METABOLISME ASAM AMINO KIMIA BIOLOGIS 2011

METABOLISME ASAM AMINO

2

Inadequate dietary protein is still a

major world problem

KWASHIORKOR - protein deficiency but adequate calories. Described in 1930s as “sickness of older child when new baby is born”, in language of Ga tribe of gold coast (now Ghana). Characteristic edema.

Two-year old child with kwashiorkor, before and two weeks after start of treatment with good protein.

3

FAMINE EDEMA

Cause: inadequate synthesis of plasma proteins, especially albumin, so that osmotic pressure is not maintained and fluid escapes into tissues. Body water in extracellular space is increased relative to body weight. Extracellular water:

Normal ~23.5% Kwashiokor ~30%

4

Protein-Energy Malnutrition

,

Aka Marasmus, Protein-Calorie Deficiency,

starvation. Other nutrients (vitamins and

minerals) are also likely to be deficient. Starvation is usually the result of war, civil strife, drought, locusts. It especially affects infants and children; growth is slowed,

infections and other diseases are common.

Protein malnutrition,

continued

NY Times, 4/17/00 Ethiopian child

5

Such extreme forms of malnutrition are rare in US, but protein deficiency can occur among:

• Pregnant and lactating women, unless they increase their protein intake. • Individuals with eating disorders (bulimia, anorexia).

• Elderly and chronically ill individuals who have lost interest in eating. • Chronic alcoholics and substance abusers.

• Hospital patients with major protein needs and limited capacity for intake

(e.g, post-surgery, severe burn victims).

• Patients with genetic disorders in amino acid absorption or metabolism.

6

Dietary protein is the source of

essential amino acids

Dietary proteins provide the amino acids that humans cannot

synthesize - the “essential” amino acids. The “non-essential” amino acids can be synthesized endogenously from intermediates of

glycolysis or the TCA cycle.

Essential

Arginine (for children only) Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Threonine Tryptophan Valine Non-essential Alanine Asparagine Aspartate Cysteine Glutamate Glutamine Glycine Proline Serine Tyrosine

7

How much protein do we need?

• In contrast to fat and glucose, there is no significant storage pool for

amino acids; we must consume protein daily.

• Requirement for protein depends on age, sex, activity.

• Proteins differ in content of essential amino acids as well as

digestibility. Diets that rely on a single source of protein may be out of balance with our nutritional needs.

ALLOWANCE FOR PROTEIN

AGE g/kg g/day Infants (0-1) ~2.2 6.5-20 Children (1-10) 1.8 - 1.25 20- 38 Teens (11-18) 1.0 - 0.8 45-55 Adults (male) 0.8 56 (female) 0.8 44 Pregnant or lactating - 20 - 30% more Athletes 1.2 -1.7

REQUIREMENT OF PROTEIN FROM DIFFERENT SOURCES

(g/day for 70 kg human) Meat/fish/eggs/milk ~ 20-25 Non-vegetarian ~ 25-30

mixed diet

Mixed vegetables ~ 30-35 Single vegetable* up to 75

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PROTEIN AND AMINO ACID METABOLISM

Nitrogen excretion dietary protein amino acids endogenous proteins a-ketoacids, NH₃ glucose, lipids energy other N compounds urea

Nitrogen balance

In N balance excretion = intake (healthy adult) Positive N balance excretion < intake (growth, pregnancy, tissue repair) Negative N balance excretion > intake (malnutrition, starvation illness, surgery, burns) digestion

9

PROTEIN AND AMINO ACID METABOLISM

Dietary protein is first hydrolyzed to amino acids, then rebuilt into endogenous protein by translation. Nitrogen excretion dietary protein amino acids endogenous proteins a-ketoacids, NH₃ glucose, lipids energy other N compounds urea DIGESTION TRANSLATION

10 • Mouth: chewing, degradation of starch by amylase make proteins more accessible.

• Stomach: acid pH denatures proteins; activates pepsinogen to cleave itself to pepsin, which initiates proteolysis.

• Duodenum: peptides from pepsin action stimulate release of cholecystekinin (pancreozymin). Cholecystekinin stimulates release of pancreatic

pro-enzymes and of enteropeptidase, a protease secreted by cells of the duodenum.

Digestion

• Pancreas (exocrine): secretion of trypsinogen, chymotrypsinogen, proelastase, procarboxypeptidase (inactive proenzymes)

11 • Duodenum: enteropeptidase activates trypsinogen to trypsin. Trypsin

activates the other proteases, each of which has different specificity. Dietary proteins converted to peptides and free amino acids.

Digestion

• Small intestine: larger peptides are degraded on the surface of intestinal epithelial cells, which absorb amino acids and small (di- and tri-) peptides. Cytoplasmic peptidases complete conversion of peptides to amino acids, which can enter the circulation.

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Protein and amino acid metabolism

Nitrogen excretion dietary protein amino acids endogenous proteins a-ketoacids, NH₃ glucose, lipids energy other N compounds urea PROTEIN TURNOVER

Katabolisme Protein



_Sumber

_{: diet, degradasi protein dalam tubuh}



_Protein

_{dicerna terlebih dahulu}

_sebelum

absorbsi



_{Proses cerna}

_{: mulut, lambung, pankreas, dan}

usus halus



_Pencerna

_{: asam lambung dan berbagai}

enzim protease



Hasil akhir

:

asam amino bebas



_Transport

_{: berbagai cara; memerlukan energi}

Pool Asam Amino

Siklus Urea Protein Diet Protein Tubuh

Asam Keto Sintesis Protein: Asam amino nonesensial Protein baru (struktural, enzim, hormon) Senyawa nitrogen lain: Heme, Purin, Pirimidin, dan Kreatin CO2 + H2O + ATP NH3 Urea Siklus Krebs

Metabolisme Asam Amino



_Lokasi:

_intraselular



_Tahapan:



_{Pelepasan gugus α-amino (}

_{transaminasi &}

deaminasi oksidatif

)



Gugus amino

digunakan untuk

biosintesis asam

amino, nukleotida

, dll; atau disekresikan dalam

bentuk urea (

siklus urea

)



_Asam

_α-keto

_{(rangka karbon) dipecah menjadi}

senyawa lain:

glukosa, CO2, asetil Ko-A,

atau

Katabolisme Asam Amino

Siklus

Urea

Glukosa

Keton

Asetil-KoA

CO2

UREA

Amino

Rangka karbon

Transaminasi:

transfer gugus

amino

ke asam

α-ketoglutarat

menghasilkan asam

glutamat

Deaminasi Oksidatif:



_Pemecahan

_Glutamat

_menjadi

_amonia

dan regenerasi

α-ketoglutarat



_{Membutuhkan enzim glutamat}

dehidrogenase



_{α-ketoglutarat digunakan kembali}

_dalam

reaksi transaminasi

Amonia hasil dari pemecahan glutamat

digunakan untuk

sintesis asam amino baru,

sintesis nukleotida, atau senyawa amino lain

(porfirin, dll)

Amonia berlebih

diekskresikan dalam bentuk

urea

(pada primata) melalui

siklus urea

Reaksi siklus urea

1

:

Karbamoil fosfat sintase 1

kondensasi CO2 dengan amonia → karbamoil fosfat

2

:

Ornitin transkarbamoilase

kondensasi ornitin dengan karbamoil fosfat → sitrulin

3

:

Argininosuksinat sintetase

Kondensasi sitrulin dengan aspartat → argininosuksinat

4

:

Argininosuksinase

Pemecahan argininosuksinat → fumarat dan arginin

5

: Arginase

Pemecahan arginin (dengan bantuan H

₂

O)→

urea

dan

ornitin

1

2

3

Katabolisme rangka karbon asam amino

 Rangka karbon 20 asam amino mengalami metabolisme

lanjut yang berbeda

 Terdiri dari 2 kelompok besar

 Ketogenik

: didegradasi menjadi

senyawa antara

metabolisme asam lemak

; asetil-KoA atau

asetoasetat

 Glukogenik

: didegradasi menjadi

senyawa antara

glikolisis atau SAS

; piruvat, α-ketoglutarat,

Suksinil-CoA, Fumarat, dan oxaloasetat

Alanin, Sistein, Glisin, Treonin, Triptofan, Serin Arginin, Glutamat, Glutamin, Histidin, Prolin Isoleusin, Metionin, Valin

Asparagin, Aspartat Leusin, Lisin,

Fenilalanin, Triptofan, Tirosin Asetoasetat Isoleusin, Leusin, Lisin, Treonin Aspartat, fenilalanin, Tirosin Glukosa

AA esensial

Degradasi menjadi

Keto Gluko

Arginin

α-ketoglutarat

√

Fenilalanin

Fumarat, asetoasetil-KoA

√

√

Histidin

α-ketoglutarat

√

Isoleusin

Suksinil-KoA, asetil-KoA

√

√

Leusin

Asetil-KoA, asetoasetil-KoA

√

Lisin

Asetoasetil-KoA

√

Metionin

Suksinil-KoA

√

Treonin

Suksinil-KoA, piruvat

√

Triptofan

Piruvat, asetil-KoA,

asetoasetil-KoA

√

√

AA

non-esensial

Degradasi menjadi

Keto Gluko

Alanin

Piruvat

√

Asparagin

Oksaloasetat

√

Aspartat

Oksaloasetat, fumarat

√

Glisin

Piruvat

√

Glutamat

α-ketoglutarat

√

Glutamin

α-ketoglutarat

√

Prolin

α-ketoglutarat

√

Serin

Piruvat

√

Sistein

Piruvat

√

Biosintesis Asam Amino

•

Semua asam amino disintesis dari

senyawa antara, kecuali

tirosin

disintesis dari asam amino

esensial fenilalanin

•

_{Asam amino esensial}

_{: untuk}

sintesis protein, tidak dapat

dibuat sendiri oleh tubuh,

terdapat pada makanan

•

_{Asam amino non esensial}

_:

dapat dibuat oleh tubuh

O₂ H₂O Fenilalanin hidroksilase Fenilalanin Tirosin

PKU (PhenylKetonUria) : Lack of Phenylalanine hidroxylase

Asam amino yang

berasal dari

3-Fosfogliserat:

Serin

Sistein

Glisin

Asam amino yang

berasal dari

aspartat:

Lisin

Metionin

Treonin

Asam amino

yang berasal

dari piruvat:

Leusin

Isoleusin

Valin

Asam amino

aromatis:

Tirosin

Fenilalanin

Triptofan

Chorismate: Prekursor Asam Amino Aromatis

- There is a single precursor for all ‘standard’ aromatic amino acids

- Made from PEP!

- From the Pentose

Phosphate Pathway

(an alternative to

glycolysis)

Biosintesis Heme

- In addition to proteins, some amino acids are used to make

co-factors and signaling molecules:

- Porphyrins, for example, are

made from Succinyl CoA and

Biosintesis Porfirin

- The fundamental unit of

porphyrins is



-aminolevulinate

(ALA)

- Made by the pyroxidal phosphate

(PLP) dependent enzyme



-aminolevulinate synthase

- We then combine 2 ALA into

Porphobilinogen

Ring close via Schiff Base

- Porphyrins are

composed of 4 PBG

subunits

- The difference

between

Uroporphyrinogen I

and III

Biosintesis Porfirin dari

PBG

Metabolisme Nukleotida

(nukleosida trifosfat)



Nukleotida

: Senyawa ester fosfat dari suatu gula

pentosa dengan basa nitrogen yang terikat pada

atom C1 dari pentosa



_Basa

_{: Purin (Adenin, Guanin) ; Pirimidin (Urasil, Timin,}

Sitosin)



_Gula

_{: Ribosa (RNA), Deoksi ribosa (DNA)}



Unit

monomer

yang berfungsi sebagai prekursor

asam nukleat

dan fungsi biokimia lainnya

contoh : AMP, GMP, UMP, TMP, CMP

Katabolisme Nukleotida



Asam nukleat

(DNA dan RNA) dari diet didegradasi

menjadi

nukleotida

oleh

nuklease pankreas dan

fosfodiesterase usus halus



_Nukleotida

_{didegradasi menjadi}

_nukleosida

_oleh

nukleotidase dan nukleosida fosfatase



_Nukleosida

_{diserap langsung}



_{Degradasi lanjutan}

Nukleosida

+ H

2

O 

basa

+ ribosa (nukleosidase)

Nukleosida

+ P

_i



basa

+ r-1-fosfate (n. fosforilase)

Katabolisme Purin (Adenin dan Guanin):



_90%

_{digunakan kembali}

_(salvage)

_(pada

mamalia)



10%

didegradasi menjadi

asam urat



_Basa

_adenin

→

inosin

→

hipoksantin

; adenosin

deaminase, nukleosidase



Asam urat pada beberapa jenis hewan

didegradasi lebih lanjut

Berbeda antar beberapa golongan hewan



_{Asam urat →}

_{primata, burung, reptil, serangga}



_{Alantoin →}

_{mamalia lain}



_{Asam alantoat →}

_ikan



_{Urea →}

_{ikan bertulang rawan dan amfibi}

Katabolisme Pirimidin (Sitosin, Timin, Urasil):



_Reaksi

_{: defosforilasilasi, deaminasi, dan}

pemutusan ikatan glikosida.



Urasil dan timin

direduksi

di hati



Produk akhir

:



ß-alanina

(dari sitosin dan urasil)



ß-aminoisobutirat

(dari timin)

Biosintesis Nukleotida



_{Biosintesis purin}

_{(Adenin dan Guanin)}

o

_Jalur

_{de novo}

→ dari prekursor sederhana

o

_Jalur

_salvage

→ dari hasil degradasinya

Biosintesis Purin jalur de novo



_{Diawali dengan sintesis}

_IMP

_(Inosin

MonoPhosphate)



Terbuat dari

6 prekursor

sederhana (

CO2

;

Glisin

;

2

Format

;

Glutamin

; dan

Aspartat

)

11 tahapan Reaksi Sintesis IMP

1.

Aktivasi ribosa-5-fosfat

2.

Penambahan

glutamin

→ atom N9

3.

Penambahan

glisin

→ C4, C5, dan N7

4.

Penambahan

format

→ C8

5.

Penambahan

glutamin

→ N3

6.

Pembentukan cincin imidazola

7.

Penambahan

bikarbonat

→ C6

8.

Penambahan

aspartat

→ N1

9.

Eliminasi fumarat

10.

Penambahan

format

→ C2

Sintesis AMP dan GMP

1.

Adenilosuksinat sintase

2.

Adenilosuksinase

3.

IMP dehidrogenase

4.

Transamidinase

AMPs

XMP

IMP

AMP

GMP

1

3

4

2

Regulasi

sintesis

Purin

Biosintesis Purin jalur salvage



_{Penggunaan ulang}

_{hasil degradasi nukleotida}

menjadi nukleotida



Memerlukan energi yang lebih rendah

daripada

sintesis de novo



_Memerlukan

_{2 enzim penting}



_HGPRT

_{(hipoksantin-guanin fosforibosil}

transferase)

Jalur salvage

Guanin

Biosintesis Pirimidin

 Diawali dengan sintesis

UMP

(Uridin MonoPhosphate)

 Terbuat dari

3 prekursor

sederhana (

HCO3-

;

Aspartat

; dan

glutamat

)

Sintesis UTP

E. coli

Manusia

dan hewan