can also be eaten.
• If used for energy, amino acids undergo
oxidative deamination. Ammonia and keto
acids are produced as by-products of
oxidative deamination. Ammonia is
converted to urea and excreted.
• Amino acids are not stored in the body

8. Protein Catabolism

9. *Metabolism of proteins is the metabolism
of amino acids. NH2 COOH
*Metabolism of amino acids is a part of the
nitrogen metabolism in body.
*Nitrogen enters the body in dietary protein.
*Dietary proteins cannot be stored as such but
used for formation of tissue proteins due to
there is a continuous breakdown of
endogenous tissue proteins.

10. N.B.
 Essential amino acids :
Lysine, Leucine, Isoleucine, Valine, Methionine, Phenylalanine,
Threonine, Tryptophan
 Nonessential amino acids:
Alanine, glycine, aspartate , glutamate, serine, tyrosine,
cysteine , proline , glutamine, aspargine
Histidine & arginine are semi essential. They are essential
only for infants growth, but not for old children or adults where
in adults histidine requirement is obtained by intestinal flora &
arginine by urea cycle.
 For formation of new tissue protein :
all essential amino acids that can not be synthesized by
organism & provided by dietary protein must be present at
the same time with nonessential amino acids that can be
synthesized by organism

11. Nitrogen Balance (NB):
Nitrogen balance is a comparison between
Nitrogen intake (in the form of dietary protein)
and
Nitrogen loss (as undigested protein in feces ,
NPN as urea, ammonia, creatinine & uric acid in urine,
sweat & saliva & losses by hair, nail, skin).
NB is important in defining
1.overall protein metabolism of an individual
2.nutritional nitrogen requirement.

12. Three states are known for NB:
a)Normal adult: will be in nitrogen equilibrium,
Losses = Intake
b)Positive Nitrogen balance:
Nitrogen intake more than losses (High
formation of tissue proteins) occurs in
growing children, pregnancy,
lactation and convulascence.
C)Negative Nitrogen balance:
Nitrogen losses more than intake
occurs in:- (Low intake of proteins) in starvation, malnutrition, GIT
diseases
- (High loss of tissue proteins ) in wasting diseases like
burns, hemorrhage& kidney diseases with albuminurea
- (High breakdown of tissue proteins ) in D.M.,

13. Protein Requirement for humans in
Healthy and Disease Conditions
The normal daily requirement of protein for
adults is 0.8 g/Kg body wt. day-1
.
• That requirement is increased in healthy conditions:
during the periods of rapid growth,
pregnancy, lactation and adolescence.
• Protein requirement is increased in disease states:
illness, major trauma and surgery.
• Req. for protein should be reduced in:
hepatic failure and renal failure

14. Biological Value for Protein (BV):
* BV is : a measure for the ability of dietary
protein to provide the essential amino acids
required for tissue protein maintenance.
* Proteins of animal sources (meat, milk,
eggs) have high BV because they contain all
the essential amino acids.
* Proteins from plant sources (wheat, corn,
beans) have low BV thus
combination of more than one plant protein is
required (a vegetarian diet) to increase its
BV.

15. DIGESTION OF PROTEIN
• Proteins are broken down by hydrolyases (peptidases or
proteases):
• Endopeptidases attack internal bonds and liberate large
peptide fragments (pepsin, trypsin, Chymotrypsin &
Elastase)
• Exopeptidases remove one amino acid at a time from
– COOH or –NH2
terminus (aminopeptidase &
carboxypeptidase)
• Endopeptidases are important for initial breakdown
of long polypeptides into smaller ones which then
attacked by exopeptidases.
• Digestion of protein can be divided into: a gastric,
pancreatic and intestinal phases.

16. I. Gastric Phase of Protein Digestion:
(represents 15% of protein digestion)
1) Pepsin: in adult stomach , secreted as pepsinogen.It is
specific for peptide bond formed by aromatic or acidic
amino acids
Pepsinogen
HCL
Pepsin
Proteinoligopeptides & polypeptides + amino acid
2) Rennin: in infants for digestion of milk protein (casein).

17. II. Pancreatic Phase of Protein Digestion
• This phase ends with free amino acids and small peptides of 2-8 amino
acid residues which account for 60% of protein digestion
Small
intestine
Dietary
protein Trypsin
Trypsinogen
Chymotrypsin
Chymotrypsinogen
Elastase
Proelastase
Enteropeptidase
BASIC
UNCHARGED
ALIPHATIC
BASIC

18. III. Intestinal Phase of protein digestion:
–Intestinal enzymes are:
aminopeptidases (attack peptide bond
next to amino terminal of polypeptide) &
dipeptidases
– The end product is free amino acids
dipeptides & tripeptides.

19. Absorption of Amino Acids and
Di- &Tripeptides:

20. Absorption of Amino Acids and
Di- &Tripeptides:
*L-amino acids are actively transported across
the intestinal mucosa (need carrier, Na +
pump, Na+
ions, ATP).
Different carrier transport systems are:
a) For neutral amino acids.
b ) For basic amino acids and cysteine.
c) For imino acids and glycine.
d) For acidic amino acids.
e) For B-amino acids (B-alanine & taurine).
*D-isomers transported by simple diffusion.

21. The transcellular movement of amino acids in an
intestinal cells:
blood
Amino acid
Amino acid
Amino acid
Na+
Na+
Na+
K+
K+
Lumen
Cytosol
Extracellular fluid
(Antiport)
(Symport)

22. Tri- & Dipeptides can actively transported faster than
their individual amino acids.
intact proteins:
1. Immunoglobulins of colostrum are
absorbed by neonatal intestines through endocytosis
without loss of their biological activity and thus
provide passive immunity to the infants.
2. Vaccines (undigested polypeptides) in
children and adults are absorbed without loss of
their biological activity producing antigenic
reaction and immunologic response.

23. METABOLIC FATES OF AMINO
ACIDS:
1- Body protein biosynthesis.
2- Small peptide biosynthesis(GSH).
3-Synthesis of non-protein
nitrogenous (NPN) compounds (creatine,
urea, ammonia and uric acid)
4- Deamination & Transamination to
synthesized a new amino acid or glucose or
ketone bodies or produce energy in starvation.

24. Sources & fates
of amino acids:
•Protein turnover :
(results from
simultaneous synthesis
& breakdown of
proteins molecules)
•Total amount of protein
in body of healthy adult
is constant (due to rate
of protein synthesis is
equal to the rate of its
breakdown).
Body protein
400 g per day,synthesis
Body protein
400 g per day breakdown
Dietary protein
Synthesis non-
essential a.as.
GL.&Glycogen
Ketone bodies
Fatty acid& steroids
CO2& E

25. Metabolism OF AMINO ACIDS:
R
1. Removal of amonia by : NH2 CH COOH
- Deamination Oxidative deamination
1) glutamate dehydrogenase in mitochondria
2) amino acid oxidase in peroxisomes
Direct deamination (nonoxidative)
1) dea. by dehydration (-H2O)
2) dea. by desulhydration (-H2S)
- Transamination (GPT & GOT)
- and transdeamination.
2. Fate of carbon-skeletons of amino acids
3. Metabolism of ammonia

26. Deamination of Amino Acids
a) Oxidative Deamination:
1) Glutamate dehydrogenase , mitochondrial , potent, major deaminase
Glutamat
NAD
or NADP
H2O
Glu. dehydrogenase
NADH + H+
NADPH + H+
α-ketoglutarate + NH3
It is allosterically stimulated by ADP &
inhibited by ATP, GTP & NADH.
Thus, high ADP (low caloric intake) increases protein degradation
high ATP ( well fed-state) decreases deamination of amino
acids & increases protein synthesis.
-NH3
α-Keto acidAmino acid

27. 2) Amino Acid Oxidases:
The minor pathway for deamination of amino acids.
They are found in peroxisomes of liver and kidney.
L-amino acid oxidases utilize FMN while D-a.a. oxidases
utilize FAD.
R
H-C-NH2
COOH
R
C = NH
COOH
R
C = O
COOH
O2
H2O2
a.a. Oxidase
FMN FMNH2
H2O
NH3
imino acid ketoacid
Catalase
H2O + O2

28. •D-amino acid oxidases are highly active
than L-amino acid oxidases especially in
kidney and liver due to:
the function of D-amino acid oxidases is
the rapid and irreversible breakdown of D-
amino acids since:
• D- amino acids are potent inhibitors to
L-amino acids oxidases

29. b) Non-oxidative deamination:
(Direct Deamination )
1) Deamination by dehydration:
Serine & Threonine
CH2
OH
H-C-NH2
COOH
PLP
CH2
C-NH2
COOH
CH3
C = NH
COOH
HOOC - C = O
CH3
Ser dehydratase
H2O
H2O
NH3Pyruvate
Serine

30. 2) Deamination by desulfhydration :
(cysteine)
CH2SH
H-C-NH2
COOH
PLP
CH2
C-NH2
COOH
CH3
C = NH
COOH
HOOC - C = O
CH3
Cys. desulfhydratase
H2S
H2O
NH3Pyruvate
Cysteine

31. Transamination:
R1
- C - COOH + R2
C COOH
NH2
H
O
R1 - C COOH + R2 C COOH
H
NH2
H
O
Aminotransferase
PLP
amino acid keto acid new keto acid new amino acid
Aminotransferases are active both in cytoplasm and mitochondria e.g.:
1. Aspartate aminotransferase (AST), Glutamate oxaloacetate transaminase (GOT),
2. Alanine aminotransferase (ALT), Glutamate pyruvate transaminase, (GPT)
In all transamination reactions, α-ketoglutarate (α –KG) acts as
amino group acceptor.
Most, but not all amino acids undergo transamination reaction with few
exceptions (lysine, threonine and imino acids)
NH2 O
α –KG
O NH2
GLU

32. The role of PLP as Co-aminotransferase :
PLP binds to the enzyme via schiff’s base & ionic salt bridge &
helps in transfer of amino group between amino acid and keto
acid (KG):
R1
- CH - COOH
NH2
R1
- CH - COOH
N
CH
R1
- C - COOH
O
N
CHO
EnzOH
CH3
N
EnzOH
CH3
N
EnzOH
H3
C
CH2
NH2
R2
- CH - COOH
NH2
R2
- C - COOH
O
R2
- C - COOH
N
CH
N
EnzOH
CH3
(amino acid)
PLP-Enz
H2O
H2O
(new amino acid)
H2O
(keto acid)H2O
Pyridoxamine
New keto acid
O
NH2
New amino acid 2
R1 R1 R1
R2
R2

33. Metabolic Significance of Transamination
Reactions
 It is an exchange of amino nitrogen between
the molecules without a net loss
 This metabolically important because:
1) There is no mechanism for storage of a protein
or amino acids.
2) In case of low energy (caloric shortage), the
organism depends on oxidation of the
ketoacids derived from transamination of amino
acids.
3) It is important for formation of the non-essential
amino acids

34. Transdeamination:
Amino acid α-ketoacid
Aminotransferase
α-ketoglutarate Glutamate
NH3
Glutamate dehydrogenase
Transamination
Deamination
Due to…L-amino acid oxidases, but not glutamate dehydrogenase, can sluggish
(decrease) the rate of deamination of the amino acids.
So… the most important and rapid way to deamination of amino acids is first
transamination with α-ketoglutarate followed by deamination of glutamate.
Therefore glutamate through transdeamination serves to a
funnel ammonia from all amino acids.
Transamination
Deamination with
Glu.D.H.
Amino acid
α-ketoglutarate
NH3
Funnel

35. THE FATE OF CARBON-SKELETONS OF
AMINO ACIDS
a) Simple degradation:
(amino acid Common metabolic intermediate)
Alanine Pyruvate
Glutamate α-ketoglutarate
Aspartate Oxaloacetate
b) Complex degradation:
(amino acid--- Keto acid----- complex pathway---- Common metabolic intermediate)
Amino acids whose ketoacids are metabolized via
more complex pathway e.g. Tyrosine, Lysine,
Tryptophan
c) Conversion of one amino acid into another amino acid before
degradation:
Phenylalanine is converted to tyrosine prior to its further degradation.

36. The common metabolic intermediates that arised from the
degradations of amino acids are: acetyl CoA, pyruvate, one of the krebs
cycle intermediates (α-ketoglutarate, succinyl CoA, fumarate& oxaloacetate)
Citrate
cycle

37. Metabolism of the Common Intermediates
1.Oxidation: all amino acids can be oxidized in
TCA cycle with energy production
2.Fatty acids synthesis: some amino acids
provide acetyl CoA e.g. leucine and lysine
(ketogenic amino acids).
3.Gluconeogenesis: ketoacids derived from amino
acids are used for synthesis of glucose (is
important in starvation).
Glucogenic Ketogenic Glucogenic&Ketogenic
Ala, Ser, Gly, Cys, Leu , Lys Phe,Tyr,Trp,Ile,Thr
Arg, His, Pro, Glu,
Gln, Val, Met, Asp, Asn.

38. METABOLISM OF AMMONIA
Ammonia is formed in body from:
a) From amino acids: 1.Transdeamination in liver (NOT T.A.)
2.amino acid oxidases and amino acid deaminases in liver and kidney.
b) Deamination of physiological amines: by monoamine oxidase
(histamine, adrenaline, dopamine and serotonine).
c) Deamination of purine nucleotides: especially adenine nucleotides
AMP IMP + NH3
d) Pyrimidine catabolism.
e) From bacterial action in the intestine on dietary protein
& on urea in the gut.
NH3 is also produced by glutaminase on glutamine .
deaminase

39. Metabolic Disposal of Ammonia
Glutamine is storehouse of ammonia & transporter form of ammonia.
In brain, glutamine is the major mechanism for removal of ammonia
while in liver is urea formation.
..Circulating glutamine is removed by kidney, liver and intestine where it is
deamidated by glutaminase .
HOOC-CH2
-CH2
-CHCOOH
NH2
NH3
ATP ADP+Pi
H2N-C-CH2-CH2-CH-COOH
O NH2
Gln synthase
Mg2+
Glutamate Glutamine
H2O
Ammonia is toxic to CNS, it is fixed into nontoxic metabolite for reuse or
excretion according to the body needs:
a) Formation of Glutamate:
α-KG + NH3
b) Glutamine Formation: Muscle, brain
Keto acid
α -Amino acidGDH T.A.
Glutamate
c) Urea formation

40. ..
Diet & body
protein
α−Α . a.
Glu.
Biosynthesis
Of purine &
Pyrimidine
Urine
NH4+Urine
Kidney
Liver
Kidney
Glutaminase
Glutamine Glutamate + NH3
H2O
This reaction is important to kidney due to kidney excretes NH4
+
ion to keep
extracellular Na+
ion in body and to maintain the acid-base balance.
Deaminase
GIT
Diet & Body
protein
glutamine
urea
Purines,pyrimidines
Various nitrogen-
containing compounds
glutaminase
Bacterial
urease

41. c) Urea Formation
 Urea is the principal end-product of protein
metabolism in humans.
 It is important route for detoxication of NH3
.
 It is operated in liver, released into blood and
cleared by kidney.
 Urea is highly soluble, nontoxic and has a high
nitrogen content (46%), so …it represents about 80-
90% of the nitrogen excreted in urine per day in man
 Biosynthesis of urea in man is an energy- requiring
process.
 It takes place partially in mitochondria and
partially in cytoplasm.

42. The Urea
Cycle
(The
Ornithine
Cycle,
Kreb's
Henseleit
Cycle):
NAD
MDH
o
H2
Glu
GluNADH2

44. Metabolic Significant Aspects of Urea Cycle
A) Energy Cost:. Energy cost of the cycle is only one ATP.
B) urea cycle is related to TCA cycle:
1. CO2
2.Aspartate arises via transamination of oxaloacetate with
glutamate. Thus, depletion of oxaloacetate will decrease urea
formation (as in malonate poisoning).
3. Fumarate enters TCA cycle
C) Sources of Nitrogen in urea :free NH3
and aspartate.
N.B. glutamate is the immediate source of both NH3
(via oxidative
deamination by Glu. Dehyd.) and aspartate nitrogen (through
transamination of oxaloacetate by AST).

45. Importance of Urea Cycle
1. Formation of arginine (in organisms
synthesizing arginine) & formation of urea (in
ureotelic organisms, man) due to presence of
arginase.
2. Liver shows much higher activity of arginase
than brain or kidney for formation of urea while
in brain or kidney is the synthesis of arginine.
3. Synthesis of non-protein amino acids (ornithine
and citrulline) in body.

46. Regulation of Urea Cycle
1) Activity of individual enzymes:
THE RATE LIMITING STEPS a) carbamoyl phosphate synthase-1
b) Ornithine transcarbamyolase.
c) Arginase.
 N-acetylglutamate is activator for carbamoyl phosphate synthase-1
It enhances its affinity for ATP.
It is synthesized from acetyl CoA and glutamate.
its hepatic concentration increases after intake
of a protein diet, leading to an increased rate of urea synthesis.
 Activity of ornithine transcarbamyolase is limited by the
concentration of its co-substrate "ornithine".

47. 2) Regulation of the flux through the cycle:
a) Flux of ammonia:
1.by amino acids release from muscle (alanine,
glutamine),
2. metabolism of glutamine in the intestine
3. amino acids degradation in the liver.
b) Availability of ornithine.
c) Availability of aspartate:
since aspartate is required in equimolar amounts with ammonia,
this is satisfied by of transdeamination .
3) Change in the level of Enzymes:
• Arginase & other urea-forming enzymes are adaptive enzymes
thus
• a protein-rich diet will increase their biosynthesis rate & the
opposite is true for low protein diet.
• However, in starvation, where the body is forced to use its own tissue
protein as fuel, there is an increase in urea-forming enzymes.

48. ONE-CARBON FRAGMENT METABOLISM
• Human body is unable to synthesize the methyl group and obtain it from diet.
• The first: met = S-adenosyl methionine (methyl donner = CH3 ) involved in
transmethylation reaction
• The second: tetrahydrofolic acid (FH4
or THF) which is a carrier of active
one-carbon units (-CH3, -CH2, -CHO, -CHNH, -CH).

49. N
CH
C
N CH2
NH
N
H
CH2
CH
N
H
CH2
NH
N
CH2
C
N CH2
NH
H
5
6
78
9
10
NADPH + H+ NADP+
DHF reductase
NADPH + H+ NADP
DHF reductase
(THF)
(active form)
(Folic acid)
10
5
The one-carbon group carried by THF is attached to its N5
or N10
or
to both.
Group Position on THF
Methyl: -CH3 N5
Methylene -CH2 N5 , N10
Formyl -CHO N5 or N10
Formimino -CHNH N5
Methenyl -CH
N5 , N10

50. • These one-carbon units are interconvertible to each other.
• The primary sources of one-carbon units are serine, glycine, histidine,
tryptophan & betaine.
• and their acceptors for biosynthesis a variety of biomolecules are
Phosphatidylethanolamine, Guanidoacetic acid, nor-Epinephrine ,Thymine,
Purine-C8 & Purine-C2 & homocysteine.

51. METABOLISM OF INDIVIDUAL AMINO
ACIDS
1. Metabolism of Glycine: nonessential, glucogenic.
Biosynthesis of glycine:
1
2
CH2
-CH-COOH
OH NH2
Hydroxymethyl transferase
PLP
THF
NH2
-C H2
-COOH
Serine Glycine
N5,N10CH2THF
H2O

52. Degradative pathway: Hyperoxaluria
1. Reaction 2.
3
2.
FpH2
H2O2
O2
CHO + NH3
COOH
CO2
Fp glyoxylat
e
(1) (2)
HCHO
(3)
COOH
COOH
Oxalate
α- KG + Glycine
Glycine
TA
Amino acid oxidase
N2NCH2COO -H
HCOOH
Oxalate
+
O -
HS-CH2-CH2-CH-COOH (Homocysteine) CH3-S-CH2CH2-CH-COOH (methionine)
NH2 NH2

53. Special Functions of Glycine:
a-Protein, Hormones & enzymes.
b- Heme c- Purines (C4
,C5
,N7
) d- Creatine
e- Glutathione
f- Conjugating reactions:
• Glycine + Cholic acid → glycocholate.
• Glycine + Benzoic acid → Hippuric acid
1.Formation of Glutathione (GSH) Dest.FR & Peroxides
γ-Glu - Cys synthase
ATP ADP + Pi
γ - glutamyl Cysteine
γ -glutamyl cysteinyl
GSH
synthase
ATP
ADP+Pi
Glutamate + Cysteine
(GSH)
+ Glycine
glycine

54. 2. Formation of creatine (Methyl guanidoacetate)
kidney
liver
Guanido
acetate
Arginine
Glycine
Creatine phosphateCreatinine
Nonenzymatic
in muscle

55. • Creatine Creatine phosphate
CPK
ATP ADP
EXCESS ATP DURING EXERCISE
• Cr-P is the storage form of high energy phosphate in muscle
• Creatinine is excreted in urine & increases on kidney failure
due to its filteration is decreased.
Its level is constant per 24 hrs
& is proportional to muscle mass in human.
NON ENZYMATIC
IN MUSCLEPi+H2O
CREATININE

56. serine
Protein
synth
Porphyrin
(heme)
purine
GSH
Creatine
Conjugation
reaction
Oxalic acid
Betaine
CO2 + NH3
N5,N10
CH2THF
glycine

57. 2. Metabolism of Serine: nonessential & glucogenic
• It is synthesize from glycine or
• intermediate of glycolysis,
• all enzymes are activated by testosterone in liver,
kidney & prostate.
CH2
OP
CHOH
COOH
CH2
OP
COOH
CH2
OP
CHNH2
COOH
NH2
3- phosphoglycerate
NAD NADH+H+
Dehydrogenase
C =
O
Glu
PLP
αKG
TA
3-Phosphoserine
3- Phosphopyruvate
HO CH2 - CH - COOH
Serine
H2OPi
Phosphatase
o
NH2

58. Degradative Pathways of Serine:
CO2
+ H2
O
Serine
Ser. dehydratase
PLP
Pyruvate + NH3
Alanine
Glucose
Serine is important in synthesis of:
a. Phosphoprotein
b. Purines & pyrimidine
c. Sphingosine
d. Choline
e. Cysteine
Serine Glycine CO2+NH3 (major)1.
2.
T.A. TCA

59. glycine
pyruvate
cysteine
choline
sphingosine
Purines &
pyrimidines
Phospho-
protein
3 phospho-
glycerate
Serine

60. 3. Metabolism of Sulfur-Containing amino acids
(Methionine, cyteine & Cystine):
a) Metabolism of methionine: (essential)
2 principal metabolic pathways:
Transmethylation and transsulfuration
Transmethylation
Met. Cysteine (diet.pr.)
NH2
+

61. In transmethylation there are:
Methyl acceptors Methyl Compounds
1- Guanidoacetic acid Creatine
2- Norepinephrine Epinephrine
3- Ethanolamine Choline
4- Uracil Thymine
SAM
SAH
(S-Adenosyl Homocysteine)

62. S-adenosylmethionine
SAM
Methionine S-adenosyl Homocysteine
SAM synthase
Pi + PPi
ATP
Me-acceptor
Me-product
Methyltransferase
H4FA
N5CH3H4FA
Methyltransferase H2Oadenosine
Homocysteine
COOH
H2N-CH
CH2
CH2
SH
COOH
CHNH2
CH2
OH
+
PLP
Cystathionine
synthase
Serine
H2N-CH
CH2
CH2 - S
COOH
CHNH2
CH2
COOH
(Degradative pathway)
or Transsulfuration
CHNH
2
CH
2
SH
COO
CHNH
2
CH
2
+
COO
CH
2
OH
Cystathionase
PL H2O
Cystathionine
Cysteine Homoserine
deaminase
PLP
NH3
α-ketobutyrate
CoAS
H
CO2
NAD+
NADH+H+
propionyl CoA Succinyl CoA.
B12
H2O
Transmethylation
Homocystinuria
Lack of
Cystathionine
synthase
C-skeleton of cysteine
From serine &
S from methionine
Methionine

63. b) Metabolism of Cysteine& Cystine:
- They are interconvertable &They are not essential
- can be synthesized from Met & Ser
SH
O2 + Fe2 + or Cu2+
(Oxidation)
S S
CH2
CHNH2
COOH
2 GSH
Cysteine
NAD+ NADH+H+
Reductase
CH2
CHNH2H2NCH
COOH
CH2
COOH
Cystine
2 moles of

64. Degredative pathway of cysteine:
SH
CH2
H2NCH
COOH
(Transamination) (Oxidative pathway)
GLu
α-KG
TA
PLP
Cys-dioxygenase
NADPH NADP
Fe++ , O2
(non oxid.
pathway)
H2O
B6
H2S SO3
-- SO4
--
NH3
SH
CH2
C=O
COOH
3-mercapto
pyruvate
SO2H
CH2
GSH
Trans-sulfurase
H2SSO4
-- MO2+, cyt b5
sulfite
oxidase
SO3
--
PAPS
(active SO4)
Pyruvic acid
CHNH2
COOH
Cys-sulfinate
αKG
GLu
TA
SO2H
CH2
C=O
COOH
desulfinase
SO3
--
SO4
--
PAPS
ATP
, PLP
Cysteine
B-sulfinyl pyruvate
ATP
Pyruvate
Transamination Oxidative pathway
Non oxid.
pathway

65. Biochemical functions of cysteine
1- PAPS Formation: (3'-phosphoadenosine,5'-phosphosulphate)active
sulphate used in formation of sulfate esters of steroids, alcohol, phenol,some lipids, proteins
and mucopolysaccharides
2- Sulfur of COASH, GSH, vasopressin, insulin
3-Detoxication reaction of bromo, chloro, iodobenzene, naphthalene and anthracene
& of phenol, cresol, indol and skatol that is formed by the action of
intestinal bacteria on some amino a cids in large intestine with formation of ethereal
sulfates which is water soluble and rapidly removed by the kidney
4- Taurine Formation ( with bile acids form taurocholate)
SH
CH2
HN2CH
COOH
Fe
2+
, O2
SO2
H
CH2
CHNH2
COOH
CO2
PLP
SO2H
CH2
NH2
CH2
[O]SO3H
NH2 - CH2 - CH2
Cys-dioxygenas
e
NADPH + H+ NADP+
Cysteine Cys-sulfinate
Hypotaurine
(Taurine)
SH
CH2
H2NCH
COOH
e

66. cystine
pyruvate
GSH
PAPS
Taurine
homocysteine
cysteine
Methionine

67. Polyamines (Spermidine & Spermine) :
(1) Spermine & spermidine are growth factors, so they are
important in cell proliferation and growth.
(2) They are important in stabilization of cells and
subcellular organelles membranes.
(3)They have multiple + Ve charges and associate with
polyanions such as DNA, RNAs and have been
involved in stimulation of RNA and DNA biosynthesis
as well as their stabilization.
(4)They exert diverse effects on protein synthesis and
act as inhibitors of protein kinases

68. Biosynthesis:
PLP
CO2
CO2
NH3
SAM
Decarboxylase
Decarboxylated SAM
Ornithine
Decarboxylase
PLP
H3N+
+
Methylthioadenosine
Putrescine
Spermidine Synthase
H3N+
H2N+
H3N+
Spermidine
Decarboxylated SAM
Methylthioadenosine
H3N+
H2N+
H2N+
H3N+
Spermine
Spermine Synthase
Arginine
Met.
1,4 Diaminobutane
1,3 Diaminopropane
1,3 Diaminopropane
A
1
2
3
4
A
1
2
3

69. Catabolism of Polyamine
H2O2
O2
O2
H2
O2
CO2 + NH3
Spermine
Polyamine
oxidase Spermidine
B-aminopropionaldehyde
Polyamine oxidase
Putrescine
oxidase

70. CH2
-CH COOH
NH2
O2
H4
biopterine H2 biopterine
CH2
-CH COOH
NH2
Tyrosine
OH
CH2
-C-COOH
CO2 O2
OH
CH2COOH
OH
O2
Fe
2+
CH
CH CH2
C-CH2
COOH
O
O
O
O
OH
OH
Phenylalanine
hydroxylase
NADP+ NADPH(H+) TA
a KG
PLP
Glu
P-Hydroxyphenylpyruvate
(PHPP)
monooxygenase
Vit C, Cu2+
Homogentisate
Oxidase
Homogentisate
C
C
Maleylacetoacetate
isomeraseGSH
Fumaryl acetoacetate
Hydrolase
Fumarate + Acetoacetate .
Phenylalanine H2O
PHPP
H2O
4. Aromatic amino acids
a) Metabolism of Phenylalanine (glucogenic & ketogenic)
OH
O
O
glucose Ketone
body
α

71. b) Tyrosine is a precursor of:
1.DOPA (3,4 dihydroxy phenylalanine)
O2
CH2CH COOH
NH2
OH
CH2CH COOH
NH2
OH
OH
O2
O2
CO2
CH2CH2NH2
OH
OH
O2
CH CH2 NH2
OH
OH
CH CH2
NH
OH
OH
OH
CH3OH
NADP+
NADPH(H+
)
H4biopterin
H2biopterin
Tyr-hydroxylase
H2O
Tyrosine
Tyrosinase (Cu++)
DOPA
Tyrosinase
Cu++
Dopaquinone
Melanins in
melanocytes.
DOPA
Decarboxylase
PLP
Dopamine
Dopamine
B-oxidase
VitC &
Cu2+
Norepinephrine
SAM SAH
Methyltransferase
Epinephrine

72. 2.Thyroid hormones:
Thyroxine Formation:
I
OH CH2
CHCOOH
NH2 I
OH CH2
CHCOOH
I
O
I
OH
I
I
CH2CHCOOH
NH2
OOH
I
I
I
I
CH2
CHCOOH
NH2
O
I
I
OH
I
CH2CHCOOH
NH2
NH2
3-Monoiodotyrosine (MIT)
3,5 Diiodotyrosine (DIT)
DIT
3,5,3/ -Tri iodothyronine (T3) 3,5,3',5'-Tetraiodothyronine (T4)
3,3',5'-Triiodothyronine (reverse T3)

73. Thyroglobulin(Tgb)
• It is the precursor of T3 and T4
• It is large, iodinated, glycosylated protein.
• It contains 115 tyrosine residues each of
which is a potential site of iodination.
• 70% iodide in Tgb exists in the inactive
forms MIT&DIT WHILE
• 30% is in T3& T4
• About 50 μg thyroid is secreted each day.

74. Biosynthesis of Thyroid hormones
Includes the following steps:
1. Concentration of iodide:
the uptake of I by the thyroid
gland is an energy dependent
process & is linked to active Na
pump.
2. Oxidation of iodide: the
thyroid is the only tissue that
can oxidize I to a higher valence
state
3. Iodination of tyrosine:
oxidized I reacts with tyrosine
residues in thyroglobulin form
MIT & DIT.
4. Coupling of iodotyrosyls:
The coupling of two DIT T4
or of MIT & DIT T3

75. c) Tryptophan (essential,glucogenic&ketogenic)
I] 3-hydroxyanthranilic acid pathway:
N
H
CH2
CHCOOH
NH2
O2
C = O
N
CHO
CH2
CHCOOH
NH2
H
C = O
NH2
CH2
CHCOOH
C = O
OH
NH2
CH2
CHCOOH
NADPNADPH(H )
H4
biopterinH2bioterin
O2
NH2
CH3CHCOOH
OH
NH2
COOH
NH2NH2
Tryptophan
Trp pyrrolase
Fe++
N-Formyl Kynurenine
Kynurenine
Formylase
H2O
Format
e
Kynurenine
3-Hydroxy kynurenine
++
H2O
Kynurenine
hydroxylase
Alanine
H2O
Kynureninase Nicotinamide nucleotide
Acetoacetyl COA
7 steps
PLP
3 steps
3-Hydroxyanthranilic acid
(NAD & NADP)
•Trp pyrrolase
Inc.by
Cortico. &
tryptophan
& Dec.by
Niacin,
NAD & NADP H
OH
3

76. II] Serotonin Pathway:
N
CH2
CHCOOH
H
NH2
O2
H2
biopterinH4
bioterin
N
H
HO
CO2
N
H
CH2 CH2 NH2
HO
CH3
COSCOA
COASH
N
H
CH2
CH2
NHCOCH3
HO
SAM
SAH
O-methyl
Transferase
N
H
CH2CH2NHCOCH3CH3
O
NH2
CH2 CHCOOH
H2O
hydroxylase
NADP+ NADPH(H+)
decarboxylase PLP
5-OH Tryptamine (Serotonin)
Melatonin
Tryptophan
5-OH Tryptohpan
N-Acetyl
Transferase
N-acetyl 5-OH tryptamine
(N-acetyl-5-methoxy-serotonin)
Tryptophan
* Neurotransmitter
* Founds in mast cells&
platelets.
* Vasoconstrictor
for B.V.& bronchioles
* Transmitter in GIT to
release the peptide
hormones.

77. III] Melatonin formation pathway
 It is the hormone of pineal body in brain of man.
Formed by the acetylation and methylation of serotonin.
 It has effects on hypothalamic-pituitary system.
It blocks the action of MSH & ACTH.
 It is important in regulation of gonad & adrenal functions.
 It has a circadian rhythm due to its formation occurs only in dark,due
to high activity of N-acetyl transferase enzyme so it is a biological
clock.
 It keeps the integrity of cells during aging due to it has an antioxidant
property
 It enhances the body defense against infection in AIDS patients by
increasing the number of immune cells.
 It reduces the risk of cancer&heart diseases

78. IV] Indol, skatol and indicant pathway:
CO2
O2
CO2
O2
Bacteria in colon
Tryptophan indol acetic acid Skatol
indoxyl indol Skatoxyl
N
OSO3K
H
(indican)
• Indol & skatol contributes to unpleasant odour of feces.
• Skatoxyl and indoxyl are absorbed from large intestine
• and conjugated with sulfate in the liver
• and excreted in urine as indican (K indoxyl sulfate).

79. Aromatic
Amino
Acids
Phenylalanine Tyrosine Tryptophane
fumarate
Aceto
acetate
Dopa &
Dopamine
Melanine
Nor
epinephrin
&
epinephrine
Thyroxin
Skatol &
Indol
Melatonin
Anthranilic Serotoninglucose ketone
Alanine Nicotinamide
Acetoacetyl
CoA

80. a) Together with B-alanine , It forms carnosine (B-alanyl histidine) and
anserine (methyl carnosine):
1. They are buffer the pH of anerobically contracting skeletal muscle
2.They activate myosin ATP-ase
3.They chelate copper and enhance Cu2+
uptake.
b) Histidine is a source of one-carbon atom.
c)
Histidine Histamine
Histamine is a chemical messenger that mediates allergic and inflammatory
reactions, gastric acid secretion and neurotransmission in the brain.
decarboxylase
5. Basic Amino Acids:
1) Histidine (glucogenic amino acid):

81. (2) Arginine: (nonessential & glucogenic amino acid):
It participates in formation of:
a)Creatine
b)Polyamines
C)Nitric oxide NO (Free radical gas).
NADPH(H+)
O2
NO
L-Arginine
NO synthase
relaxes smooth muscle
(vasodilation)
prevents platelet
aggregation
neurotransmitter
in brain
possesses tumoricidal
and bactericidal action
in macrophages.
NADP+
L-Citrulline

82. 3) Lysine: (essential, ketogenic)
it is involved in the formation of histone, hydroxylysine &
carnitine:
NH2
(CH2)4
H-C-NH ...... protein
Transmethylation
CH3
N
(CH2
)4
H-C-NH ...... protein
CH3 CH3
COOH
CH3
N
(CH2
)3
CH3 CH3
COOH
Hydroxylase
CH3
N
CH2
CH3 CH3
CHOH
CH2
COOH
Aldolase
Oxidation
H2N-CH2-COOH
glycine
CH3
N
(CH2
)3
CH3 CH3
COOH
CHOH
H-C-NH2
Hydroxylase
Protease
CH3
N
(CH2
)4
CH3 CH3
COOH
H-C-NH2
Trimethyl lysine
COOH
3 SAM 3 SAH
Lysine-bound protein Trimethyl lysine-bound protein
γ
β
α
-Hydroxy-γ-trimethylammonium butyrate
(carnitine)
β
+
+
+
+
+
at B-carbon
γ-Trimethyl ammonium butyrate
β-OH Trimethyl
lysine

83. 6. Acidic Amino Acids :
1.Glutamic acid : (nonessential & glucogenic amino
acid).
It participates in formation of:
1- GSH.
2- Glutamine: as storage and transporter form of ammonia
3- GABA (δ-aminobutyric acid) neurotransmitter in brain.
HOOC CH2
- CH2
CH COOH
PLP
Glu-decarboxylase
HOOC CH2 CH2 CH2 NH2 (GABA)
NH2 TAPLP
HOOC CH2 - CH2 COOH HOOC CH2 CH2 CHO
Succinic semialdchyde
dehydrogenase
NAD+NADH(H+)
Succinic acid
Glutamic acid
Succinic semialdchyde

84. 2. Aspartic acid: Acidic, non essential & glucogenic
1. Arginosuccinate in urea cycle.
2. Alanine by decarboxylation.
3. Oxalate & glucose by T.A.
Amino acids as precursors of neurotransmitters
1. Arginine --------------NO
2.Tryptophan-----------Serotonin
3. Histidine--------------Histamine
4. Phenyl alanine------dopa,dopamine, NE&E
5.Glutamic acid--------GABA