Caudales Amino Acid Metabolism

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Amino Acid Metabolism



2

Dy namics of ProteinAnd Amino Acid Metabolism

Dietar y Proteins Digestion to Amino Acids

Transport in Blood to Cells

Protein S y nthesis Functional Proteins

Protein Degradation In

Proteasomes FollowingTagging With Ubiquitin

Amino Acids

Metabolites



3

Digestion of ProteinsStomach: Pepsinogen Pepsin (max. act. pH 2)

Small Intestine: Tr y psinogen Tr y psin

Tr y psin cleaves:

Chy motr y psinogen to chy motr y psin

Proelastase to elastaseProcarbox y peptidase to carbox y peptidase

Aminopeptidases (from intestinal epithelia)

Enteropeptidase



4

Lumen

Amino Acids Oligopeptides

Intestinal Absorption

Oligopeptides

Amino Acids

Peptidases

Blood

Transport Protein



5

Incorporation of NH 4+

Into Organic

Compounds1) NH 4

++ HCO3

-+ 2 ATP NH 2 CO2 PO3

-2 + 2 ADP +

Carbamoy l Phosphate P i + 2 H +

2) NH 4+

+

Carbamoy l

Phosphate

S y nthase I

(CPS-I)

Glutamate

dehy drogenaseO

- O 2 CCH 2 CH 2 CCO 2 -

E-K etoglutarate Glutamate

3+

-2 2 2 2

-

T A y cle

NADP+NADPH +

H+

mitochondria



6

Incorporation of NH 4+

Into Organic

Compounds (Cont.)

NH

+

¡ O¢

CCH ¢

CH ¢

CHCO¢

¡ + NH 4++

2 ATP

£

¤

2 2 2 2 ¥

Glutamine

Glutamate Glutamine

S y nthaseMg

¦ ¦

of glutamine donated to other compounds

in sy nthesis of purines, py rimidines,

and other amino acids

)



7

Biosy nthesis of Amino Acids:

Transaminations

Amino Acid 1 +E-K eto Acid 2 Amino Acid 2 +E-K eto Acid 1

§

+

-2 2 2 2

-

Glutamate

R- 2 -+

O

-O 2 CCH 2 CH 2 CCO 2

-

E-K etoglutarate

̈

̈

©

+

P y ridoxal phosphate (P LP)Dependent Aminotransferase



8

Transaminations: ole of P LP

2 P 3-2

3

2 2 2 -

3+

2 -

2 P 3-2

3

2

2 P 3-2

3

2 2 2 -

2 -

2 2

2 P 3-2

3

2

- 2 2 2 2 -

+ +

++

- 2 2 2 2

-

2

Tautomerization



9

TransaminationsGlutamate E-K etoglutarate

+ +

P y ruvate Alanine

Glutamate E-K etoglutarate

+ +

Oxaloacetate Aspartate

Glutamate-P y ruvate

Aminotransferase

(Alanine Transferase ALT)

Glutamate-Oxaloacetate

Aminotransferase

(Aspartate Transferase AST)

Blood levels of these aminotransferases, also called transaminases,are important indicators of liver disease



10

Metabolic Classification of the AminoAcids

� Essential and Non-essential

� Glucogenic and K etogenic



11

Non-Essential Amino Acids in Humans

� Not required in diet

� Can be formed from E-keto acids by

transamination and subsequent reactions

� Alanine

� Asparagine

� Aspartate

� Glutamate� Glutamine

� Gl y cine

� Proline

� Serine

� C y steine (from Met*)� T y rosine (from Phe*)

* Essential amino acids



12

Essential Amino Acids in Humans

� Required in diet

� Humans incapable of forming requisite

carbon skeleton

� Arginine*

� Histidine*

� Isoleucine

� Leucine� Valine

� Ly sine

� Methionine

� Threonine

� Pheny lalanine� Tr y ptophan

* Essential in children, not in adults



13

Glucogenic Amino Acids� Metabolized to E-ketoglutarate, py ruvate, oxaloacetate,

fumarate, or succiny l CoAPhosphoenolpy ruvate Glucose

� Aspartate

� Asparagine

� Arginine

� Pheny lalanine

� T y rosine� Isoleucine

� Methionine

� Valine

� Glutamine

� Glutamate

� Proline

� Histidine

� Alanine

� Serine

� C y steine

� Gl y cine

� Threonine

� Tr y ptophan



14

K etogenic Amino Acids� Metabolized to acet y l CoA or acetoacet y l CoA

Animals cannot convert acet y l CoA or acetoacet y l CoA to py ruvate

� Isoleucine

� Leucine *

� Ly sine *

� Threonine

� Tr y ptophan

� Pheny lalanine� T y rosine

* Leucine and l y sine are onl y ketogenic



15

Amino Acids Formed From E-K etoglutarate

-

-

-

-

-

Transamination or

Glutamatedehy drogenase

E-K eto-

glutarate

Glutamate

Glutamine

Glutamine

sy nthase

! !

" # 2 -

$

4 Steps

Proline

%

&

% 2 2 2 2 - rnithine

5 Steps

Arginine

Urea y cle

'

(

2

2 N= - N 2 2 2 2 -

Guanidino group



16

GABA Formation

H 3+

-O 2 CCH 2 CH 2 CHCO 2

-

H 3+

-O 2 CCH 2 CH 2 CH 2

Glutamate Gamma-aminobut y rate

(GABA)

GABA is an important inhibitor y neurotransmitter in the brain

Drugs (e.g., benzodiazepines) that enhance the effectsof GABA are useful in treating epilepsy

Glutamatedecarbox y lase

CO2



17

Arginine S y nthesis: The Urea C y cle

H 3+

-O 2 CC H 2 C H 2 C H C O 2

-

H C OC H 3

-O 2 CC H 2 C H 2 C H C O 2

-

H 3+

H 3 C H 2 C H 2 C H 2 C H C O 2

-+

H 4

+ +

H

C O

3

-H

2 C O

2 P O

3

-2

Glutamate -Acet y lglutamate

Ornithine

H 3+

H 2 C O H C H 2 C H 2 C H 2 C H C O 2

-

)

-Acet y lglutamatesy nthase

CoASAc

4 Steps

CPS -I

Ornithine

Transcarbamoy lase ( OTC)

(mitochondria)

Citrulline

Ureido group

Carbamoy l phosphate

Activates





19

Urea Formation

� Occurs primaril y in liver; excreted by kidney

� Principal method for removing ammonia

� H y perammonemia:

� Defects in urea c y cle enz y mes (CPS, OTC, etc.)

� Severe neurological defects in neonates

� Treatment:

» Stop protein intake

» Dial y sis

» Increase ammonia excretion: Na benzoate, Na pheny lbut y rate, L-

arginine, L-citrulline



20

Blood Urea Nitrogen

� Normal range: 7-18 mg./d L

� Elevated in amino acid catabolism

� Glutamate N-acet y lglutamateCPS-1 activation

� Elevated in renal insufficienc y

� Decreased in hepatic failure



21

S y nthesis of Nitric Oxide

NH 3+NH 2

H 2 N =C-HN CH 2 CH 2 CH 2 CHCO 2 -

+

NH 3+

NH 2 CONH CH 2 CH 2 CH 2 CHCO 2 - + NO

Nitric oxide sy nthase (NOS)

Arginine

Citrulline



22

Nitric Oxide

� Cell messenger

� Implicated in a wide range of phy siological

and pathophy siological events:

� Vasodilation:

� Activates guany l y l c y clase cGMP � Nitrogl y cerin Gl y cerin + NO

� Sildenafil (Viagra): in vascular smooth muscle:

NO cGMP GMP

Phospho-

diesterase-5

Blocks



23

Formation of Serine

G H H

I H

P

G Q G

R

S

P

I

I G

P

S

I H

P

G Q G

R

S

P

I G

P

S

I = G

T U

V

+U

W U

X

Y ` Y

V

a X

W

W Y

X

a

T U

V

+U

W U

X

Y U

W Y

X

a

W

Glucose Gl y col y sis

hospho

gl y ceratehospho

hy drox y py ruvate

hosphoserineSerine (Ser)

y ruvate

Dehy drogenase

b AD+b ADH +

H +

Glutamate

E-K etoglutarate

Transaminase

Phosphatase

3 Steps

Inhibits



24

Conversion of Serine to Gl y cine

N

N

N

NH2N

OH

CH2NHR

H

H

N

H

NCH2

N

H2C

Folate

Tetrahy drofolate(FH 4)

Dihy drofolatereductase

N 5 , N 10 -Methy lene FH 4

NH 3+H

C H 2 OH

CO 2 -

C Serine

NH 3+H

H

CO 2 -

C

Gl y cine

Serine hy drox y methy l transferase (P LP-dep.)

K ey intermediate

in biosy nthesis of

purines and

formation of

thy mine Important in

biosy nthesis of heme,porphy rins, and purines



25

Sulfur-Containing Amino Acids

c

d

C S C C C C -

e

f

S C g

C g

C C g

-

h

i

C p C C p

-

h

i

S C q

C q

C C q

-r

s

S C t

C C t

-C

u

C C v

C v

-

Methionine(Essential)

L- omoc y steine

Methionine

S y nthase

(Vit. B1 -dep.)F 4

5-Methy l

F 4

w x

y

�

x

C x �

� x

C �

�

-

C Serine

C y stathionine

C y stathionine

F-sy nthase

(P LP-dep.)

C y stathioninel y ase

C y steine(Non-essential)

+

F-H y drox y -but y rate



26

Homoc y steine

Homoc y steinuria

� Rare; deficienc y of c y stathionine F-sy nthase

� Dislocated optical lenses

� Mental retardation

� Osteoporosis� Cardiovascular disease death

High blood levels of homoc y steine associated with

cardiovascular disease

� May be related to dietar y folate deficienc y

� Folate enhances conversion of

homoc y steine to methionine



27

Methionine Metabolism: Methy l Donation

�

�

�

�

�

�

�

�

�

-� 2 � �

�

�

�

2 �

�

2 - � -�

2 �

�

�

2

�

�

3 +�

�

3

+3

+

3 2 2 2 -

�

�

�

�

�

�

�

�

�

-� 2 � �

�

�

�

2 �

�

2 - � -�

2 �

�

�

2

�

�

3+

�

�

�

�

�

� � � �

� 3 � � � 2 � � 2 � � 2 - � - � 2 �

� � 2

� � 3

+

-Adenosy l methioninesy nthase

ATP

-Adenosy l

Methionine

( AM)

-Adenosy l

homoc y steine

Methy l-transferases

Decarbox y lated AM

AM

Decarbox y lase

2

Methionine

R-

R- 3

+



28

Pol y amine Biosy nthesis

3+

3 2 2 2 2 -

+

3

3

++++

3

3

++

rnithine(from urea c y cle)

Putrescine

2

� rnithine

decarbox y lase

( � DC )

(P LP-dep.)

Decarbox y lated SAM

Spermidinesy nthase

5¶-Methy lthio-

adenosine

� 3 �

�

�

� � 3

�

+++

Spermidine

Spermine

Decarbox y lated

SAM

Spermine

sy nthase

5¶-Methy lthio-

adenosine



29

Pol y amines

� Spermidine and spermine found in virtuall y

all procar y otic and eucar y otic cells

� Precise role undefined � Bind to nucleic acids

� Inhibition of biosy nthetic pathway :

H 2 N NH 2

O 2 H

HF 2

E-Difluoromethy l-

ornithine ( DFMO)

(Eflornithine) - inhibits ODC;

used to treat Pneumoc y stis carinii infectons



30

Creatine and Creatinine

H 3+H 2

+H 2 =C-H C H 2 C H 2 C H 2 C H C O 2

-

ArginineGl y cine Ornithine

Arginine-gl y cine

transamidinase

( K idney )H 2

H 2 =C-H C H 2 C O 2 -

+

Guanidoacetate

HPO3

-2

C H 3

+H 2 =C- C H 2 C O 2

-

Guanidoacetate

Methy ltransferase

( Liver)

SAM + AT P

S-Adenosy l-

homoc y steine

+ ADP

P hosphocreatine

H

C H 3

H

O

Creatinine(Urine)

�

on-enz y matic (Muscle)

H 2

C H 3

H 2 =C- C H 2 C O 2 -

+

Creatine kinase(Muscle)

AT P

Creatine ADP

+ P i



Creatine and Creatinine

31

Creatine:

� Dietar y supplement

� Used to improve athletic performance

Creatinine:� Urinar y excretion generall y constant;

proportional to muscle mass

Creatinine Clearance Test:

� Compares the level of creatinine in urine (24 hrs.)

with the creatinine level in the blood � Used to assess kidney function

� Important determinant in dosing of several drugs

in patients with impaired renal function



32

Histidine Metabolism:Histamine Formation

N

N H

H �

H �

�

N H �

N

N H

H �

H �

N H �

Histidine Histamine

Histidine

decarbox y lase

�

Histamine:

� S y nthesized in and released by mast cells

� Mediator of allergic response: vasodilation, bronchoconstriction

(H 1 receptors)

� H 1 blockers: Diphenhy dramine (Benadr y l)

Loratidine ( laritin)

� Stimulates secretion of gastric acid (H

receptors) H

blockers: imetidine (Tagamet); ranitidine (Zantac)



33

Pheny lalanine and T y rosine

C 2 C C 2-

3+

C 2 C C 2-

3+

2

C C C 3

2

C C C 3

Pheny lalanine(Essential)

T y rosine

( on-essential)

Pheny lalanine-4-

Monoox y genase

(Pheny lalanine

hy drox y lase)

2

2

+

+

ADP + +

ADP +

Tetrahy drobiopterin

(B 4)

Dihy drobiopterin



34

Normal Utilization of Pheny lalanine

Pheny lalanine

Protein (~25%)

T y rosine (~75%)





36

Sapropterin ( K uvan)

Indicated for reduction of pheny lalanine blood levels in patients with BH 4-responsive P K U



37

Catecholamine Biosy nthesis

C 2 C C 2-

3+

C 2 C C 2-

3+

C 2 C 2 2

C C 2 2

C C 2 C 3

T y r hy drox y lase

2

T y rosine Dihy drox y pheny lalanine

( D PA)

Dopamine

D PA

decarbox y lase C 2

Dopamine

hy drox y lase

orepinephrine

Catechol

Epinephrine

(Adrenaline)

SAM

S -Adenosy l -

homoc y steine

Methy l

transferase

D PA, dopamine, norepinephrine,

and epinephrine are all neurotransmitters



38

L-DOPA in Parkinsonism

Blood Brain

Blood Brain Barrier

L-DOPA L-DOPA Dopamine

Dopamine

H O

H OCH 2 -C -C O 2 H

CH 3

H H 2 C arbidopa

Blocks

Parkinsonism associated with

dopamine in brain through loss of

neurons in basal ganglia.C arbidopa + L-DOPA



39

Monoamine Oxidase (MAO)

MAO

(in mitochondria)

R R¶

OH H Norepi

OH CH 3 Epi H H Dopamine

CHCH 2 NH R'

HO

HO

R

CHCHO

HO

HO

R

CHCO 2 H

HO

HO

RUrinar y metabolite

MAO inhibitors (e.g., trany lc y promine) are useful

in the treatment of depression

Brain levels of dopamine and norepi.; alsoserotonin

Aldehy de

dehy drogenase

R=OH Vanill y lmandelic acid (VMA)R=H Homovanillic acid (HVA)



40

T y ramineOH

CH 2 CH 2 H 2

T y ramine

OH

CH 2 CHO

MAO

� T y ramine found naturall y in several t y pes of cheese;also beer and red wine.

� T y ramine intake can cause hy pertensive crisis inpersons taking a MAO inhibitor ( norepi release)

( blood pressure)



41

Catechol-O-Methy l Transferase (COMT)

C C 2 R'

H O

H O

R

C H C H 2 H R'

H O

C H 3 O

R

COMT

Inactivemetabolite

SAM S-Adenosy l-

homoc y steine

� COMT found in c y toplasm� Terminates activit y of catecholamines

� Catecholamine excretion products result from

combined actions of MAO and COMT

� Inhibitors of COMT (e.g., tolcapone) useful in Parkinson¶s disease

Activecatecholamine



42

Homogentisic Acid Formation

C H 2 C H C 2-

H 3+

H

H

H

C H 2 C 2-

Transamination

T y rosinep-H y drox y pheny l -

py ruvate

Homogentisate

p-H y drox y pheny l -

py ruvate

diox y genase(ascorbate-dep.)

2

C 2

C H 2 CC 2-

H

Homogentisate

diox y genase

2

C leavage of aromatic ring

Fumarate + acetoacetate

Deficient inalkaptonuria



43

Alkaptonuria

� Deficienc y of homogentisate diox y genase

� Urine turns dark on standing� Oxidation of homogentisic acid

� Asy mptomatic in childhood

� Tendenc y toward arthritis in adulthood



44

Melanin Formation

C H 2 C H C 2 -

H 3+

C H 2 C H C 2 -

H 3+

HO

HO

H ighl y colored

pol y meric intermediates

Melanin

(Black pol y mer)

T y r hy drox y lase

DOPA

Dopaquinone

C H 2 C H C O 2 -

H 3+

HO

T y rosine

T y rosinase

Melanin formed in skin (melanoc y tes), ey es, and hair

In skin, protects against sunlight

Albinism: genetic deficienc y of t y rosinase

O2



45

Tr y ptophan Metabolism: Serotonin Formation

H

C H 2 C H C O 2 -

H 3

+

H

C H 2 C H C O 2 -

H 3

HO

+

H

C H 2 C H 2 H 2

HO

Tr y ptophan(Trp)

Indole ring

Trp

hy drox y lase

O2

5-H y drox y -

tr y ptophan

Decarbox y lase

C O2 5-H y drox y -

tr y ptamine (5-H T);

Serotonin



46

Serotonin

� Serotonin formed in:� Brain (neurotransmitter; regulation of sleep, mood, appetite)

� Platelets (platelet aggregation, vasoconstriction)

� Smooth muscle (contraction)

� Gastrointestinal tract (enterochromaffin cells - major storage site)

� Drugs affecting serotonin actions used to treat:� Depression

�Serotonin-selective reuptake inhibitors (SS RI)

� Migraine

� Schizophrenia� Obsessive-compulsive disorders

� Chemotherapy -induced emesis

Some hallucinogens (e.g., LS D) act as serotonin agonists



47

� Food supplement promoted for serotonin effects� L-Tr y ptophan disaster (1989):

� Eosinophilia-my algia sy ndrome (EMS)

(http://emedicine.medscape.com/article/1066811-overview)

� Severe muscle and joint pain

� Weakness

� Swelling of the arms and legs

� Fever

� Skin rash

� Eosinophilia� Many hundreds of cases; several deaths

� Traced to impurities

L-Tr y ptophan



48

Serotonin Metabolism: 5-HIAA

H

C H 2 C H 2 H 2

H O

H

C H 2 C H O

H O

H

C H 2 CO 2 H

H O

Serotonin

MAO

Dehy drogenase

5-H y drox y indole acetic

acid (5-HIAA) (Urine)

C arcinoid tumors:

� Malignant GI tumor t y pe� Excretion of large amounts of 5-HIAA



49

Serotonin Metabolism: Melatonin

N H

CH 2 CH 2 NHCOCH 3

H 3 CO

N H

CH 2 CH 2 NH 2

HO2 Steps

Serotonin Melatonin

Melatonin:

� Formed principall y in pineal gland � S y nthesis controlled by light, among other factors

� Induces skin lightening

� Suppresses ovarian function

� Possible use in sleep disorders



50

Tr y ptophan Metabolism:Biosy nthesis of Nicotinic Acid

N

-

N j

Tr y ptophan

N

Nicotinic acid (Niacin)

Several steps

Nicotinamide adenine

dinucleotide (NAD)

Caudales Amino Acid Metabolism

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