metabolism of amino acids -...

Metabolism of amino acids

Vladimíra Kvasnicová

Classification of proteinogenic AAs-metabolic point of view

1) biosynthesis in a human body

� nonessential (are synthesized)

� essential (must be present in a diet)

2) degradation within cells

� glucogenic (Glc can be formed from their carbon sceleton)

� ketogenic (= AAs degraded to acetyl-CoA)

Essential amino acids

1) branched chain: Val, Leu, Ile

2) aromatic: Phe (→ Tyr), Trp

3) basic: His, Arg, Lys

4) sulfur-containing: Met (→ Cys)

5) other: Thr

„10“

Essential amino acids PVT TIM HALL

1) branched chain: Val, Leu, Ile

2) aromatic: Phe (→ Tyr), Trp

3) basic: His, Arg, Lys

4) sulfur-containing: Met (→ Cys)

5) other: Thr

Essential / conditionally essential /nonessential amino acids

essential: Val, Leu, Ile, Thr, Phe, Trp, His, Arg, Lys, Met

noness.: Gly, Ala, Pro, Ser, Tyr, Asn, Gln, Asp, Glu, Cys

AAs ~ organically bound nitrogen

dietary proteins proteosynthesis

body proteins AAs pool N-compound synthes.

de novo biosynthesis degradation (E,glc,fat)

The figure is from http://web.indstate.edu/thcme/mwking/nitrogen-metabolism.html (Jan 2007)

Insertion of an inorganic nitrogen to organic comp.in a human metabolism

Synthesis of AAs in a human body- 5 substrates -

1. oxaloacetate → Asp, Asn

2. αααα-ketoglutarate → Glu, Gln, Pro, (Arg)

3. pyruvate → Ala

4. 3-phosphoglycerate → Ser, Cys, Gly

5. Phe → Tyr

Synthesis of AAs in a human body - important reactions -

1. transamination

Pyr→ Ala OA → Asp αααα-ketoGlt → Glu

2. amidation

Asp → Asn Glu → Gln

3. synthesis from other amino acids

Phe → Tyr Ser → Gly Glu → Pro

Met + Ser → Cys


Transamination reaction! REVERSIBLE !

enzymes: amino transferases

coenzyme: pyridoxal phosphate (vit. B6 derivative)

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

alanine aminotransferase(ALT = GPT)

aspartate aminotransferase(AST = GOT)

Amino transferases important in medicine („transaminases“)

glutamine synthetase

„amidation“of glutamate

= side chain carboxylic group of Glu is converted

to amide group

GLUTAMINE

= the most important transport form af amino

nitrogen in blood


Synthesis of

ASPARAGINE

needs glutamine as–NH2 group donor

(it is not ammonia as in the Gln synthesis)


The figure is from http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html (Jan 2007)

Synthesis of Tyr from Phe

The figure is from http://www.biocarta.com/pathfiles/GlycinePathway.asp (Jan 2007)

Synthesis of serine and glycineglycolysis


Formation of activated methionine= S-adenosylmethionine (SAM)

SAM is used as –CH3 group donorin metabolic methylations


Synthesis of Cys from Met and Ser

The figure is from http://www.biocarta.com/pathfiles/Cysteine2Pathway.asp (Jan 2007)


B12

Regeneration of Met

(vitamins: folate+B12)

Some amino acids are used for synthesis of other N-compound:

1) Gln, Asp, Gly → purines, pyrimidines

2) Gly → porphyrines, creatine (+ Arg and Met)

3) Arg → NO

4) Cys → taurine

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

Decarboxylation of AAs gives monoamines(= biogenic amines)

1) Tyr → catecholamines (adrenaline, noradrenaline, dopamine)

2) Trp → serotonin (= 5-hydroxytryptamine)

3) His → histamine

4) Ser → etanolamine → choline → acetylcholine

5) Cys → cysteamine

Asp → ββββ-alanine

Glu → γγγγ-aminobutyrate (GABA)

coenzyme A

TEST / Choose correct statement(s)

a) valine is a branched chain amino acid

b) serine contains thiol group in its side chain

c) glutamate is an essential amino acid

d) tryptophan is a precursor of catecholamines

Degradation of amino acids (AAs)

1) -NH2 group removing from AA

2) detoxification of the amino group

3) metabolism of carbon sceleton of AA

� 7 products

7 degradation products of AAs

1. pyruvate ←←←← Gly, Ala, Ser, Thr, Cys, Trp

2. oxaloacetate ←←←← Asp, Asn

3. αααα-ketoglutarate ←←←← Glu, Gln, Pro, Arg, His

4. succinyl-CoA ←←←← Val, Ile, Met, Thr

5. fumarate ←←←← Phe, Tyr

6. acetyl-CoA ←←←← Ile

7. acetoacetyl-CoA ←←←← Lys, Leu, Phe, Tyr, Trp

glucogenic AAs

ketogenic AAs

The figure is from http://www.biocarta.com/pathfiles/glucogenicPathway.asp (Jan 2007)

The entrance of amino acids into the citrate cycle

The figure is from http://www.biocarta.com/pathfiles/asparaginePathway.asp (Jan 2007)

An example of AA degradation to produce intermediate of the citrate cycle

Fate of amino nitrogen derived from AAs

a) in extrahepatic tissues

� transamination (forms mainly Ala and Glu + 2-oxoacids)

� deamination (only some AAs: Ser,Thr,His; releases NH3)

� amidation Glu + NH3 → Gln (needs ATP)

b) in the liver

� see a)

� oxidative deamination of Glu (forms αααα-ketoGlt + NH3)

enzyme: glutamate dehydrogenase (GMD = GLD)

Glutamine is principaltransport form of amino nitrogen

The figure is from http://www.sbuniv.edu/~ggray/CHE3364/b1c25out.html (Dec 2006)

Transport of amino nitrogen

from degraded muscle proteins

excreted products

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

Glucose-alanine cycle


The figure is from http://courses.cm.utexas.edu/archive/Spring2002/CH339K/Robertus/overheads-3/ch18_ammonia-transport.jpg(Jan 2007)

Metabolism of amino nitrogen


GLUTAMATE DEHYDROGENASE

removes amino group from carbon skeleton of Glu in the liver

1. –NH2 from AAs was transfered by transamination → Glu

2. free ammonia is released by oxidative deamination of Glu

Transport and detoxification of amino nitrogen- SUMMARY -

• aminotransferases → glutamate or alanine

• glutamine synthetase → glutamine

• glutaminase → glutamate + NH4+

• glutamate dehydrogenase → 2-oxoglutarate + NH4+

• liver: urea cycle→ urea

• kidneys: glutaminase → glutamate + NH4+

→ urine

TEST / The products can be formed from carbon skeleton of the amino acids:

a) aspartate → oxaloacetate

b) lysine → glucose

c) alanine → fat

d) glutamine → αααα-ketoglutarate

TEST / Amino nitrogen released from carbon skeletons of AAs can be transported in

blood as

a) NH4+

b) alanine

c) glutamine

d) urea

Urea (ornithine) cycle

= detoxification pathway (NH3 is toxic for brain)

• proceeds only in the liver

• is localized in mitochondria /cytoplasm

• carbamoyl phosphate synthetase I (= mitoch.)

• can acidify the organism (consumes HCO3-)

• needs energy (3 ATP, but 4 energy rich bonds)

• is connected with citrate cycle through fumarate

• urea is end product of –NH2 metabolism (→ urine)

The figure is from http://www.biocarta.com/pathfiles/ureacyclePathway.asp (Jan 2007)

Detoxification of ammonia in the liver

The figure is from http://courses.cm.utexas.edu/archive/Spring2002/CH339K/Robertus/overheads-3/ch18_TCA-Urea_link.jpg(Jan 2007)

Interconnection of the urea cycle with the citrate cycle

• arginineN-acetylglutamatesynthetase

• N-acetylglutamatecarbamoyl phosphatesynthetase I(= mitochondrial)

inhibitionactivationregulatory enzyme

Regulation of urea cycle

allosteric regulation + enzyme induction by protein rich diet or by metabolic changes during starvation

Urea synthesis is inhibited by acidosis– HCO3

- is saved

TEST / Detoxification of ammonia in a human body includes

a) urea cycle proceeding only in the liver

b) cleavage of glutamine in the liver and the kidneys

c) consumption of energy in a form of ATP

d) formation of ornithine from citrulline and carbamoyl phosphate

metabolism of amino acids -...

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